HK1242718B - Apoe mimetic peptides and higher potency to clear plasma cholesterol - Google Patents

Description

APOE mimetic peptides and their higher efficacy in clearing plasma cholesterol

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/031,585, filed July 31, 2014, which is incorporated herein by reference in its entirety.

Statement Regarding Federally Funded Research

This invention was made with government support under RO1 HL 090803 awarded by the National Institutes of Health. The government has certain rights in this invention.

Reference to a sequence listing submitted as a text file via EFS-WEB

The Sequence Listing filed on July 20, 2015 as a 229,376-byte text file named "21085.0187P1_ST25.txt" created on July 20, 2015 is hereby incorporated by reference pursuant to 37 C.F.R. §1.52(e)(5).

background

In the United States, heart disease is the leading cause of death for both men and women. Several risk factors contribute to the development of cardiovascular disease, including genetic predisposition to the disease, gender, lifestyle factors such as smoking and diet, age, high blood pressure, and hyperlipidemia (including hypercholesterolemia). Several of these factors, particularly hyperlipidemia and hypercholesterolemia (high blood cholesterol concentration), provide significant risk factors associated with atherosclerosis.

Atherosclerosis is associated with an inflammatory response caused by the accumulation of low-density lipoprotein (LDL) molecules in blood vessels. It can be asymptomatic for many years. Atherosclerosis causes hardening and narrowing of blood vessels. There are several treatments for atherosclerosis, such as lifestyle changes, medications, and medical procedures. Statins are well-known therapeutic agents for atherosclerosis. Statins have been shown to reduce the risk of heart disease; however, withdrawal of statin therapy eliminates the protective effect (Heeschen et al., Circulation. 105:1446-1452, 2002).

The current approach to treating atherosclerosis is to provide early intervention and lifelong treatment. This approach is problematic because it requires identifying asymptomatic patients early in their lifespan and maintaining treatment over the duration of their lifespan, as the risk increases with age. In addition, the most effective treatments currently available do not prevent major cardiac events in all patients, whether as primary or secondary interventions. Therefore, there is a need for a therapy that can provide rapid benefits in reducing atherosclerosis and has a long-term effect that does not require constant administration. The compositions and methods disclosed herein provide a therapy for atherosclerosis that has a sustained therapeutic effect even after treatment is withdrawn.

Overview

Disclosed are synthetic apolipoprotein E (ApoE) mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises acetylated aminohexanoic acid (Ac-Aha).

Also disclosed is a synthetic ApoE mimetic peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein Ac-Aha may be located at the N-terminus of the peptide.

Also disclosed are synthetic ApoE mimetic peptides comprising an ApoE receptor binding domain and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the lipid-associating peptide comprises a class A amphipathic-coil domain. For example, the class A amphipathic-coil domain can be DWLKAFYDKVAEKLKEAF (SEQ ID NO: 5), DWLRAFYDKVAEKLREAF (SEQ ID NO: 618), DWLRALYDKVAEKLREAL (SEQ ID NO: 619), DLLRALYDKVAEKLREAW (SEQ ID NO: 620), or FAEKLKEAVKDYFAKLWD (SEQ ID NO: 616).

Also disclosed is a synthetic ApoE mimetic peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the receptor binding domain of ApoE can be covalently linked to the lipid-associating peptide.

Also disclosed is a synthetic ApoE mimetic peptide comprising the receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the apolipoprotein E is from a species selected from the group consisting of: human, mouse, rabbit, monkey, rat, cow, pig, and dog.

Also disclosed is a synthetic ApoE mimetic peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the synthetic peptide is protected with an amide group at the C-terminus.

Also disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the receptor binding domain of ApoE is LRKLRKRLLR (SEQ ID NO: 4), LRRLRRRLLR (SEQ ID NO: 11), LRKMRKRLMR (SEQ ID NO: 7), or RLTRKRGLK (SEQ ID NO: 13).

Also disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the receptor binding domain of ApoE is LRKLRKRLLR (SEQ ID NO: 4), LRRLRRRLLR (SEQ ID NO: 11), LRKMRKRLMR (SEQ ID NO: 7), RLTRKRGLK (SEQ ID NO: 13), LRRMRRRLMR (SEQ ID NO: 621), or RLTRRGK (SEQ ID NO: 622).

Also disclosed is a synthetic ApoE mimetic peptide comprising the receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the synthetic ApoE mimetic peptide can be Ac-Aha-hE18A-NH ₂ or Ac-Aha-[R]hE18A-NH ₂ .

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid moiety, an ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises an acetylated ω-amino fatty acid moiety, wherein the acetylated ω-amino fatty acid moiety is located at the N-terminus of the peptide. In some aspects, the ω-amino fatty acid moiety can be inserted between the lipid-associating peptide and the receptor binding domain of ApoE.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid moiety, an ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the lipid-associating peptide comprises a class A amphipathic helical domain. For example, the class A amphipathic helical domain is DWLKAFYDKVAEKLKEAF (SEQ ID NO: 5), DWLRAFYDKVAEKLREAF (SEQ ID NO: 618), DWLRALYDKVAEKLREAL (SEQ ID NO: 619), DL LRALYDKVAEKLREAW (SEQ ID NO: 620), or FAEKLKEAVKDYFA KLWD (SEQ ID NO: 616).

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the lipid-associating peptide comprises a class A amphipathic helical domain, wherein the receptor binding domain of ApoE can be covalently linked to the lipid-associating peptide.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the apolipoprotein E may be from a species selected from the group consisting of: human, mouse, rabbit, monkey, rat, cow, pig, and dog.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid moiety, an ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the synthetic peptide is protected with an amide group at the C-terminus.

Disclosed are synthetic ApoE mimetic peptides comprising an ApoE receptor binding domain and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the ApoE receptor binding domain can be LRKLRKRLLR (SEQ ID NO: 4), LRRLRRRLLR (SEQ ID NO: 11), LRKMRKRLMR (SEQ ID NO: 7), or RLTRKRGLK (SEQ ID NO: 13). The ApoE receptor binding domain can also be, but is not limited to, LRKLRKRFFR (SEQ ID NO: 12), LRKLPKRLLR (SEQ ID NO: 8), LRNVRKRLVR (SEQ ID NO: 9), MRKLRKRVLR (SEQ ID NO: 10), LRRLRRRLLR (SEQ ID NO: 11), LRKLRKRFFR (SEQ ID NO: 12), LRKLRKRLLR (SEQ ID NO: 4), or LRKMRKRLMR (SEQ ID NO: 7).

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the receptor binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO: 4), LRRLRRRLLR (SEQ ID NO: 11), LRKMRKRLMR (SEQ ID NO: 7), RLTRKRGLK (SEQ ID NO: 13), LRRMRRRLMR (SEQ ID NO: 621), or RLTRRGK (SEQ ID NO: 22).

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the synthetic ApoE mimetic peptide can be: butyryl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 623); hexanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 624); octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 625); decanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 626); lauroyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 627); WLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 627); myristoyl-LR RLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 628); palmitoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 629); stearoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 630); palmitoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 631); arachidonoyl-LRRRLRLLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: NO: 632); behenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 633); oleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 634); ricinoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKE AF-NH ₂ (SEQ ID NO: 635); linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 636); vacceoyl-LRRL RRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: NO: 637); gadoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 638); erucyl-LRRLRRRLLR-DWLKAFYDKVAEKL KEAF-NH ₂ (SEQ ID NO: 639); cetoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 640); neuraminoyl-LR RLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 641); adrenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 642); α-linolenoyl-LRRLRRRLLR-DWLKAFYD KVAEKLKEAF- _NH2 (SEQ ID NO: 643); γ-linolenoyl-LRRLRRRLL R-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 644); EPA-LRRL RRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 645); or DHA-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 646). In the foregoing, the fatty acid moiety is shown on the left and is linked to the peptide LRRLRRRLLR (SEQ ID NO: 11). "EPA" indicates the moiety derived from 5,8,11,14,17-eicosapentaenoic acid; and "DHA" indicates the moiety derived from 4,7,10,13,16,19-docosahexaenoic acid.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid moiety derived from a natural oil or fat, such as fish oil, wherein the synthetic ApoE mimetic peptide can be: (fish oil)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 647). In the foregoing, "(fish oil)" refers to fatty acids in fish oil, including but not limited to fish oil components such as EPA and DHA, attached to the peptide LRRLRRRLLR (SEQ ID NO: 11). Thus, the synthetic ApoE mimetic peptides are a mixture of peptides comprising fatty acid groups derived from the fish oil used to prepare them.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the synthetic ApoE mimetic peptide can be: 4-amino-butyryl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 648); 6-amino-hexanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 649); 8-amino-octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 650); 10-amino-decanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 651); NO: 651); 12-amino-lauroyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 652); 14-amino-myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 653); 16-amino-palmitoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 654); 16-amino-palmitoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 655); 18-amino-stearoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 656); 18-amino-oleoyl-LR LRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 657); 18-amino-linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 658) or 20-amino-arachidonoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 659). In the foregoing, the fatty acid moiety is shown on the left and is linked to the peptide LRRLRRRLLR (SEQ ID NO: 11).

Disclosed are pharmaceutical compositions comprising any one of the synthetic ApoE mimetic peptides disclosed herein and a pharmaceutically acceptable carrier.

Disclosed are methods comprising administering to a subject any one of the disclosed synthetic ApoE mimetic peptides, thereby affecting plasma LDL, plasma VLDL, or both.

Disclosed are methods comprising administering any of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein the synthetic ApoE mimetic peptide is administered as a composition comprising the synthetic ApoE mimetic peptide and a pharmaceutically acceptable carrier.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein LDL binding to cells of the subject is enhanced.

Disclosed are methods comprising administering any of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein degradation of LDL by cells of the subject is increased.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein LDL cholesterol in the subject is lowered.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein binding of VLDL to cells of the subject is enhanced.

Disclosed are methods comprising administering any of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein degradation of VLDL by cells of the subject is increased.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein VLDL cholesterol in the subject is lowered.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein the total plasma concentration of cholesterol in the subject is reduced.

Disclosed are methods comprising administering to a subject any one of the disclosed synthetic ApoE mimetic peptides, thereby affecting plasma LDL, plasma VLDL, or both, wherein the synthetic ApoE mimetic peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein the subject has coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, peripheral arterial disease (PAD), cerebrovascular disease, diabetic-derived cardiovascular disease, macular degeneration, congestive heart failure, and/or systemic lupus erythematosus.

Also disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any of the disclosed synthetic apolipoprotein E mimetic peptides.

Disclosed are methods of lowering plasma cholesterol, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein the synthetic apolipoprotein E mimetic peptide is administered as a composition comprising the synthetic apolipoprotein E-mimetic peptide and a pharmaceutically acceptable carrier.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein LDL binding to cells of the subject is enhanced.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein degradation of LDL by cells of the subject is increased.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein LDL cholesterol in the subject is lowered.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein VLDL binding to cells of the subject is enhanced.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein degradation of VLDL by cells of the subject is increased.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein VLDL cholesterol in the subject is lowered.

Disclosed are methods of lowering plasma cholesterol, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein the total plasma concentration of cholesterol in the subject is reduced.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein the synthetic apolipoprotein E mimetic peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.

Disclosed are methods for lowering plasma cholesterol, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein the subject suffers from coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebrovascular disease, diabetic-derived cardiovascular disease, macular degeneration, congestive heart failure, and/or systemic lupus erythematosus.

Also disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any of the disclosed synthetic apolipoprotein E mimetic peptides.

Disclosed are methods for treating atherosclerosis, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein the synthetic apolipoprotein E mimetic peptide is administered as a composition comprising the synthetic apolipoprotein E mimetic peptide and a pharmaceutically acceptable carrier.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein binding of LDL to cells of the subject is enhanced.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein degradation of LDL by cells of the subject is increased.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein LDL cholesterol in the subject is lowered.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein binding of VLDL to cells of the subject is enhanced.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein degradation of VLDL by cells of the subject is increased.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein VLDL cholesterol in the subject is reduced.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein the total plasma concentration of cholesterol in the subject is reduced.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein the synthetic apolipoprotein E mimetic peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.

Disclosed are methods for treating atherosclerosis, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E mimetic peptides, wherein the subject suffers from coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebrovascular disease, diabetic cardiovascular disease, macular degeneration, congestive heart failure, and/or systemic lupus erythematosus.

Also disclosed are methods for treating a subject suffering from a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or compositions thereof.

Disclosed are methods for treating a subject suffering from a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or a composition thereof, wherein the synthetic apolipoprotein E mimetic peptide is administered as a composition comprising the synthetic apolipoprotein E mimetic peptide and a pharmaceutically acceptable carrier.

Disclosed are methods for treating a subject suffering from a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or compositions thereof, wherein LDL binding to cells of the subject is enhanced.

Disclosed are methods for treating a subject suffering from a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or compositions thereof, wherein degradation of LDL by cells of the subject is increased.

Disclosed are methods for treating a subject suffering from a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or compositions thereof, wherein the subject's LDL cholesterol is reduced.

Disclosed are methods for treating a subject suffering from a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or compositions thereof, wherein VLDL binding to cells of the subject is enhanced.

Disclosed are methods for treating a subject having a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or compositions thereof, wherein degradation of VLDL by cells of the subject is increased.

Disclosed are methods for treating a subject having a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or compositions thereof, wherein VLDL cholesterol in the subject is reduced.

Disclosed are methods for treating a subject having a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or compositions thereof, wherein the total plasma concentration of cholesterol in the subject is reduced.

Disclosed are methods for treating a subject suffering from a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or compositions thereof, wherein the synthetic apolipoprotein E mimetic peptide is administered in an amount from about 0.01 mg/kg to about 12 mg/kg.

Disclosed are methods for treating a subject suffering from a lipid disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E mimetic peptides or compositions thereof, wherein the lipid disorder is coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebrovascular disease, diabetic-derived cardiovascular disease, macular degeneration, congestive heart failure, and/or systemic lupus erythematosus.

Also disclosed are dosing regimens comprising at least one treatment cycle followed by a rest period, wherein the treatment cycle comprises administering an effective amount of any of the disclosed Apo E mimetic peptides to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein no Apo E mimetic peptide is administered during the rest period. In some cases, the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide once a week for three months. In some cases, the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide once every two weeks for up to 12 weeks.

Disclosed are dosing regimens comprising at least one treatment cycle followed by a rest period, wherein the treatment cycle comprises administration of an effective amount of any of the disclosed Apo E mimetic peptides to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein no Apo E mimetic peptide is administered during the rest period, and wherein the dosing regimen further comprises a second treatment cycle after the rest period.

Also disclosed are methods of treating acute coronary syndrome (ACS), comprising administering to a subject an effective amount of any disclosed Apo E mimetic peptide for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein the treatment cycle is followed by a rest period, wherein the Apo E mimetic peptide is not administered during the rest period.

Disclosed are methods for treating acute coronary syndrome (ACS), comprising administering to a subject an effective amount of any disclosed Apo E mimetic peptide for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein the treatment cycle is followed by a rest period, wherein the Apo E mimetic peptide is not administered during the rest period, and wherein the rest period is at least four weeks.

Disclosed are methods for treating acute coronary syndrome (ACS), comprising administering to a subject an effective amount of any disclosed Apo E mimetic peptide for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after the Apo E mimetic peptide is withdrawn, wherein the treatment cycle is followed by a rest period, wherein the Apo E mimetic peptide is not administered during the rest period, and further comprising a second treatment cycle after the rest period. In some cases, the second treatment cycle can be administered after a four-week rest period. In some cases, the second treatment cycle can be administered one year from the start of the initial treatment cycle.

Disclosed are methods for treating acute coronary syndrome (ACS), comprising administering to a subject an effective amount of any disclosed Apo E mimetic peptide for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein the treatment cycle is followed by a rest period during which the Apo E mimetic peptide is not administered, and further comprising a second treatment cycle after the rest period during which an ACS therapy other than the Apo E mimetic peptide is administered during the rest period.

Disclosed are methods for treating acute coronary syndrome (ACS), comprising administering to a subject an effective amount of any disclosed Apo E mimetic peptide for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after the Apo E mimetic peptide is withdrawn, wherein the treatment cycle is followed by a rest period, wherein the Apo E mimetic peptide is not administered during the rest period, and further comprising a second treatment cycle after the rest period, wherein an ACS therapy other than the Apo E mimetic peptide is administered during the rest period, wherein the ACS therapy other than the Apo E mimetic peptide is a conventional LDL-lowering therapy or a HDL-raising therapy. In some cases, the conventional LDL-lowering therapy may be a statin. In some cases, the HDL-raising therapy may be an Apo A1-raising drug, a CETP inhibitor, a phospholipase A2 inhibitor, Apo A1 Milano, or an Apo A1 mimetic.

Disclosed are methods for treating acute coronary syndrome (ACS), comprising administering to a subject an effective amount of any disclosed Apo E mimetic peptide for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein the treatment cycle is followed by a rest period, wherein the Apo E mimetic peptide is not administered during the rest period, and further comprising a second treatment cycle after the rest period, wherein an ACS therapy other than the Apo E mimetic peptide is administered during the rest period, wherein the ACS therapy other than the Apo E mimetic peptide is a conventional LDL-lowering therapy or HDL-raising therapy, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide once a week for three months.

Also disclosed are monoclonal antibodies that specifically bind to any of the disclosed synthetic ApoE peptides.

Also disclosed is a synthetic ApoE mimetic peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-AHA, wherein the receptor binding domain of apolipoprotein E is scrambled.

Also disclosed are synthetic apolipoprotein E mimetic peptides consisting of a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide, wherein both the receptor binding domain of apolipoprotein E and the lipid-associating peptide are scrambled.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the disclosed methods and compositions and, together with the description, serve to explain the principles of the disclosed methods and compositions.

Figure 1 depicts several strategies for developing highly potent peptides.

Figures 2A-2G show comparative analytical HPLC profiles of the indicated ApoE mimetic peptide analogs. Chromatography was performed as follows: C-18 column - 250 x 4.6 mm; mobile phase was a 30-70% acetonitrile gradient in water over 35 minutes (with 0.1% TFA).

Figure 3 shows cholesterol reduction (percent reduction in plasma cholesterol) of the indicated apoE mimetic peptide analogs in apoE null mice (100 μg/mouse) after single dose administration (n=4 animals/group). Baseline levels are relative plasma cholesterol levels at the time of dose administration. Time points show plasma cholesterol levels at the indicated times after single dose administration. Single doses were administered using saline vehicle.

Comparative analytical HPLC profiles of three active ApoE mimetic peptide analogs are shown in Figure 4. Chromatography was performed as follows: C-18 column - 250 x 4.6 mm; mobile phase was a 30-70% acetonitrile gradient in water over 12 minutes (containing 0.1% TFA).

Figures 5A-5B show representative data for the effect of three active ApoE mimetic peptide analogs at a dose level of 50 μg (Figure 5A) or a dose level of 100 μg (Figure 5B) on lowering plasma cholesterol (% reduction). The study was conducted in apoE-null mice (n=4 animals/group). Time points show plasma cholesterol levels at the indicated times after a single dose administration. A single dose was administered using saline vehicle. The data show that AC-Aha-[R]hE18A- _NH2 was highly effective in lowering plasma cholesterol in ApoE-null mice at 50 and 100 μg/mouse.

Figure 6 shows a model whereby _CH3- ( _CH2 ) _n -CO-(apoE mimetic peptide) molecules are more readily attached to lipid particles compared to apoE mimetic peptides that do not contain an alkyl carboxyl moiety, thereby providing a model for enhanced hepatic clearance.

Figure 7 is a table showing the experimental design. ApoE-null mice were dosed with the peptides Ac-he18A- _NH2 (AEM-28), Ac-[R]he18A- _NH2 (AEM-28(R)), or Ac-Aha-[R]he18A- _NH2 (AES-21) at a concentration of 100 μg/mouse in normal saline via tail vein injection. Blood was collected by buccal bleed before and 1, 6, and 24 hours after dosing. Serum samples can be analyzed for total serum cholesterol (using a Waco total cholesterol kit).

Figures 8A and 8B are graphs showing total cholesterol (mg/dL) versus time (Figure 8A) and total cholesterol (% before dosing) versus time (Figure 8B), respectively. Three different peptides were administered to approximately 10-week-old female apoE-null mice via tail vein injection using 100 ug of peptide in normal saline. The error bars shown are the standard error of the mean (SEM). All results (n=5 animals) except Group 1 (n=4 animals for all time points).

FIG. 9 is a table showing the results from the mouse injections described in FIG. 8 .

FIG. 10 is a table showing the results of total serum cholesterol (as % of pre-dose levels).

Figure 11 shows the experimental design. ApoE-null mice were dosed with AC-hE18A-NH2 (AEM-28), AC-[R]hE18A-NH2 (AEM-28(R)), or AC-Aha-[R]hE18A-NH2 (AES2-21) at a concentration of 50 μg/mouse in normal saline via tail vein injection. Blood was collected by buccal bleed before dosing and 1, 6, and 24 hours after dosing. Serum samples can be analyzed for total serum cholesterol using a total cholesterol kit (Wako Chemicals USA, Inc., Richmond, VA).

Figures 12A and 12B are graphs showing total cholesterol (mg/dL) versus time and total cholesterol (% before administration) versus time, respectively. Three different peptides were administered to approximately 10-week-old female ApoE KO mice using 100 ug of peptide in normal saline via tail vein injection. The animals were allowed to recover for two weeks and then given a second dose of 50 μg of peptide in normal saline. The error bars shown are the standard deviation of the mean (SEM). All results (n=5 animals). "AEM-28 saline" represents the peptide AC-hE18A-NH2; "AEM-28 (R) saline" represents the peptide AC-[R]hE18A-NH2; and "AES2-21" represents the peptide AC-Aha-[R]hE18A-NH2.

FIG. 13 is a table showing raw cholesterol values.

FIG. 14 is a table showing the % of cholesterol before administration.

Figure 15 shows representative data of plasma triglyceride profiles in a sucrose-fed rat model. The data show that triglyceride levels increased after two weeks of a diet containing 65% (w/v) sucrose. The study was conducted in male Sprague-Dawley rats.

Figure 16 shows representative data for the effects of the disclosed synthetic apolipoprotein E mimetic peptides on triglyceride levels in rats fed a high sucrose (65% (w/v)) diet for two weeks at the indicated times following a single dose (intravenous tail vein injection) of the indicated peptides (in saline vehicle) or control (saline). "Control" refers to rats administered saline; "AEM-28" refers to rats administered (intravenously via the tail vein) 5 mg/kg of the peptide Ac-hE18A- _NH2 ; "R-AEM-28" refers to rats administered (intravenously via the tail vein) 5 mg/kg of the peptide Ac-[R]hE18A- _NH2 ; and "Aha-R-AEM-28" refers to rats administered (intravenously via the tail vein) 5 mg/kg of the peptide Aha-[R]hE18A- _NH2 .

Figure 17 shows representative data for the effects of the disclosed synthetic apolipoprotein E mimetic peptides on triglyceride levels in rats fed a high sucrose (65% (w/v)) diet 48 hours after administration of the indicated peptides or a control (saline). "Saline" indicates rats administered saline (intravenously via the tail vein); "AEM-28" indicates rats administered 5 mg/kg of the peptide Ac-hE18A- _NH2 (intravenously via the tail vein); "R-AEM-28" indicates rats administered 5 mg/kg of the peptide Ac-[R]hE18A- _NH2 (intravenously via the tail vein); and "Aha-R-AEM-28" indicates rats administered 5 mg/kg of the peptide Aha-[R]hE18A- _NH2 (intravenously via the tail vein).

Figure 18 shows representative data for the effects of the disclosed synthetic apolipoprotein E mimetic peptides on plasma cholesterol levels in rats fed a high sucrose (65% (w/v)) diet for two weeks, 48 hours after administration of the indicated peptides or a control (saline). "Saline" indicates rats administered saline (intravenously via the tail vein); "AEM-28" indicates rats administered 5 mg/kg of the peptide Ac-hE18A- _NH2 (intravenously via the tail vein); "R-AEM-28" indicates rats administered 5 mg/kg of the peptide Ac-[R]hE18A- _NH2 (intravenously via the tail vein); and "Aha-R-AEM-28" indicates rats administered 5 mg/kg of the peptide Aha-[R]hE18A- _NH2 (intravenously via the tail vein).

Figure 19 shows representative data for the effects of the disclosed synthetic apolipoprotein E mimetic peptides on plasma glucose levels 48 hours after administration of the indicated peptides (in saline vehicle) or control (saline). Prior to peptide injection, rats were fed a high sucrose (65% (w/v)) diet. "Saline" indicates rats administered saline (intravenously via the tail vein); "AEM-28" indicates rats administered 5 mg/kg of the peptide Ac-hE18A- _NH2 (intravenously via the tail vein); "R-AEM-28" indicates rats administered 5 mg/kg of the peptide Ac-[R]hE18A- _NH2 (intravenously via the tail vein); and "Aha-R-AEM-28" indicates rats administered 5 mg/kg of the peptide Aha-[R]hE18A- _NH2 (intravenously via the tail vein).

Figures 20A-20E show representative analytical HPLC profiles of the disclosed synthetic apolipoprotein E mimetic peptides comprising fatty acid moieties. Chromatography was performed as follows: C-18 Vydac column - 250 x 4.6 mm; mobile phase: water/acetonitrile (0.1% TFA) gradient, 35-70% over 12 minutes.

Figure 21 shows representative data for the effects of disclosed synthetic apolipoprotein E mimetic peptides comprising fatty acid moieties on plasma cholesterol levels (% reduction in plasma cholesterol). Data were obtained using apoE null mice (female; group = 4) that were administered 100 μg of the indicated peptides (in saline vehicle) at the indicated times after peptide administration. The peptides administered in this study were dialyzed after synthesis without further HPLC purification. Baseline levels are plasma cholesterol levels at the time of peptide administration. All peptides were administered by intravenous tail vein injection.

Figure 22 shows representative data for the effects of the disclosed synthetic apolipoprotein E mimetic peptides comprising fatty acid moieties on plasma cholesterol levels. Data were obtained using apoE null mice (female; group = 3) administered 50 μg of the indicated peptides. This study was also performed as described for Figure 21. The times shown are after a single dose of 50 μg administered by intravenous tail vein injection.

Figure 23 shows representative data for the effects of the disclosed synthetic apolipoprotein E mimetic peptides comprising fatty acid moieties on plasma cholesterol levels. Data were obtained using apoE null mice (female; group = 3) administered 100 μg of the indicated peptides. This study was also performed as described for Figure 21. The times shown are after a single dose of 50 μg administered by intravenous tail vein injection.

Figure 24 shows representative dose-response data for the effect of myristoyl-LRRLRRRLLR-18A-NH2 (i.e., myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 628)) on plasma cholesterol levels. Data were obtained using apoE-null mice (female; group = 5) administered the indicated dose levels. Samples were collected 24 hours after peptide administration. The study was performed as described in Figure 21. The indicated doses were administered intravenously via tail vein injection.

Figure 25 shows representative dose-response data for the effect of myristoyl-LRRLRRRLLR-18A-NH2 (i.e., myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 628)) on plasma cholesterol levels. Data were obtained using apoE-null mice (female; group = 5) administered the indicated dose levels. Samples were collected at the indicated times after peptide administration. The study was performed as described in Figure 21. The indicated doses were administered via intravenous tail vein injection.

Figure 26 shows data from the study described in Figure 25 replotted as percent maximum reduction in plasma cholesterol (at 5 hours) versus dose level (μg). Data are shown as solid circles with lines, and a hyperbola is the resulting fit to the data.

Figure 27 shows data from the study described in Figure 25 replotted as the maximum percent reduction in plasma cholesterol at 24 hours versus dose level (μg). Data are shown as solid circles with lines, and a hyperbola is the resultant fit to the data.

Figure 28 shows representative dose-response data for the effect of octanoyl-LRRLRRRLLR-18A-NH2 (i.e., octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 625)) on plasma cholesterol levels (mg/dL). Data were obtained using apoE-null mice (female; group = 5) administered the indicated dose levels. Samples were collected at the indicated times after peptide administration. The study was performed as described in Figure 21. The indicated doses were administered by intravenous tail vein injection.

Figure 29 shows representative dose-response data for the effect of octanoyl-LRRLRRRLLR-18A-NH2 (i.e., octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 625)) on plasma cholesterol levels (percentage of baseline plasma cholesterol levels). Baseline levels are plasma cholesterol levels at the time of peptide administration. Data were obtained using apoE-null mice (female; Group = 5) administered the indicated dose levels. Samples were collected at the indicated times after peptide administration. The study was also performed as described in Figure 21. The indicated doses were administered by intravenous tail vein injection.

Figure 30 shows data from the study described in Figures 28-29 replotted as the maximum percent reduction in plasma cholesterol (at 5 hours) versus dose level (μg). Data are shown as solid circles with lines, and a hyperbola is the resultant fit to the data.

Figure 31 shows data from the study described in Figures 28-29 replotted as percent reduction in plasma cholesterol at 24 hours versus dose level (μg). Data are shown as solid circles with lines, and a hyperbola is the resultant fit to the data.

Details

The disclosed methods and compositions may be understood more readily by reference to the following detailed description of specific embodiments and the Examples included therein, and to the Figures and their previous and following descriptions.

It should be understood that, unless otherwise indicated, the disclosed methods and compositions are not limited to specific synthetic methods, specific analytical techniques or specific reagents and may vary accordingly. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

A. Definition

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

As used in the specification and the appended claims, the singular forms "a," "an," and "the" may include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a mixture of compounds, reference to "a pharmaceutical carrier" includes a mixture of two or more such carriers, and the like.

As used herein, the word "or" refers to any one member of a particular list and also includes any combination of members of that list.

Ranges can be expressed herein as from "about" a specific value and/or to "about" another specific value. The term "about" is used herein to indicate approximately in the region, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the proposed numerical value. Typically, the term "about" is used herein to modify the numerical value above and below the value by 20% variance. When such a range is represented, another embodiment includes from a specific value and/or to another specific value. Similarly, when a value is represented as an approximation by using the antecedent "about," it should be understood that the specific value forms another embodiment. It should also be understood that the endpoints of each range are important relative to the other endpoint and independently of the other endpoint.

As used herein, the term "amino acid sequence" refers to a list of abbreviations, letters, characters or words for amino acid residues. The amino acid abbreviations used herein are the conventional single-letter codes for amino acids and are represented as follows: A, alanine; C, cysteine; D, aspartic acid; E, glutamic acid; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine V, valine; W, tryptophan; and Y, tyrosine.

As used in the specification and appended claims, a residue of a chemical substance refers to a moiety that is the resultant product of a chemical substance in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the _chemical substance. Thus, an ethylene glycol residue in a polyester refers to one or more _-OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more -CO( _CH2 ) _8CO- moieties in the polyester, regardless of whether the residue was obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

As used herein, "peptide" refers to any peptide, oligopeptide, polypeptide, gene product, expression product, or protein. A peptide is composed of consecutive amino acids. The term "peptide" includes naturally occurring molecules or synthetic molecules.

As used herein, the term "Apo E mimetic" is interchangeable with apolipoprotein-E mimetic peptide. Apo E mimetic is a peptide related to, characterized by, or mimics ApoE. Apo E mimetic includes Apo E peptides (i.e., peptides derived from full-length Apo E).

As used herein, "reverse orientation," "reverse orientation," "reverse analog," or "reverse sequence" refers to a peptide or portion of a peptide that has an amino acid sequence that is reversed compared to the peptide in a non-reverse orientation (i.e., the original sequence read (or written) from right to left). For example, if a peptide has the amino acid sequence ABCDE, then a reverse analog or peptide having its reverse sequence is as follows: EDCB A. In a two-domain peptide such as Ac-hE-18A-NH2, the hE sequence is read from right to left or the 18A sequence is read from right to left. A reverse analog of LRKLRKRLLR-DWLKAFYDKVAEKLKEA F (SEQ ID NO: 1) can be RLLRKRLKRL-DWLKAFYD KVAEKLKEAF (SEQ ID NO: 2) or LRKLRKRLLR-FAEKLKEAVKD YFAKLWD (SEQ ID NO: 3).

As used herein, "two-domain peptide," "two-domain synthetic peptide," or "two-domain Apo E mimetic peptide" means a peptide comprising a lipid-associating peptide/domain and a receptor-binding peptide/domain.

As used herein, "single domain peptide," "single domain synthetic peptide," or "single domain Apo E mimetic peptide" means a peptide that comprises either a lipid-associating peptide/domain or a receptor-binding peptide/domain, but not both.

As used herein, "domain-swapped," "swapped domain," or "swapped" peptide means that the lipid-associating peptide is covalently linked to the receptor binding domain of apolipoprotein E such that the lipid-associating peptide is located at the N-terminus of the synthetic apolipoprotein E mimetic peptide. For example, peptide 18A-hE is an example of a domain-swapped peptide.

As used herein, "scrambled," "scrambled version," or "scrambled peptide" means that the composition of the amino acid sequence is the same as that of the unscrambled peptide, but the sequence of amino acids has been altered so that the peptide cannot form an α-amphipathic helix or does not have lipid-binding (or HSPG-binding) properties. However, in some cases, as described herein, the scrambled peptide remains capable of forming a different helical structure, such as a π-helix. For example, if a peptide has the amino acid sequence ABCDE, a scrambled version of the peptide can have the amino acid sequence DEABC. Scrambled peptides are typically indicated by having "Sc" preceding the scrambled portion of the peptide. For example, Sc-hE-18A indicates that the hE portion of the peptide is scrambled.

As used herein, "sample" refers to an animal; a tissue or organ from an animal; a cell (in a subject, taken directly from a subject, or maintained in culture or from a cultured cell line); a cell lysate (or lysate fraction) or a cell extract; or a solution containing one or more molecules derived from cells or cellular material (e.g., polypeptides or nucleic acids) that are assayed as described herein. A sample can also be any body fluid or excretion containing cells or cellular components (e.g., blood, urine, feces, saliva, tears, bile).

As used herein, "subject" refers to the target of administration, e.g., an animal. Thus, the subject of the disclosed methods can be a vertebrate, e.g., a mammal. For example, the subject can be a human. The term does not denote a particular age or sex. Subject is used interchangeably with "individual" or "patient."

As used herein, "modulate" means to change by increasing or decreasing.

As used herein, "lipid binding domain E" and "lipid binding peptide" are used interchangeably. Both terms used herein may refer to the lipid binding domain of apolipoprotein E.

As used herein, "isolated polypeptide" or "purified polypeptide" means a polypeptide (or fragment thereof) that is substantially free of materials with which the polypeptide is normally associated in nature. The polypeptides of the present invention or fragments thereof can be obtained, for example, by extraction from a natural source (e.g., a mammalian cell), by expressing a recombinant nucleic acid encoding the polypeptide (e.g., in a cell or in a cell-free translation system), or by chemically synthesizing the polypeptide. In addition, polypeptide fragments can be obtained by any of these methods or by cleavage of the full-length protein and/or polypeptide.

As used herein, "18A" when used in the context of a peptide or peptide sequence refers to the peptide DWLKAFYDKVAEKLKEAF (SEQ ID NO: 5). The peptide sequence can exist as an isolated peptide or as a sequence within a larger peptide sequence.

As used herein, "hE" when used in the context of a peptide or peptide sequence refers to the peptide LRKLRKRLLR (SEQ ID NO: 4). The peptide sequence may exist as an isolated peptide, or as a sequence within a larger peptide sequence.

As used herein, "[R]hE" when used in the context of a peptide or peptide sequence refers to the peptide LRRLRRRLLR (SEQ ID NO: 11). The peptide sequence may exist as an isolated peptide, or as a sequence within a larger peptide sequence.

The term "aliphatic" as used herein includes both saturated and unsaturated, straight-chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be understood by those skilled in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, and alkynyl moieties. Therefore, the term "alkyl" as used herein includes straight-chain and branched alkyl groups. Similar conventions apply to other general terms, such as "alkenyl," "alkynyl," and the like. In certain embodiments, "lower alkyl" as used herein is used to represent those alkyl groups (substituted, unsubstituted, branched, or unbranched) having about 1 to 6 carbon atoms. "Substituted alkyl" refers to an alkyl group substituted with one or more functional groups. Substituents include, but are not limited to, any of the substituents mentioned below, i.e., the substituents listed below that result in the formation of stable compounds.

As used herein, "alkenyl" refers to a monovalent group derived from a hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom.

As defined herein, " _Cn " (where "n" is an integer) describes a hydrocarbon molecule or fragment (eg, an alkyl group), where "n" represents the number of carbon atoms in the fragment or molecule.

As used herein, "fatty acid moiety" refers to any molecular species and/or molecular fragment comprising the acyl component of a fatty acid (carboxylic acid). That is, a fatty acid moiety is a group comprising an acyl portion that can be derived from a fatty acid, i.e., typically in the form of RC(=O)-, wherein R represents the fatty chain of the corresponding fatty acid.

As used herein, the term "fatty acid" is intended to include monocarboxylic acids having an aliphatic chain ("tail"), wherein the aliphatic chain can be saturated, monounsaturated (having one unsaturated bond at any position on the aliphatic chain), or polyunsaturated (having at least two unsaturated bonds at any position on the aliphatic chain). The unsaturated bonds on the aliphatic chain can be double (cis and/or trans configuration) or triple bonds. The length of the fatty chain (saturated, monounsaturated, or polyunsaturated) of the fatty acid can vary from 8 to 32 carbon atoms. The fatty acids can be derived from natural sources (animal or plant sources), synthetic sources, or semi-synthetic sources.

As used herein, the term "fatty acid" includes saturated fatty acids, which do not contain any double or triple bonds in the hydrocarbon chain. Saturated fatty acids include, but are not limited to, propionic acid (C3) (e.g., C3 means that propionic acid has 3 carbon atoms in its hydrocarbon chain; the number of carbon atoms in the hydrocarbon chain of other example fatty acids is expressed similarly herein), butyric acid (C4), valeric acid (C5), hexanoic acid (C6), heptanoic acid (C7), octanoic acid (C8), nonanoic acid (C9), decanoic acid (C10), undecanoic acid (C11), dodecanoic acid (C12), tridecanoic acid (C13), myristic acid (C14), pentadecanoic acid (C15), palmitic acid (C16), heptadecanoic acid (C17), isostearic acid (C18), benzoic acid (C19), benzoic acid (C20), benzoic acid (C21), benzoic acid (C22), benzoic acid (C23), benzoic acid (C24), benzoic acid (C25), benzoic acid (C26), benzoic acid (C27), benzoic acid (C28), benzoic acid (C29), benzoic acid (C30), benzoic acid (C31), benzoic acid (C32), benzoic acid (C33), benzoic acid (C34), benzoic acid (C35), benzoic acid (C36), benzoic acid (C37), benzoic acid (C38), benzoic acid (C39), benzoic acid (C40), benzoic acid (C41), benzoic acid (C42), benzoic acid (C43), benzoic acid (C44), benzoic acid (C45), benzoic acid (C46), benzoic acid (C47), benzoic acid (C48), benzo ), nonadecanoic acid (C19), eicosanoic acid (C20), heneicosanoic acid (C21), docosanoic acid (C22), tricosanoic acid (C23), tetracosanoic acid (C24), pentacosanoic acid (C25), hexacosanoic acid (C26), heptacosanoic acid (C27), octacosanoic acid (C28), nonacosanoic acid (C29), melic acid (C30), unicosanoic acid (C31), dotriacontanoic acid (C32), tricariacontanoic acid (C33), tetratriacontanoic acid (C34), pentatriacontanoic acid (C35), and hexatriacontanoic acid (C36).

As used herein, the term "fatty acid" also includes monounsaturated fatty acids containing one double bond or triple bond in the hydrocarbon chain and polyunsaturated fatty acids containing more than one double bond and/or triple bond in the hydrocarbon chain. Such acids include, but are not limited to, ω3, ω6, ω9 fatty acids, other fatty acids such as myristoleic acid and palmitoleic acid, and conjugated fatty acids. Examples of monounsaturated and polyunsaturated fatty acids include, but are not limited to, (a) ω3 fatty acids, such as hexadecatrienoic acid (C16:3); (e.g., C16:3 means that hexadecatrienoic acid has 16 carbon atoms and 3 double bonds in its hydrocarbon chain; the number of carbon atoms and double bonds in the hydrocarbon chain of other exemplary unsaturated fatty acids is expressed in a similar manner herein), alpha linolenic acid (C18:3) and eicosapentaenoic acid (20:5), (b) ω6 fatty acids, such as linoleic acid (C18:2), docosadienoic acid (C22:2), arachidonic acid (C20:4) and tetracosatetraenoic acid (C24:5), (c) ω9 fatty acids, such as oleic acid (C18:1), eicosenoic acid (C20:1) and tetracosenoic acid (C24:1) and (d) conjugated fatty acids, such as rumenic acid (C18:2), eleostatic acid (C18:3) and rumelenic acid (C18:3).

As used herein, the term "fatty acid" also includes branched-chain fatty acids. Examples of branched-chain fatty acids include, but are not limited to, monomethyl branched-chain fatty acids, such as 14-methylpentadecanoic acid, 6-methyloctanoic acid, 4-methyl-3-pentenoic acid (4-methyl-3-pentenoic acid (pyroterebic acid)), 2-methyl-2E-butenoic acid (tiglic acid), 2-methyl-2Z-butenoic acid (angelic acid), polymethyl branched-chain acids, isoprenoid fatty acids (vitaminol, all-trans retinoic acid), branched-chain methoxy fatty acids, and hydroxyl and other fatty acids, such as 2-hydroxyoctanoic acid and 4-oxopentanoic acid (levulinic acid).

The term "fatty acid" also includes a mixture that comprises a fatty acid, such as a natural oil or fat, which can comprise a component that is not a fatty acid. Natural oil or fat that are understood to comprise a fatty acid mixture include but are not limited to animal tallow, soybean oil, coconut oil, palm oil, palm kernel oil, rapeseed oil, cottonseed oil, linseed oil, sunflower oil, fish oil, algae oil etc.

The term "ω-amino-fatty acid" refers to a fatty acid characterized by the amino group on the distal carbon of its hydrocarbon chain. The ω-amino-fatty acid moiety used in the context of the present invention can be a saturated or unsaturated hydrocarbon chain. These parts have a carboxyl group at one end of the hydrocarbon chain and an amido group at the other end. The hydrocarbon chain connecting the carboxyl group and the amido group in such ω-amino-fatty acid moiety has 3 to 32 carbon atoms conventionally.

Exemplary ω-amino-fatty acids include, but are not limited to, 4-amino-butyric acid, 6-amino-hexanoic acid, 8-amino-octanoic acid, 10-amino-decanoic acid (10-amino-decanoic acid), 12-amino-lauric acid (12-amino-dodecanoic acid), 14-amino-myristic acid (14-amino-tetradecanoic acid), 14-amino-myristoleic acid, 16-amino-palmitic acid (16-amino-hexadecanoic acid), 18-amino-stearic acid, 18-amino-oleic acid, 16-amino-palmitoleic acid, 18-amino-linoleic acid, 18-amino-linolenic acid, and 20-amino-arachidonic acid.

As used herein, a "dosing regimen" refers to at least one treatment cycle followed by at least one rest period. A dosing regimen may include more than one treatment cycle and more than one rest period. For example, a dosing regimen may include a three-month treatment cycle followed by a one-year rest period. Another example may include a six-month treatment cycle followed by a six-month rest period, followed by a three-month treatment cycle followed by a one-year rest period.

As used herein, "dose" or "dosage" refers to a specific amount of a therapeutic agent, such as an Apo E mimetic, taken at a specific time.

As used herein, "treating" means administering a disclosed composition to a subject, such as a human or other mammal (e.g., an animal model), suffering from atherosclerosis to prevent or delay worsening of the effects of the disease or disorder, or to partially or completely reverse the effects of the disease.

As used herein, "preventing" means minimizing the chance of developing atherosclerosis in a subject with an increased predisposition to developing atherosclerosis.

As used herein, the term "treatment cycle" refers to a defined period of time during which an Apo E mimetic is administered. A treatment cycle encompasses a wide range of dosages of an Apo E mimetic and varying lengths of time during which the Apo E mimetic is administered. For example, a treatment cycle can be three months in which an Apo E mimetic is administered twice weekly during the three months.

As used herein, an "effective amount" means an amount of a composition or Apo E mimetic sufficient to provide the desired effect. For example, an effective amount of an Apo E mimetic can be an amount that provides a therapeutic effect and provides a sustained therapeutic effect after the treatment is withdrawn. An effective amount of an Apo E mimetic is an amount that can cause the benefits described by the following: reduced atherosclerosis, reduced arterial wall hardness, reduced isolated systolic hypertension, reduced arterial inflammation, increased antioxidant capacity of the HDL fraction, and/or improved myocardial function, as well as an amount that allows for a sustained therapeutic effect after the Apo E mimetic is withdrawn. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease being treated (or the underlying genetic defect), the specific compound used, its mode of administration, and the like. Therefore, it is not possible to specify an exact "effective amount." However, a suitable "effective amount" can be determined by one of ordinary skill in the art using only routine experimentation.

As used herein, a "sustained therapeutic effect" is a therapeutic effect that persists after treatment has been withdrawn. For example, a sustained therapeutic effect may persist even after the acute cholesterol-lowering effect has worn off.

As used herein, "rest period" refers to a period of time during which an Apo E mimetic is not administered.

As used herein, "atherosclerotic burden" refers to the amount of atherosclerosis in a patient's arteries. This can include coronary, carotid, peripheral, and other arteries. Atherosclerotic plaques can be complex lesions with smooth muscle and a collagen-containing fibrous cap, areas of calcification, cholesterol crystals, and cholesterol-containing macrophages (foam cells) and/or less complex and more unstable lesions with less calcification and a thinner fibrous cap and more foam cells and cholesterol (unstable lesions). Unstable lesions may invade the lumen of the artery or expand away from the lumen of the artery.

The phrase "lipid disorder" means that a subject has excess lipids or increased inflammatory lipids in their blood. Lipids include, but are not limited to, lipids such as ox-LDL (i.e., oxidized PAPC (1-palmitoyl 2-arachidonoyl phosphatidylcholine)). Oxidation of PAPC or PLPC (lipid components of LDL) produces oxidized lipids. Having a lipid disorder can make it more likely that an inflammatory disease, such as atherosclerosis and heart disease, will develop. Lipid disorders can be caused by genetic predisposition or diet.

As used herein, "lipoprotein" refers to a biochemical assembly containing both proteins and lipids. Lipids or their derivatives can be covalently or non-covalently bound to proteins. Many enzymes, transport proteins, structural proteins, antigens, adhesins, and toxins are lipoproteins. Examples include high- and low-density lipoproteins of the blood, transmembrane proteins of mitochondria and chloroplasts, and bacterial lipoproteins.

As used herein, "high-density lipoprotein" (HDL) refers to a class of lipoproteins that vary slightly in size (8-11 nm in diameter) and that transport cholesterol. HDL cholesterol is the cholesterol associated with HDL. About a quarter to a third of blood cholesterol is carried by high-density lipoprotein (HDL). HDL cholesterol is called the "good" cholesterol because high levels of HDL appear to protect against heart attacks. Low levels of HDL (less than 40 mg/dL for men and less than 50 mg/dL for women) also increase the risk of heart disease. Medical experts believe that HDL tends to transport cholesterol away from the arteries and back to the liver, where it passes through the body. Some experts believe that HDL removes excess cholesterol from arterial plaques, thereby slowing their accumulation.

As used herein, "very low density lipoprotein" (VLDL) refers to a subclass of lipoproteins. It is assembled in the liver from cholesterol and apolipoproteins. It is converted into low density lipoprotein (LDL) in the bloodstream. VLDL particles have a diameter of 30-80 nm. VLDL transports endogenous products, while chylomicrons transport exogenous (dietary) products.

As used herein, "low-density lipoprotein" or "LDL" refers to lipoproteins that vary in size (about 22 nm) and can contain varying amounts of triglycerides and cholesterol esters; they actually have a mass and size distribution. Each native LDL particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein with 4536 amino acid residues) and a phospholipid coating that surrounds the triglycerides and cholesterol esters, keeping them soluble in an aqueous environment. LDL is often called bad cholesterol. LDL cholesterol is the cholesterol associated with LDL. When too much LDL cholesterol circulates in the blood, it can slowly accumulate on the inner walls of the arteries that supply the heart and brain. It can, along with other substances, form plaques (thick, hard deposits) that can narrow the arteries, making them less flexible. This condition is called atherosclerosis. If a clot forms and blocks a narrowed artery, it can lead to a heart attack or stroke.

Cholesterol cannot dissolve in the blood. It must be transported to and from cells by carriers called lipoproteins. LDL and HDL, along with triglyceride-rich lipoproteins (VLDL) and Lp(a) cholesterol, make up your total cholesterol count, which can be measured through a blood test.

As used herein, the phrase "nucleic acid" refers to naturally occurring or synthetic oligonucleotides or polynucleotides, whether DNA or RNA or DNA-RNA hybrids, single-stranded or double-stranded, sense or antisense, which are capable of hybridizing to complementary nucleic acids via Watson-Crick base pairing. The nucleic acids of the present invention may also include nucleotide analogs (e.g., BrdU) and non-phosphodiester internucleoside linkages (e.g., peptide nucleic acids (PNA) or thiodiester linkages). In particular, nucleic acids may include, but are not limited to, DNA, RNA, cDNA, gDNA, ssDNA, dsDNA, or any combination thereof.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the disclosed methods and compositions belong. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the methods and compositions of the present invention, particularly useful methods, devices and materials are as described. The publications cited herein and the materials cited therein are specifically incorporated herein by reference. Nothing herein should be construed as an admission that the present invention is not entitled to such disclosure as prior invention. It is not admitted that any reference constitutes prior art. The discussion of the references states what their authors claim, and the applicant reserves the right to question the accuracy and relevance of the references. It will be clearly understood that although many publications are cited herein, such citations do not constitute an admission that any of these documents constitute part of the common general knowledge in this area.

B. Apo E mimetic peptide

Apolipoprotein E mimetic peptides or Apo E mimetics are disclosed. Non-limiting examples of Apo E mimetic peptides are provided herein. The Apo E mimetic peptides can be single domain peptides or dual domain peptides. Compositions containing the Apo E mimetic peptides are also disclosed.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises acetylated aminohexanoic acid (Ac-Aha).

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein Ac-Aha is located at the N-terminus of the peptide. In some aspects, Aha can be inserted between the lipid-associating peptide comprising a class A amphipathic helical domain.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the lipid-associating peptide comprises a class A amphipathic helical domain. For example, the class A amphipathic helical domain is DWLKAFYDKVAEKLKEAF (SEQ ID NO: 5), DWLRAFYDKVA EKLREAF (SEQ ID NO: 618), DWLRALYDKVAEKLREAL (SEQ ID NO: 619), DLLRALYDKVAEKLREAW (SEQ ID NO: 620), or FA EKLKEAVKDYFAKLWD (SEQ ID NO: 616).

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the lipid-associating peptide comprises a class A amphipathic helical domain, wherein the receptor binding domain of ApoE can be covalently linked to the lipid-associating peptide.

Disclosed are synthetic ApoE mimetic peptides comprising the receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the apolipoprotein E may be from a species selected from the group consisting of: human, mouse, rabbit, monkey, rat, cow, pig, and dog.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, and wherein the synthetic peptide is protected with an amide group at its C-terminus.

Disclosed are synthetic ApoE mimetic peptides comprising an ApoE receptor binding domain and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the ApoE receptor binding domain can be LRKLRKRLLR (SEQ ID NO: 4), LRRLRRRLLR (SEQ ID NO: 11), LRKMRKRLMR (SEQ ID NO: 7), or RLTRKRGLK (SEQ ID NO: 13). The ApoE receptor binding domain can also be, but is not limited to, LRKLRKRFFR (SEQ ID NO: 4), LRKLPKRLLR (SEQ ID NO: 8), LRNVRKRLVR (SEQ ID NO: 9), MRKLRKRVLR (SEQ ID NO: 10), LRRLRRRLLR (SEQ ID NO: 11), LRKLRKRFFR (SEQ ID NO: 12), LRKLRKRLLR (SEQ ID NO: 4), or LRKMRKRLMR (SEQ ID NO: 7).

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the receptor binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO: 4), LRRLRRRLLR (SEQ ID NO: 11), LRKMRKRLMR (SEQ ID NO: 7), RLTRKRGLK (SEQ ID NO: 13), LRRMRRRLMR (SEQ ID NO: 621) or RLTRRGK (SEQ ID NO: 622).

Disclosed are synthetic ApoE mimetic peptides comprising an ApoE receptor binding domain and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the synthetic ApoE mimetic peptide can be Ac-Aha-hE18A- _NH2 or Ac-Aha-[R]hE18A- _NH2 . The ApoE mimetic peptide of Ac-Aha-hE18A- _NH2 is Ac-Aha-LRKLRKRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 1). The ApoE mimetic peptide of Ac-Aha-[R]hE18A- _NH2 is Ac-Aha-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 662).

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid moiety, an ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises an acetylated ω-amino fatty acid moiety, wherein the acetylated ω-amino fatty acid moiety is located at the N-terminus of the peptide. In some aspects, the ω-amino fatty acid moiety can be inserted between the lipid-associating peptide comprising a class A amphipathic helical domain.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid moiety, an ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the lipid-associating peptide comprises a class A amphipathic helical domain. For example, the class A amphipathic helical domain is DWLKAFYDKVAEKLKEAF (SEQ ID NO: 5), DWLRAFYDKVAEKLREAF (SEQ ID NO: 618), DWLRALYDKVAEKLREAL (SEQ ID NO: 619), DLLR ALYDKVAEKLREAW (SEQ ID NO: 620), or FAEKLKEAVKDYFAKL WD (SEQ ID NO: 616).

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the lipid-associating peptide comprises a class A amphipathic helical domain, wherein the receptor binding domain of ApoE can be covalently linked to the lipid-associating peptide.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the apolipoprotein E may be from a species selected from the group consisting of: human, mouse, rabbit, monkey, rat, cow, pig, and dog.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid moiety, an ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the synthetic peptide is protected with an amide group at the C-terminus.

Disclosed are synthetic ApoE mimetic peptides comprising an ApoE receptor binding domain and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the ApoE receptor binding domain can be LRKLRKRLLR (SEQ ID NO: 4), LRRLRRRLLR (SEQ ID NO: 11), LRKMRKRLMR (SEQ ID NO: 7), or RLTRKRGLK (SEQ ID NO: 13). The ApoE receptor binding domain can also be, but is not limited to, LRKLRKRFFR (SEQ ID NO: 4), LRKLPKRLLR (SEQ ID NO: 8), LRNVRKRLVR (SEQ ID NO: 9), MRKLRKRVLR (SEQ ID NO: 10), LRRLRRRLLR (SEQ ID NO: 11), LRKLRKRFFR (SEQ ID NO: 12), LRKLRKRLLR (SEQ ID NO: 4), or LRKMRKRLMR (SEQ ID NO: 7).

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the receptor binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO: 4), LRRLRRRLLR (SEQ ID NO: 11), LRKMRKRLMR (SEQ ID NO: 7), RLTRKRGLK (SEQ ID NO: 13), LRRMRRRLMR (SEQ ID NO: 621), or RLTRRGK (SEQ ID NO: 622).

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid portion, an ω-amino fatty acid portion, or an acetylated ω-amino fatty acid portion, wherein the synthetic ApoE mimetic peptide can be: butyryl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 623); hexanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 624); octanoyl-LRRLRRRLLR-DWLKAFYDKVAE KLKEAF- _NH2 (SEQ ID NO: 625); decanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 626); lauroyl-LRRLRRRLLR KVAEKLKEAF- _NH2 (SEQ ID NO: 629); stearoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 630); palmitoleoyl _- LRRLRRRLLR-DWLKAFYD KVAEKLKEAF- _NH2 (SEQ ID NO: 631); arachidonoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 632) _. NO: 632); Behenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF--NH ₂ (SEQ ID NO: 633); Oleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 634); Ricinoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKE AF-NH ₂ (SEQ ID NO: 635); Linolenoyl-LRRLRRRLLR-DWLKAFYD KVAEKLKEAF-NH 2 (SEQ ID NO: 636); Isooleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 637); Gadolinium-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: NO: 638); erucyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 6239); cetyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 640); ceruloyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 641); adrenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 642); α-linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 643); γ-linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 644); EPA-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 645); or DHA-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 646). In the foregoing, the fatty acid moiety is shown on the left and is linked to the peptide LRRLRRRLLR (SEQ ID NO: 11). "EPA" indicates the moiety derived from 5,8,11,14,17-eicosapentaenoic acid; "DHA" indicates the moiety derived from 4,7,10,13,16,19-docosahexaenoic acid.

Disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises a fatty acid moiety derived from a natural oil or fat (e.g., fish oil), wherein the synthetic ApoE mimetic peptide can be: (fish oil)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 663). In the foregoing, "(fish oil)" refers to fatty acids in fish oil, including but not limited to fish oil components such as EPA and DHA, attached to the peptide LRRLRRRLLR (SEQ ID NO: 11). Thus, the synthetic ApoE mimetic peptides are a mixture of peptides comprising fatty acid groups derived from the fish oil used to prepare them.

In some cases, the synthetic ApoE mimetic peptide can be any of the disclosed fatty acid-containing peptides.

In some cases, the synthetic ApoE mimetic peptide can be any disclosed peptide comprising an acetylated fatty acid.

Also disclosed are synthetic ApoE mimetic peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha, wherein the receptor binding domain of apolipoprotein E is scrambled. Examples of scrambled receptor binding domains of ApoE are provided below.

Also disclosed are synthetic apolipoprotein E mimetic peptides consisting of a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide, wherein the receptor binding domain of apolipoprotein E and the lipid-associating peptide are scrambled. Examples of scrambled ApoE receptor binding domains and scrambled lipid-associated peptides are provided below.

Apolipoprotein E mimetic peptides have a direct cholesterol-lowering effect by providing an alternative ligand for receptors on the liver to clear atherogenic apolipoprotein B containing lipoproteins (LDL, VLDL, and β-VLDL), and have direct beneficial effects on the arterial wall. New, more effective coronary atherosclerosis imaging methods allow direct measurement of the benefits to the arterial wall (Van Velzen et al., Hellenic J Cardiol 50: 245-263, 2009). Apo E mimetic peptides can enhance the removal of cholesterol from the arterial wall, synergize with HDL, and increase the formation of lipid-deficient pro-β-HDL that accepts cholesterol from macrophages. Apo E mimetic peptides can stimulate macrophage-mediated clearance of dead and dying cells from the arterial wall (efferocytosis), improve the quality of HDL by increasing PON-1 levels and reducing plasma lipid hydroperoxide levels, reduce the macrophage content in atherosclerotic lesions, resulting in more stable lesions, and reduce inflammation in the arterial wall. As a result, Apo E mimetic peptides reduced the size of atherosclerotic lesions faster than apoA-I mimetic peptides and faster than statins (HMG-CoA reductase inhibitors). Even when cholesterol levels were the same as in saline-treated animals, the recovery of atherosclerotic lesions in Apo E mimetic peptide-treated animals continued. Therefore, these effects cannot be explained simply by cholesterol reduction.

1. Apolipoprotein E

Apolipoprotein E (Apo E) plays an important role in the metabolism of triglyceride-rich lipoproteins (e.g., very low density lipoproteins (VLDL) and chylomicrons). Apolipoprotein E mediates the high-affinity binding of Apo E-containing lipoproteins to low-density lipoprotein (LDL) receptors (Apo B, E receptor) and members of its gene family, including LDL receptor-related protein (LRP), very low density lipoprotein receptor (VLDLR), and Apo E2 receptor (Apo E2R) (Mahley, R.W., (1988) Science 240, 622-630). The putative and complex role of Apo E in atherosclerosis has been emphasized by several observations: (i) mice overexpressing human Apo E have lower levels of total plasma cholesterol (Shimono, H.N. et al., (1992) Eur. J. Clin. Invest. 90, 2084-2991), (ii) intravenous injection of human Apo E into cholesterol-fed rabbits protects these animals from atherosclerosis (Yamada et al., (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 665-669), and (iii) Apo E gene deletion in mice produces spontaneous atherosclerosis (Zhang, S.H. et al., (1992) Science 258, 468-471). Spontaneous atherosclerosis is ameliorated when initiated in E-deficient mice (Spangenberg, J. et al. (1997) Biochem. Biophys. Acta 1349, 109-121).

Apo E is a lipid-binding protein with two major domains (Mahley, R.W., et al. J. Lipid Res. 1999, 40: 622-630). X-ray crystallography has shown that the 22 kDa amino-terminal domain is a 4-helix bundle (Wilson, C. et al. Science 1991; 252: 1817-1822) and contains a positively charged receptor-binding domain. For this region to mediate binding to very low-density lipoprotein (VLDL) receptors, the apolipoprotein must associate with the lipoprotein surface; this is achieved via the C-terminal amphipathic helical region. If the 4-helix bundle containing the positively charged receptor-binding domain is not open on the lipoprotein surface, VLDL is defective in binding to the receptor. Therefore, both the positively charged arginine (Arg)-rich cluster domain of Apo E and the C-terminal amphipathic helical domain are required for increased uptake of lipoproteins containing atherogenic Apo E.

Apo E is secreted as a 299 amino acid residue protein with a molecular weight of 34,200. Based on the fact that Apo E is cleaved by thrombin into two fragments, the two-domain hypothesis was initially proposed to explain the fact that the C-terminal region (192-299) of Apo E is required for its binding to hypertriglyceridemic VLDL and the N-terminal 22 kDa domain (1-191) is required for binding to LDL-R (Bradley, W.A. et al., (1986) J. Lipid Res. 27, 40-48). Additional physicochemical characterization of the protein and its mutants has expanded this concept and has shown that region 192-211 binds phospholipids, while the amino-terminal domain (1-191) is a globular structure that contains the LDL receptor binding domain in a 4-helical bundle (Wilson, C. et al., (1991) Science 252, 1817-1822). Studies using synthetic peptides (Sparrow et al. Biochemistry 31(4):1065-8, 1992) and monoclonal antibodies have pinpointed the LDL receptor binding domain of apo E between positions 129 and 169, a domain rich in the positively charged amino acids Arg and Lys (Rall, S.C., Jr. et al., (1982) PNAS USA 79, 4696-4700; Lalazar, A. et al., (1988) J. Biol. Chem. 263, 3542-2545; Dyer, C.A. et al., (1991) J. Biol. Chem. 296, 22803-22806; and Dyer, C.A. et al., (1991) J. Biol. Chem. 266, 15009-15015).

To test the hypothesis that a minimal arginine-rich ApoE receptor binding domain (141-150) is sufficient to enhance low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) uptake and clearance when covalently linked to a class A amphipathic helix, a peptide was synthesized in which the receptor binding domain of human Apo E, LRKLRKRLLR (SEQ ID NO: 4) (hApo E [141-150], also referred to as "hE"), was linked to 18A, a well-characterized high-affinity lipid-associating peptide (DWLKAFYDKVAEKLKEAF (SEQ ID NO: 5), also referred to as "18A") to generate a peptide denoted hApo E [141-150]-18A (also referred to as "hE-18A") (see U.S. Pat. No. 6,506,880, which is incorporated herein by reference in its entirety for teaching specific ApoE receptor binding domains). A terminally protected analog of hE-18A, designated Ac-hE18A-NH2, was also synthesized. The importance of lysine residues and the role of hydrophobic residues in the receptor-binding domain were also investigated using two analogs, LRRLRRRLLR (SEQ ID NO: 11)-18A (also referred to as "hE(R)-18A") and LRKMRKRLMR (SEQ ID NO: 7)-18A (also referred to as "mE18A"). The human Apo E receptor-binding domain was modified to replace arginine (R) residues with lysine (K) residues at positions 143 and 146 (LRRLRRRLLR; SEQ ID NO: 11), thereby linking the mouse Apo E receptor-binding domain (LRKMRKRLMR; SEQ ID NO: 7) to 18A. The dual-signature peptides were then tested for their effects on cellular uptake and degradation of human LDL/VLDL.

It was determined that in MEF1 cells with induced LDL receptors, LDL internalization was enhanced by three-, five-, and seven-fold by Ac-mE-18A-NH ₂ , Ac-hE-18A-NH ₂ , and Ac-hE(R)-18A-NH ₂ , respectively. All three peptides increased LDL degradation by 100%. Both Ac-hE-18A-NH ₂ and the control peptide Ac-18A-NH ₂ interacted with VLDL, resulting in the displacement of apoE from VLDL. However, despite the absence of apoE, only Ac-hE-18A-NH _2- associated VLDL increased VLDL uptake by six-fold and degradation by three-fold compared to VLDL alone. However, within the LDL concentration range studied, LDL binding to fibroblasts was not saturable in the presence of these peptides.

In addition, similar enhancement of LDL internalization was observed that was independent of the presence of LDL receptor-related protein (LRP) or LDL receptor or both. However, pre-treatment of cells with heparinase and heparanase eliminated greater than 80% of the enhanced peptide-mediated cellular LDL uptake and degradation. The data show that the two-domain peptide enhances LDL uptake and degradation by binding to LDL via the amphipathic lipid binding domain (18A). However, the smallest 141-150Arg-rich domain does not reduce LDL levels, but does so only in combination with the 18A lipid association domain, does not provide LDL-receptor binding, but directs the LDL-peptide complex to the HSPG pathway for uptake and degradation by fibroblasts.

2. Fatty acids

The disclosed peptides can be linked to a fatty acid moiety, an ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety. In various aspects, the fatty acid moiety, the ω-amino fatty acid moiety, or the acetylated ω-amino fatty acid moiety is linked to the disclosed peptide via the N-terminal amino group of the peptide.

In various aspects, the linkage between the fatty acid moiety, ω-amino fatty acid moiety, or acetylated ω-amino fatty acid moiety and the N-terminal amino group of the peptide has a structure represented by the following formula:

wherein A is an aliphatic group having 2 to 32 carbon atoms. In another aspect, the aliphatic group is an alkyl group. In another aspect, the aliphatic group contains 0 to 3 double bonds. In another aspect, the aliphatic group is an alkenyl group.

In another aspect, the fatty acid moiety attached to the disclosed peptide is derived from a purified fatty acid. In another aspect, the fatty acid moiety attached to the disclosed peptide is derived from a saturated fatty acid. In another aspect, the fatty acid moiety attached to the disclosed peptide is derived from an unsaturated fatty acid. In another aspect, an unsaturated fatty acid is a polyunsaturated fatty acid having two or more double bonds.

In various aspects, the synthetic ApoE mimetic peptide comprises a fatty acid moiety.

Exemplary fatty acids from which the fatty acid moiety is derived include, butyric acid, hexanoic acid, caprylic acid, capric acid, decanoic acid, lauric acid, myristic acid, palmitic acid, pentadecanoic acid, stearic acid, arachidic acid, behenic acid, erucic acid, lignoceric acid, heptadecanoic acid, myristoleic acid, palmitoleic acid, oleic acid, gadoleic acid, ricinoleic acid, vaccenic acid, linoleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, licanic acid, margaroleic acid, arachidic acid, gadoleic acid, nervonic acid, arachidonic acid, docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and the like.

Exemplary saturated fatty acids include, but are not limited to, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicosanoic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanic acid, heneicosanoic acid, dotriacontanic acid, trictriacontanic acid, tetratriacontanic acid, pentatriacontanic acid, and hexatriacontanic acid.

Exemplary unsaturated fatty acids include, but are not limited to, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA), erucic acid, docosahexaenoic acid (DHA), and docosapentaenoic acid.

In various aspects, the fatty acid moiety attached to the disclosed peptide is derived from an unpurified fatty acid or a mixture of fatty acids (e.g., natural oils or fats). Typically, natural oils or fats are heterogeneous mixtures of generally hydrophobic compounds comprising one or more fatty acids. The fatty acid source can include natural oils or fats, such as, but not limited to, animal fats, bio-oils, or vegetable oils such as soybean oil, coconut oil, palm oil, palm kernel oil, rapeseed oil, cottonseed oil, linseed oil, sunflower oil, fish oil, algae oil, etc.

On the other hand, natural oil or fat contain or be rich in one or more ω-3 fatty acids, for example marine oil, for example fish oil, krill oil and algae oil.Any oil containing DHA and/or EPA can be used.On the other hand, natural oil or fat contain by weight at least 70% or about 70% DHA, for example by weight at least 75% or about 75%, at least 80% or about 80%, at least 85% or about 85% or at least 90% or about 90% DHA.On the other hand, natural oil or fat contain 5% or about 5% to 15% or about 15% EPA, for example by weight 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% EPA.On the other hand, natural oil or fat contain and be no more than 10% or about 10% EPA or be less than 10% or about 10% EPA.

In another aspect, the fatty acid moiety is derived from ω-3 fatty acids. As used herein, the term "ω-3 polyunsaturated fatty acids" or "ω-3 fatty acids" refers to a family of unsaturated fatty carboxylic acids that have a common carbon-carbon bond at the n-3 position (i.e., the third bond from the methyl end of the molecule). Typically, they contain from about 16 to about 24 carbon atoms and 3 to 6 carbon-carbon double bonds. ω-3 polyunsaturated fatty acids can be found in nature, and these natural ω-3 polyunsaturated fatty acids typically have all carbon-carbon double bonds in the cis configuration.

Exemplary ω-3 fatty acids include, but are not limited to, 7,10,13-hexadecatrienoic acid (sometimes abbreviated as 16:3(n-3)); 9,12,15-octadecatrienoic acid (α-linolenic acid (ALA), 18:3(n-3)); 6,9,12,15-octadecatetraenoic acid (octadecatetraenoic acid (STD), 18:4(n-3)); 11,14,17-eicosatrienoic acid (eicosatrienoic acid (ETE), 20:3(n-3)); 8,11,14,17-eicosatetraenoic acid (eicosatetraenoic acid (ETA), 20:4(n-3)); 5,8,11,14,17-eicosapentaenoic acid (eicosapentaenoic acid (EPA), (20: 5(n-3)); 7,10,13,16,19-docosapentaenoic acid (docosapentaenoic acid (DPA), 22:5(n-3)); 4,7,10,13,16,19-docosahexaenoic acid (docosahexaenoic acid (DHA), 22:6(n-3)); 9,12,15,18,21-eicosapentaenoic acid (tetracosapentaenoic acid, 24:5(n-3)); and 6,9,12,15,18,21-tetracosahexaenoic acid (tetracosahexaenoic acid, 24:6(n-3). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are naturally present in fish oils and have been used in a variety of dietary/therapeutic compositions.

Lipid acid of various lengths has been considered. In one aspect, lipid acid comprises the chain length between C6 to C24, C10 to C24, C10 to C28 or C10 to C32, comprises the synthetic fatty acid with odd carbon number. On the other hand, lipid acid comprises following chain length that is selected from: C10, C12, C14, C16, C18, C20, C20, C22 and C24. On the other hand, lipid acid has the chain length that is selected from C14, C16 and C18. On the other hand, lipid acid has the chain length that is selected from C13, C15 and C17. On the other hand, lipid acid has 4 to 28 carbon.

In various aspects of the invention, the fatty acid aliphatic chain contains 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32 carbon atoms.

In various fields, lipid acid is naturally occurring lipid acid. On the other hand, lipid acid is short-chain fatty acid (for example, less than 6 carbon), medium-chain fatty acid (for example, 6 to 12 carbon), long-chain fatty acid (for example, more than 12 carbon) or very long-chain fatty acid (for example, more than 22 carbon). On the other hand, lipid acid is the unsaturated fatty acid of cis configuration. In another embodiment, lipid acid is the unsaturated fatty acid of trans configuration.

In various aspects, the synthetic ApoE mimetic peptide comprises an ω-amino fatty acid moiety.

Exemplary ω-amino-fatty acid moieties are derived from ω-amino-fatty acids, including but not limited to 4-amino-butyric acid, 6-amino-hexanoic acid, 8-amino-octanoic acid, 10-amino-decanoic acid (10-amino-decanoic acid), 12-amino-lauric acid (12-amino-dodecanoic acid), 14-amino-myristic acid (14-amino-tetradecanoic acid), 14-amino-myristoleic acid, 16-amino-palmitic acid (16-amino-hexadecanoic acid), 18-amino-stearic acid, 18-amino-oleic acid, 16-amino-palmitoleic acid, 18-amino-linoleic acid, 18-amino-linolenic acid and 20-amino-arachidonic acid. In another aspect, the ω-amino-fatty acid moiety is derived from 6-amino-hexanoic acid.

In other aspects, the ω-amino fatty acid moiety is 4-amino-butyryl, 6-amino-hexanoyl, 8-amino-octanoyl, 10-amino-decanoyl, 12-amino-lauroyl, 14-amino-myristoyl, 14-amino-myristoleoyl, 16-amino-palmitoyl, 18-amino-stearoyl, 18-amino-oleoyl, 16-amino-palmitoleoyl, 18-amino-linoleoyl, 18-amino-linolenoyl or 20-amino-arachidonoyl. In another aspect, the ω-amino fatty acid moiety is 6-amino-hexanoyl (or alternatively, 6-aminohexanoyl).

In various aspects, the ω-amino-fatty acid moiety is derived from an ω-amino-fatty acid having the following structure:

wherein A is an aliphatic group having 2 to 32 carbon atoms. In another aspect, the aliphatic group is an alkyl group. In another aspect, the aliphatic group contains 0 to 3 double bonds. In another aspect, the aliphatic group is an alkenyl group. In various aspects, A is -(CH ₂ ) ₅ -.

In another aspect, the ω-amino-fatty acid moiety is linked to the peptide via the N-terminal amino group of the peptide, and after being linked to the peptide, the ω-amino-fatty acid moiety has the structure:

wherein A is an aliphatic group having 2 to 32 carbon atoms. In another aspect, the aliphatic group is an alkyl group. In another aspect, the aliphatic group contains 0 to 3 double bonds. In another aspect, the aliphatic group is an alkenyl group. In various aspects, A is -(CH ₂ ) ₅ -.

In various aspects, the synthetic ApoE mimetic peptides comprise an acetylated ω-amino fatty acid moiety. In another aspect, the disclosed peptides can be linked to any disclosed ω-amino-fatty acid and then further comprise an acetyl moiety on the ω-amino group.

In another aspect, the ω-amino-fatty acid moiety is linked to the peptide via the N-terminal amino group of the peptide, and after being linked to the peptide, the ω-amino group is acetylated, the ω-amino-fatty acid moiety having the following structure:

wherein A is an aliphatic group having 2 to 32 carbon atoms. In another aspect, the aliphatic group is an alkyl group. In another aspect, the aliphatic group contains 0 to 3 double bonds. In another aspect, the aliphatic group is an alkenyl group. In various aspects, A is -(CH ₂ ) ₅ -.

Fatty acids from which the fatty acid moiety is derived are commercially available and can be prepared by various chemical methods (Recent Developments in the Synthesis of Fatty Acid Derivatives, eds. Knothe G and Derksen JTB, AOCS Press 1999, ISBN 1-893997-00-6.)

3. Single domain peptides

Single-domain synthetic Apo E mimetics are disclosed. The single-domain synthetic Apo E mimetics can be composed of the receptor binding domain or the lipid-associated peptide of Apo E.

i. Receptor binding domain peptides

The receptor binding domain peptide used for the synthesis of Apo E mimetic can be a human receptor binding domain peptide of Apo E. For example, the disclosed synthetic Apo E mimetic receptor binding domain peptide can comprise the amino acid sequence of LRKLRKRLLR, LRRLRRRLLR, or LRKLRKRFFR. The synthetic Apo E mimetic receptor binding domain peptide can also be derived from a species selected from mouse, rabbit, monkey, rat, cow, pig, and dog.

Examples of receptor binding domain peptides that can be used in the disclosed synthetic Apo E mimetics are provided in Table 1.

The italicized residues in Table 1 represent changes relative to the human sequence; however, the nature of the amino acids is conserved. The bold italicized residues in Table 1 represent differences from the human sequence at that position.

The receptor binding domain peptide for synthesizing Apo E mimetics can also be the LDL receptor (LDLR) binding domain of apolipoprotein B (ApoB). The LDL receptor (LDLR) binding domain of ApoB can have the sequence RLTRKRGLK. ApoB-100 is a 550,000 Da glycoprotein with 9 amino acids (3359-3367) that serves as the binding domain for the LDL receptor (Segrest et al., J. Lipid. Res. 42, pp. 1346 to 1367 (2001)). When bound to LDLR in clathrin-coated pits, LDL is internalized by endocytosis and moves to endosomes, where a decrease in pH causes the receptor to dissociate from the LDL. The receptor is recycled back to the cell surface, while LDL is moved into lysosomes where the particles are degraded (Goldstein et al., Ann. Rev. Cell Biol. 1, pp. 1 to 39 (1985)). When used with the disclosed peptides, the LDL receptor (LDLR) binding domain of ApoB can also be altered and/or modified as described herein for Apo E. For example, the LDL receptor (LDLR) binding domain of ApoB can be used with the disclosed lipid-associating peptides, wherein the LDL receptor (LDLR) binding domain of ApoB is covalently linked to the lipid-associating peptide. In addition, the LDL receptor (LDLR) binding domain of ApoB can be scrambled, in reverse orientation, or can be part of a domain-switch peptide as described below.

ii. Lipid-associated peptides

The lipid-associated peptide can be used alone or in combination with an Apo E mimetic peptide. The lipid-associated peptide of these synthetic Apo E mimetics can be, but is not limited to, class A amphipathic helical peptides, class A amphipathic helical peptide mimetics of apoA-I having aromatic or aliphatic residues in the nonpolar face, small peptides including pentapeptides, tetrapeptides, tripeptides, dipeptides and amino acid pairs, Apo-J (G* peptide) and peptide mimetics, such as those described below.

a. Class A amphipathic helical peptides

In one aspect, lipid-associating peptides for use in the disclosed methods include class A amphipathic helical peptides, such as those described, for example, in U.S. Patent No. 6,664,230 and PCT Publications WO 02/15923 and WO 2004/034977. Peptides comprising class A amphipathic helices ("class A peptides") have been found to be capable of alleviating one or more symptoms of atherosclerosis and treating other disorders.

Class A peptides are characterized by the formation of α-helices that result in the separation of polar and nonpolar residues, thereby forming polar and nonpolar faces, in which positively charged residues are located at the polar-nonpolar interface and negatively charged residues are located in the center of the polar face (see, e.g., Anantharamaiah (1986) Meth. Enzymol, 128: 626-668). It is noted that the fourth exon of apo A-I, when folded into 3.667 residues/turn, produces a class A amphipathic helical structure.

A class A peptide designated 18A (see, e.g., Anantharamaiah (1986) Meth. Enzymol, 128: 626-668) was modified as described herein to produce a peptide that can be administered orally and is highly effective in inhibiting or preventing one or more symptoms of atherosclerosis and/or other indications described herein. Without being bound by a particular theory, it is believed that the disclosed peptides may act in vivo by providing a seed molecule that mitigates LDL oxidation.

Increasing the number of Phe residues on the hydrophobic surface of 18A can increase lipid affinity, as determined by calculations described by Palgunachari et al. (1996) Arteriosclerosis, Thrombosis, & Vascular Biol. 16: 328-338. In theory, systematic replacement of residues in the nonpolar face of 18A with Phe can produce 6 peptides. Peptides with an additional 2, 3, and 4 Phe residues would have theoretical lipid affinity (λ) values of 13, 14, and 15 units, respectively. However, if the additional Phe residues increase from 4 to 5 (to 19 λ units), the λ value jumps by four units. Increasing to 6 or 7 Phe residues produces less significant increases (20 and 21 λ units, respectively).

A number of these class A peptides were prepared, including peptides designated as 4F, D4F, 5F, and D5F, among others. Various class A peptides inhibited lesion development in atherosclerosis-susceptible mice and rabbits. Furthermore, the peptides demonstrated varying but significant degrees of efficacy in alleviating one or more symptoms of various conditions described herein. A number of these peptides are shown in Table 2.

Table 2: Class A peptides.

*Linkers are underlined; NMA is N-methylphenylcarbamate

In some aspects, the peptides include 4F (a variant of D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ ID NO: 16) in Table 2, also referred to as L-4F, in which all residues are L-amino acids) or D-4F, in which one or more residues are D-amino acids. In any of the peptides described herein, the C-terminus and/or N-terminus and/or internal residues can be blocked with one or more blocking groups described herein.

Although the various peptides of Table 2 are illustrated with an acetyl group or an N-methylphenylene lactamyl protecting the amino terminal and an amide protecting the carboxyl terminal, any of these protecting groups can be eliminated and/or replaced by another protecting group group as described herein. The peptides can comprise one or more D-amino acids as described herein. In some aspects, each amino acid (e.g., each enantiomeric amino acid) of the peptides of Table 2 is a D-amino acid.

It should also be noted that Table 2 is not exhaustive. Using the teachings provided herein, other suitable class A amphipathic helical peptides can be routinely generated (e.g., by conservative or semi-conservative substitutions (e.g., replacing E with D), extensions, deletions, etc.). Thus, for example, one embodiment utilizes truncations of any one or more of the peptides set forth herein (e.g., peptides defined as 2F, 3F, 3F ¹⁴ , 4F, 5F, 6F, or 7F in Table 2). Thus, for example, AFYDKVAEKLKEAF (amino acids 5 to 18 of SEQ ID NO: 5) illustrates a 14-amino acid peptide comprising one or more D amino acids from the C-terminus of 18A, while others illustrate other truncations.

Longer peptides are also suitable. Such longer peptides can fully form Class A amphipathic helices, or Class A amphipathic helices (helices) can form one or more domains of a peptide. In addition, the present invention encompasses polymeric forms (e.g., concatemers) of peptides. Thus, for example, the peptides shown herein can be (directly or via a linker (e.g., a carbon linker, or one or more amino acids) coupled together with one or more intervening amino acids). Exemplary polymeric peptides include 18A-Pro-18A and the peptides in the following table (Table 2B), which in certain embodiments comprise one or more D amino acids, more preferably each amino acid as described herein D amino acids and/or one or both ends protected.

Table 2B: Multimeric peptides.

b. Class A amphipathic helical peptidomimetics of apoA-I having aromatic or aliphatic residues in the nonpolar face.

Modified class A amphipathic helical peptides are ^also disclosed. Certain preferred peptides incorporate one or more aromatic residues at the center of the nonpolar face (e.g., 3F ^Cπ ) (as present in 4F) or have one or more aliphatic residues at the center of the nonpolar face (e.g., 3F ^Iπ ), see, for example, Table 3. Without being bound by a particular theory, due to the presence of π electrons at the center of the nonpolar face, the central aromatic residue on the nonpolar face of the peptide 3F ^Cπ can allow water molecules to penetrate near the hydrophobic lipid alkyl chains of the peptide-lipid complex, thereby allowing the entry of reactive oxygen species (e.g., lipid hydroperoxides), thereby shielding them from the cell surface. Peptides with aliphatic residues at the center of the nonpolar face (e.g., 3F ^Iπ ) can function similarly but not as effectively as 3F ^Cπ .

In one aspect, the peptides can convert proinflammatory HDL to antiinflammatory HDL or make antiinflammatory HDL more antiinflammatory, and/or reduce the monocyte chemotactic activity induced by LDL produced by arterial wall cells to a level equal to or greater than that of D4F or other peptides shown in Table 2.

Table 3: Modified class A peptides.

c. Other class A and some class Y amphipathic helical peptides.

A class A amphipathic helical peptide having the same amino acid composition as one or more of the above-mentioned class A amphipathic helical peptides. Thus, for example, in certain embodiments, the present invention encompasses a peptide having the same amino acid composition as 4F. Thus, in certain embodiments, the present invention includes an active agent comprising a peptide consisting of 18 amino acids, wherein the 18 amino acids consist of 3 alanines (A), 2 aspartates (D), 2 glutamics (E), 4 phenylalanines (F), 4 lysines (K), 1 valine (V), 1 tryptophan (W), and 1 tyrosine (Y); and wherein the peptide forms a class A amphipathic helix; and protects phospholipids from oxidation by oxidants. In various embodiments, the peptide comprises at least one "D" amino acid residue; and in certain embodiments, the peptide comprises all "D" amino acid residues. A variety of such peptides are shown in Table 4. Also contemplated are reverse (retro-), inverted, retro-inverted, and cyclically permuted forms of these peptides. Table 4 provides the sequence and identifier designation of a representative 18 amino acid long class A amphipathic helical peptide having an amino acid composition comprising 3 alanines (A), 2 aspartates (D), 2 glutamates (E), 4 phenylalanines (F), 4 lysines (K), 1 valine (V), 1 tryptophan (W), and 1 tyrosine (Y).

Table 4: 18 amino acid long A-type amphipathic helical peptides.

Biologically active and useful peptides can be readily identified. Thus, for example, the following peptides have been accurately identified as active: 3F1; 3F2; 4F, its reverse (inverse) form and its retro-inverse form. The lipid-associating peptide may comprise a peptide that is 18 amino acids in length and forms a class A amphipathic helix, wherein the peptide has an amino acid composition of 2 aspartic acids, 2 glutamic acids, 4 lysines, 1 tryptophan, 1 tyrosine, no more than 1 leucine, no more than 1 valine, no less than 1 and no more than 3 alanines, and has 3 to 6 amino acids from the following group: phenylalanine, α-naphthylamine, β-naphthylamine, histidine, and the polar face in the helical wheel representation of the class A amphipathic helix contains 9 or 10 amino acids, including 4 amino acids that are positively charged at neutral pH, two positively charged residues are located at the interface between the polar and non-polar faces, two of the 4 positively charged residues on the polar face are contiguous and on the non-polar face two of the amino acid residues from the following group: phenylalanine, α-naphthylamine, β-naphthylamine, histidine are also contiguous, and if 4 or more amino acids from this group are present on the non-polar face, then at least 2 non-contiguous residues from this group are also present. In some cases, all acidic amino acids are glutamic acid, rather than having two aspartic acids and two glutamic acids.In some aspects, the lipid-associating peptide can be 18A, wherein each acidic amino acid of 18A is a Glu residue.

Certain class Y and class A amphipathic helical peptides are disclosed. Class Y amphipathic helical peptides are known to those skilled in the art (see, for example, Segrest et al. (1992), J. Lipid Res. 33: 141-166; Oram and Heinecke (2005) Physiol Rev. 85: 1343-1372). These peptides include, but are not limited to, 18 amino acid peptides that form class A amphipathic helices or class Y amphipathic helices described by Formula I:

D X X K Y X X D K X Y D K X K D Y

wherein D is independently Asp or Glu; K is independently Lys or Arg; X is independently Leu, and is not Leu, Val, Ile, Trp, Phe, Tyr, β-Nal, or α-Nal, and all X residues are on the nonpolar face (e.g., when viewed in a helical wheel diagram), except for those on the polar face that may be between two K residues; Y is independently Ala, His, Ser, Gln, Asn, or Thr on the nonpolar face (e.g., when viewed in a helical wheel diagram), and Y is independently one Ala on the polar face, one His on the polar face, one Ser, one Gln, one Asn, or one Thr (e.g., when viewed in a helical wheel diagram), wherein no more than two Ks are contiguous (e.g., when viewed in a helical wheel diagram); and wherein no more than three Ds are contiguous (e.g., when viewed in a helical wheel diagram), and the fourth D is separated from the other Ds by Y. Representative peptides of this type include those with histidine and/or α- and/or β-napthalanine, which are shown in Table 5. Also contemplated are reverse (retro-), inverted, retro-inverted, and cyclically permuted forms of these peptides.

Table 5: Class Y amphipathic helical peptides.

Examples of class A 4F and Rev 4F analogs with β-Nph. Similarly, α-Nph analogs can be designed. Similar to the above analogs, His can be incorporated into Nph analogs. D>E analogs, E>D analogs, and D-E switch analogs are additional possibilities similar to the above analogs.

As described above for 4Nph, a minimum of 7 additional analogs for each analog are given below.

For each analog described below, a minimum of 7 additional analogs are possible by switching D-E, D>E, and E>D and single D or E analogs as described above.

For the following analogs, other analogs may exist by incorporating His or α-Nph and β-Nph

For each of the analogs below, using the examples above, additional H and Nph analogs are possible. For each analog, 7 analogs can be generated with the changes described in the examples given above.

It should also be noted that any peptide described herein may comprise non-natural amino acids in addition to or in place of the corresponding natural amino acids identified herein. Such modifications include, but are not limited to, acetylation, amidation, formylation, methylation, sulfation, and the like. Exemplary non-natural amino acids include, but are not limited to, ornithine, norleucine, norvaline, N-methylvaline, 6-N-methyllysine, N-methylisoleucine, N-methylglycine, sarcosine, inosine, iso-isoleucine, isodesmolysine, 4-hydroxyproline, 3-hydroxyproline, iso-hydroxylysine, hydoxylisine, N-ethylasparagine, N-ethylglycine, 2,3-diaminopropionic acid, 2,2'-diaminopropionic acid, desmosine, 2,4-diaminobutyric acid, 2-aminopimelic acid, 3-aminoisobutyric acid, 2-aminoisobutyric acid, 2-aminoheptanoic acid, 6-aminohexanoic acid, 4-aminobutyric acid, 2-aminobutyric acid, β-alanine, 3-aminoadipic acid, 2-aminoadipic acid, etc. In certain embodiments, one or more "natural" amino acids of the peptides described herein can be substituted with the corresponding non-natural amino acid (e.g., as described above).

In certain embodiments, the present invention specifically contemplates the use of modified lysines. Such modifications include, but are not limited to, biotinylation of ε-lysine and/or methylation of ε-lysine. Illustrative peptides comprising ε-methylated lysine include, but are not limited to, Ac-DWFK( _eCH3 ) _2- AFYDK( _eCH3 ) _2- VAEK( _eCH3 ) _-2- FK( _eCH3 ) _2- EAF-NH( _CH3 ) ₂ (SEQ ID NO: ₅₇₃ ) _and Ac-DWFK( _eCH3 ) _2AFYDK (eCH3)2VAEK( _eCH3 ) _2FK ( _eCH3 ) _2EAF -NH( _CH3 ) (SEQ ID NO:574). Other modified amino acids include, but are not limited to, ornithine analogs and homoaminoalanine analogs ((CH ₂ ) ₄ --NH ₂ in place of Lys, which may be (CH ₂ ) ₂ --NH ₂ in place of Haa and (CH ₂ ) ₃ --NH ₂ in place of Orn], etc. Note that these modifications are illustrative and not intended to be limiting. Illustrative 4F analogs with modified amino acids are shown in Table 6.

Table 6: Exemplary 4F analogs comprising modified amino acids.

εN-dimethyl-Lys derivative of 4F (εN-Dime)

εN-diethyl-Lys derivative of 4F (εN-Diet)

εN-monomethyl-Lys derivative of 4F (εN–Me)

εN-ethyl Lys derivative of 4F (εN–Et)

Homologous Lys analogs of 4F(hK)(--CH ₂ ) ₅ -NH ₂

4. Dual-domain peptides

Also disclosed are dual-domain peptides that can be synthetic Apo E mimetic peptides composed of a combination of the disclosed receptor binding domain of apolipoprotein E and the disclosed lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide.

Also disclosed are synthetic Apo E mimetic peptides comprised of a combination of a disclosed apolipoprotein B receptor binding domain and a disclosed lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide. Non-limiting examples of the disclosed synthetic Apo E mimetic peptides are provided in Table 7. The disclosed synthetic Apo E mimetic peptides can also be N-terminally protected using acetyl and amino groups. Table 7 provides non-limiting representative examples of disclosed synthetic Apo E mimetic peptides comprising dual domains.

Table 7: Two-domain peptides.

i. Domain-Switch Peptides

Also disclosed are synthetic Apo E mimetics comprised of a combination of a disclosed receptor binding domain of apolipoprotein E and a disclosed lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a domain-swapped orientation. Also disclosed are synthetic Apo E mimetics comprised of a combination of a disclosed receptor binding domain of apolipoprotein B and a disclosed lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a domain-swapped orientation. These peptides may be referred to as "domain-swapped," "swapped domains," or "swapped" peptides. For example, disclosed are synthetic Apo E mimetics comprised of a combination of a disclosed receptor binding domain of apolipoprotein E and a disclosed lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a domain-swapped orientation as described above and in Table 7.

Specifically, the lipid-associating peptide is covalently linked to the receptor binding domain of apolipoprotein E such that the lipid-associating peptide is located at the N-terminus of the synthetic apolipoprotein E mimetic peptide. Table 8 provides non-limiting examples of disclosed synthetic Apo E mimetics comprising a combination of a disclosed receptor binding domain of apolipoprotein E and a disclosed lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a domain-switch orientation.

Table 8: Domain-swap peptides.

The disclosed domain-swapped synthetic Apo E mimetics can also be N-terminally protected using acetyl and amino groups.

ii. Peptides with reverse orientation

Also disclosed are synthetic Apo E mimetic peptides consisting of a combination of a disclosed receptor binding domain of apolipoprotein E and a disclosed lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a reversed orientation. For example, disclosed are synthetic Apo E mimetic peptides consisting of a combination of a disclosed receptor binding domain of apolipoprotein E and a disclosed lipid-associating peptide, wherein the sequence of the receptor binding domain or the sequence of the lipid-associating peptide, or both, are in a reversed orientation. Also disclosed are synthetic Apo E mimetic peptides consisting of a combination of a disclosed receptor binding domain of apolipoprotein B and a disclosed lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a reversed orientation. Table 9 provides non-limiting examples of disclosed synthetic Apo E mimetic peptides comprising a combination of a disclosed receptor binding domain of apolipoprotein E and a disclosed lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a reversed orientation.

Table 9: Reverse orientation peptides.

iii. Scrambled peptides

Also disclosed are synthetic Apo E mimetic peptides consisting of: a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide, and wherein the receptor binding domain of apolipoprotein E is scrambled. For example, disclosed are synthetic Apo E mimetic peptides consisting of: a receptor binding domain of apolipoprotein E comprising the amino acid sequence of D-W-L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F (SEQ ID NO: 69); and a lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide. Also disclosed are synthetic Apo E mimetic peptides consisting of: a receptor binding domain of apolipoprotein B and a lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide, and wherein the receptor binding domain of apolipoprotein B is scrambled.

Also disclosed are synthetic Apo E mimetic peptides consisting of: a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide, and wherein the lipid-associating peptide is scrambled. For example, disclosed herein are synthetic Apo E mimetic peptides comprising: a lipid binding domain of apolipoprotein E comprising the amino acid sequence of E-W-L-K-A-F-V-Y-E-K-V-F-K-L-K-E-F-F (SEQ ID NO: 70) and a receptor binding domain peptide, wherein the lipid binding domain is covalently linked to the receptor binding domain peptide.

Also disclosed are synthetic Apo E mimetics consisting of a receptor binding domain of apolipoprotein E and a lipid-associating peptide of apolipoprotein E, wherein both the receptor binding domain and the lipid-associating peptide are scrambled. Table 10 provides non-limiting examples of disclosed scrambled synthetic Apo E mimetics comprising a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein the receptor binding domain is covalently linked to the lipid-associating peptide, wherein the receptor binding domain of apolipoprotein E is scrambled.

Table 10: Scrambled domain peptides.

The disclosed scrambled synthetic Apo E mimetics can also be protected at the N- and C-termini using acetyl and amide groups. The disclosed scrambled synthetic Apo E mimetics can also be in the reverse orientation as described above.

iv.Key

Any suitable linker can be used according to the present invention. The peptide bond can be selected from: --CH ₂ NH--, --CH ₂ S--, --CH ₂ --CH ₂ --, --CH═CH-- (cis and trans), --COCH ₂ --, --CH(OH)CH ₂ --, --CH ₂ SO--, etc., by methods known in the art and further described in the following references: Spatola (1983) p. 267, Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, B. Weinstein, ed., Marcel Dekker, New York; Spatola (1983) Vega Data 1 (3) Peptide Backbone Modifications. (general review); Morley (1980) Trends Pharm Sci pp. 463-468 (general review); Hudson et al. (1979) Int J Pept Prot Res 14:177-185 (--CH ₂ NH--, CH ₂ CH ₂ --); Spatola et al. (1986) Life Sci 38:1243-1249 (--CH ₂ --S); Hann, (1982) J Chem Soc Perkin Trans 1307-314 (--CH--CH--, cis and trans); Almquist et al. (1980) J Med. Chem. 23:1392-1398 (--COCH ₂ --); Jennings-White et al. (1982) Tetrahedron Lett. 23:2533 (--COCH ₂ --); Szelke et al., European Appln. EP 45665 (1982) CA:97:39405 (1982) (--CH(OH)CH2-); Holladay et al. (1983) Tetrahedron Lett 24:4401-4404 (--C(OH) _CH2- ); and Hruby (1982) Life Sci., 31:189-199 (--CH2 _- S--)).

A particularly preferred non-peptide bond is --CH ₂ NH-- Such peptide mimetics can have significant advantages over polypeptide embodiments, including, for example: more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), reduced antigenicity, etc.

In one aspect, the linker is a cleavable linker. Cleavable linkers include protease-cleavable peptide linkers, nuclease-sensitive nucleic acid linkers, lipase-sensitive lipid linkers, glycosidase-sensitive carbohydrate linkers, pH-sensitive linkers, hypoxia-sensitive linkers, photocleavable linkers, heat-labile linkers, enzyme-cleavable linkers (e.g., esterase-cleavable linkers), ultrasound-sensitive linkers, x-ray-cleavable linkers, and the like, to name a few.

5. Variants

The receptor binding domain or lipid-binding peptide can be modified or altered as described above. For example, the receptor binding domain or lipid-associated peptide can be mutated, scrambled, and/or oriented in the opposite direction. Any other modification or alteration disclosed herein for a dual-domain polypeptide can also be applied to a single-domain peptide.

Many other variants or derivatives of the peptides disclosed herein are also encompassed. For example, scrambled peptides can also be in the reverse orientation, or can be in the switched orientation. In addition, reverse-oriented peptides can be in the switched orientation. All other combinations of the disclosed peptides are also encompassed. Non-limiting examples of peptides have been described herein (e.g., see Tables 1 to 5). As used herein, the terms "analog" and "variant" and "derivative" are used interchangeably. Variants and derivatives are well known to those skilled in the art and can involve amino acid sequence modifications. Such amino acid sequence modifications generally fall into one or more of three categories: substitutions; insertions; or deletion variants. Insertions include amino and/or carboxyl terminal fusions and intrasequence insertions of single or multiple amino acid residues. Insertions are generally smaller insertions than amino or carboxyl terminal fusions, for example, about 1 to 4 residues. These variants are generally prepared by site-specific mutagenesis of nucleotides in protein-encoding DNA, thereby generating DNA encoding the variants, which is then expressed in recombinant cell culture. Techniques for generating substitution mutations at predetermined sites in DNA with a known sequence are well known, such as M13 primer mutagenesis and PCR mutagenesis. Amino acid replacements are typically single residues, but can occur simultaneously at multiple different positions. Replacements, deletions, insertions, or any combination thereof can be combined to yield a final derivative or analog. Substitution variants are variants in which at least one residue has been removed and a different residue inserted in its place. Such replacements are typically performed according to Tables 11 and 12 and are referred to as conservative replacements.

Substantial changes in functional or immunological identity are achieved by selecting substitutions that are less conservative than those in Table 11, i.e., by selecting residues that differ more significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. The substitutions generally expected to produce the greatest changes in protein properties are those in which: (a) a hydrophilic residue, e.g., seryl or threonyl, is replaced by (or is replaced by) a hydrophobic residue, e.g., leucyl, isoleucyl, phenylalanyl, valyl, or alanyl; tryptophan, tyrosyl (b) cysteine, or proline is replaced by (or is replaced by) any other residue; (c) a residue having a positively charged side chain, e.g., lysyl, arginyl, or histidyl, is replaced by (or is replaced by) a negatively charged residue, e.g., glutamyl or aspartyl; or (d) a residue having a bulky side chain, e.g., phenylalanine, in this case, is replaced by (or is replaced by) a residue having no side chain, e.g., glycine, in this case, or (e) by increasing the number of sulfation sites and/or glycosylation sites.

Table 11: Amino Acid Substitutions

Ala Ser Arg Gly; Gln; Lys Asn Gln; His Asp Glu Cys Ser Gln Asn; Lys Glu Asp Gly Ala His Asn; Gln Ile Leu; Val Leu Ile; Val Lys Arg; Gln Met Leu; Ile

Phe Met; Leu; Tyr Ser Thr Thr Ser Trp Tyr Tyr Trp; Phe Val Ile; Leu

Table 12: Amino Acid Abbreviations

Alanine Ala(A) Isoleucine AIle Arginine Arg(R) Asparagine Asn(N) Aspartic acid Asp(D) Cysteine Cys(C) glutamate Glu(E) Glutamine Gln(Q) Glycine Gly(G) Histidine His(H) Isoleucine Ile(I) Leucine Leu(L) Lysine Lys(K) Phenylalanine Phe(F) Pralines Pro(P) Pyroglutamate PGlu(U) Serine Ser(S) Threonine Thr(T) Tyrosine Tyr(Y) Tryptophan Trp(W) Valine Val(V)

It will be appreciated that one approach to defining variants and derivatives of the proteins disclosed herein is to define them based on homology/identity to specific known sequences. Specifically disclosed are variants of the synthetic Apo E mimetics and other proteins or peptides disclosed herein that have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% homology to the synthetic ApoE mimetics specifically described herein. Those skilled in the art readily understand how to determine the homology of two proteins.

Polypeptides can be modified by natural processes (e.g., post-translational processing) or by chemical modification techniques well known in the art. Modification can occur at any position in the polypeptide, including the peptide backbone, amino acid side chains, and amino or carboxyl termini. The same type of modification can be present at several sites in a given polypeptide to the same or varying degrees. In addition, a given polypeptide can have many types of modifications. Modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent cross-linking or cyclization, the covalent attachment of flavin, the covalent attachment of heme moieties, the covalent attachment of nucleotides or nucleotide derivatives, the covalent attachment of lipids or lipid derivatives, the covalent attachment of phosphatidylinositols, disulfide bond formation, demethylation, the formation of cysteine or pyroglutamic acid, formylation, γ-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, PEGylation, proteolytic processing, phosphorylation, prenylation, racemization, selenization, sulfation, and transfer RNA-mediated amino acid addition to proteins such as arginylation. (See Proteins-Structure and Molecular Properties 2nd Edition, T.E. Creighton, W.H. Freeman and Company, New York (1993); Posttranslational Covalent Modification of Proteins, B.C. Johnson, Ed., Academic Press, New York, pp. 1-12 (1983)).

Variants can also include peptide mimetics. As used herein, "peptide mimetics" refers to mimetics of protein function that include some changes in normal peptide chemistry. Peptide mimetics are typically short sequences of amino acids that mimic one or more functions of a specific protein in biological properties. Peptide analogs enhance some properties of the original peptide, such as improved stability, improved efficacy, enhanced delivery, increased half-life, and the like. Methods for preparing peptide mimetics based on known polypeptide sequences are described in, for example, U.S. Patent Nos. 5,631,280; 5,612,895; and 5,579,250. The use of peptide mimetics can involve the incorporation of non-amino acid residues having non-amide bonds at a given position. One embodiment of the present invention is a peptide mimetic, wherein the compound has a bond, a peptide backbone, or an amino acid component substituted with a suitable mimetic. Some non-limiting examples of unnatural amino acids that can be suitable amino acid mimetics include β-alanine, L-α-aminobutyric acid, L-γ-aminobutyric acid, L-α-aminoisobutyric acid, L-ε-aminocaproic acid, 7-aminoheptanoic acid, L-aspartic acid, L-glutamic acid, N-ε-Boc-N-α-CBZ-L-lysine, N-ε-Boc-N-α-Fmoc-L-lysine, L-methionine sulfone, L-norleucine, L-norvaline, N-α-Boc-N-δCBZ-L-ornithine, N-δ-Boc-N-α-CBZ-L-ornithine, Boc-p-nitro-L-phenylalanine, Boc-hydroxyproline, and Boc-L-thioproline.

6. Nucleic Acids

When various peptide sequences are discussed in this specification, it should be understood that nucleic acids encoding those polypeptide sequences are also disclosed. This includes all degenerate sequences related to a particular polypeptide sequence, i.e., all nucleic acids having a sequence encoding a particular polypeptide sequence, as well as all nucleic acids encoding variants and derivatives of the disclosed protein sequences, including degenerate nucleic acids. Therefore, although each specific nucleic acid sequence may not be set forth herein, it should be understood that each sequence is in fact disclosed and described herein by the disclosed polypeptide sequence.

7. Blocking/Protecting Groups and D Residues

The disclosed compositions may comprise an acetyl group followed by a protecting group. The protecting group may be, but is not limited to, a fatty acid. The fatty acid may be a saturated, unsaturated, or essential fatty acid. The fatty acid may include, but is not limited to, DHA, EPA, linoleic acid, or any other saturated amino acid, such as myristic acid.

While the various compositions described herein may be shown without protecting groups, in certain embodiments (e.g., particularly for oral administration), they may carry one, two, three, four, or more protecting groups. The protecting groups may be coupled to the C-terminus and/or N-terminus of the peptide and/or to one or more internal residues of the peptide (e.g., one or more R groups on the constituent amino acids may be blocked). Thus, for example, in certain embodiments, any of the peptides described herein may carry, for example, an acetyl group protecting the amino terminus and/or an amide group protecting the carboxyl terminus. An example of such a "doubly protected peptide" is Ac-LRKLRKRLLRDWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 1) with a blocking group, either or both of which may be removed and/or replaced by another protecting group as described herein. Without being bound by a particular theory, the present inventors have discovered that blocking the subject peptides of the present invention, particularly blocking the amino and/or carboxyl termini, can improve oral delivery and may also increase serum half-life.

Many protecting groups are suitable for this purpose. These groups include, but are not limited to, acetyl, amide, and alkyl groups, with acetyl and alkyl groups being particularly preferred for N-terminal protection and amide groups being preferred for carboxyl terminal protection. For example, protecting groups may include, but are not limited to, alkyl chains such as those found in fatty acids, acetonyl, formyl, and the like. Carboxyl protecting groups include amides, esters, and ether-forming protecting groups may also be used. For example, acetyl groups may be used to protect the amino terminus and amide groups may be used to protect the carboxyl terminus. These blocking groups enhance the helix-forming tendency of peptides. Additional blocking groups include alkyl groups of various lengths, for example, groups having the formula: CH ₃ (CH ₂ ) _n CO, where n is from about 1 to about 20, preferably from about 1 to about 16 or 18, more preferably from about 3 to about 13, and most preferably from about 3 to about 10.

In addition, protecting groups include, but are not limited to, alkyl chains such as those found in fatty acids, acetonyl, formyl, and the like. For example, carboxyl protecting groups can include amide, ester, and ether-forming protecting groups. These blocking groups can enhance the helical formation tendency of the peptide. Blocking groups can include alkyl groups of various lengths, such as those having the formula: CH ₃ (CH ₂ ) n CO, wherein n is from about 3 to about 20, preferably from about 3 to about 16, more preferably from about 3 to about 13, and most preferably from about 3 to about 10.

Other protecting groups include, but are not limited to, Fmoc, tert-butyloxycarbonyl (t-BOC), 9-fluorenylacetyl, 1-fluorenylcarboxyl, 9-fluorenylcarboxyl, 9-fluorenone-1-carboxyl, benzyloxycarbonyl, xanthene (Xan), trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), mesitylene-2-sulfonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), toluenesulfonyl (Tos), 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), 4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), benzyloxy (BzlO), benzyl (Bzl), benzoyl (Bz), 3-nitro-2-pyridylsulfenyl (Npys), 1-(4,4-dimentyl-2,6-dioxocyclohexylidene)ethyl (Dde), 2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl (2-Cl-Z), 2-bromobenzyloxy-carbonyl (2-Br-Z), benzyloxymethyl (Bom), cyclohexyloxy (cHxO), tert-butoxymethyl (Bum), tert-butoxy (tBuO), tert-butyl (tBu), acetyl (Ac), and trifluoroacetyl (TFA).

Protecting/blocking groups are well known to those skilled in the art, as are methods for coupling these groups to appropriate residues comprising the peptides of the present invention (see, for example, Greene et al., (1991) Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc. Somerset, NJ). For example, acetylation can be accomplished during synthesis when acetic anhydride is used on the peptide resin. Amide protection can be achieved by selecting an appropriate resin for synthesis.

The compositions disclosed herein may also include one or more D- (dextrorotatory rather than levorotatory) amino acids as described herein. For example, at least two enantiomeric amino acids, at least 4 enantiomeric amino acids, or at least 8 or 10 enantiomeric amino acids may be "D" amino acids. Furthermore, every other or even every amino acid (e.g., every enantiomeric amino acid) of the peptides described herein may be a D- amino acid.

Additionally, at least 50% of the enantiomeric amino acids may be in the "D" form, at least 80% of the enantiomeric amino acids may be in the "D" form, and at least 90% or even all of the enantiomeric amino acids may be in the "D" form.

FMOC-Aha can be added as the last amino acid to the growing chain using a normal amino acid chain extension procedure (using HOBt+DCC or HBTU as a condensing agent). After removal of the FMOC group using 20% piperidine in DMF, the NH2 can be acetylated using excess acetic anhydride under alkaline conditions, or acetic acid can be condensed using an amino acid condensing agent for peptide chain extension.

C. Pharmaceutical Compositions

Disclosed are pharmaceutical compositions comprising any of the synthetic ApoE mimetic peptides disclosed herein and a pharmaceutically acceptable carrier.

"Pharmaceutically acceptable" refers to a material or carrier that will be selected to minimize any degradation of the active ingredient and minimize any adverse side effects in the subject, as is known to those skilled in the art. Examples of carriers include dimyristoylphosphatidylcholine (DMPC), phosphate-buffered saline, or multivesicular liposomes. For example, PG:PC:cholesterol:peptide or PC:peptide can be used as carriers in the present invention. Other suitable pharmaceutically acceptable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) A.R. Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of a pharmaceutically acceptable salt is used in the formulation to make the formulation isotonic. Other examples of pharmaceutically acceptable carriers include, but are not limited to, saline, Ringer's solution, and dextrose solution. The pH of the solution can be from about 5 to about 8, or from about 7 to about 7.5. Other carriers include sustained-release formulations, such as semipermeable matrices of solid hydrophobic polymers containing the composition, the matrix being in the form of shaped articles such as membranes, stents (which are implanted in blood vessels during angioplasty), liposomes, or microparticles. It is obvious to those skilled in the art that certain carriers may be more preferable depending on, for example, the route of administration and the concentration of the composition being administered. These are most typically standard carriers for administering drugs to humans, including solutions such as sterile water, physiological saline, and buffered solutions at physiological pH.

The pharmaceutical composition may further include a carrier, a thickening agent, a diluent, a buffer, a preservative, etc., as long as the expected activity of the polypeptide, peptide, nucleic acid, or vector of the present invention is not affected. The pharmaceutical composition may further include one or more active ingredients (in addition to the composition of the present invention), such as an antimicrobial agent, an anti-inflammatory agent, an anesthetic, etc. The pharmaceutical composition may be administered in a variety of ways, depending on whether local or systemic treatment is desired and the area to be treated.

Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcohol/water solutions, emulsions or suspensions, including physiological saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, glucose and sodium chloride, lactated Ringer's solution or fixed oils. Intravenous vehicles include fluids and nutritional supplements, electrolyte supplements (e.g., based on Ringer's dextrose) etc. Preservatives and other additives, such as antimicrobials, antioxidants, chelating agents and inert gases etc., may also be present.

Formulations for topical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

The composition for oral administration is included in powder or granule, water or non-aqueous medium suspension or solution, capsule, sachet or tablet.Thickening agent, correctives, diluent, emulsifying agent, dispersing aid or adhesive may be desired.Some compositions can potentially be used as pharmaceutically acceptable acid or base addition salt, described pharmaceutically acceptable acid or base addition salt is by forming with inorganic acid and organic acid reaction, described inorganic acid is hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid and phosphoric acid for example, described organic acid is formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid and fumaric acid for example, or described pharmaceutically acceptable acid or base addition salt is by forming with inorganic base for example sodium hydroxide, ammonium hydroxide, potassium hydroxide and organic base for example single, two, three alkyl and arylamine and substituted ethanolamine reaction.

D. Methods of affecting LDL and VLDL

Disclosed are methods comprising administering any of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both. The ApoE mimetic peptide can be a synthetic ApoE mimetic peptide comprising an ApoE receptor binding domain and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha. For example, the synthetic ApoE mimetic peptide can be Ac-Aha-hE18A- _NH2 or Ac-Aha-[R]hE18A- _NH2 .

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein the synthetic ApoE mimetic peptide is administered as a composition comprising the synthetic ApoE mimetic peptide and a pharmaceutically acceptable carrier.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein LDL binding to cells of the subject is enhanced.

Disclosed are methods comprising administering any of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein degradation of LDL by cells of the subject is increased.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein the subject's LDL cholesterol is lowered.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein binding of VLDL to cells of the subject is enhanced.

Disclosed are methods comprising administering any of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein degradation of VLDL by cells of the subject is increased.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein VLDL cholesterol in the subject is lowered.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein the total plasma concentration of cholesterol in the subject is reduced.

Disclosed are methods comprising administering to a subject any of the disclosed synthetic ApoE mimetic peptides, thereby affecting plasma LDL, plasma VLDL, or both, wherein the synthetic ApoE mimetic peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the ApoE mimetic peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range therebetween.

Disclosed are methods comprising administering any one of the disclosed synthetic ApoE mimetic peptides to a subject, thereby affecting plasma LDL, plasma VLDL, or both, wherein the subject has coronary artery disease, rheumatoid arthritis, systemic lupus erythematosus, diabetes, Alzheimer's disease, PAD, cerebrovascular disease, diabetic-derived cardiovascular disease, macular degeneration and/or congestive heart failure, or a bacterial infection.

E. Methods for lowering plasma cholesterol

Disclosed are methods for lowering plasma cholesterol, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides. The ApoE mimetic peptide can be a synthetic ApoE mimetic peptide comprising an ApoE receptor binding domain and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha. For example, the synthetic ApoE mimetic peptide can be Ac-Aha-hE18A- _NH2 or Ac-Aha-[R]hE18A- _NH2 .

Disclosed are methods for lowering plasma cholesterol, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein the synthetic ApoE mimetic peptide is administered as a composition comprising the synthetic ApoE mimetic peptide and a pharmaceutically acceptable carrier.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein LDL binding to cells of the subject is enhanced.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any of the disclosed synthetic ApoE mimetic peptides, wherein degradation of LDL by cells of the subject is increased.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein LDL cholesterol in the subject is lowered.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein VLDL binding to cells of the subject is enhanced.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any of the disclosed synthetic ApoE mimetic peptides, wherein degradation of VLDL by cells of the subject is increased.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein VLDL cholesterol in the subject is lowered.

Disclosed are methods of lowering plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein the total plasma concentration of cholesterol in the subject is reduced.

Disclosed are methods for lowering plasma cholesterol, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein the synthetic ApoE mimetic peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the ApoE mimetic peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range therebetween.

Disclosed are methods for lowering plasma cholesterol, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein the subject suffers from coronary artery disease, rheumatoid arthritis, systemic lupus erythematosus, diabetes, Alzheimer's disease, PAD, cerebrovascular disease, diabetic-derived cardiovascular disease, macular degeneration, and/or congestive heart failure.

F. Methods for treating atherosclerosis

Disclosed are methods for treating atherosclerosis, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides. The ApoE mimetic peptide can be a synthetic ApoE mimetic peptide comprising an ApoE receptor binding domain and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha. For example, the synthetic ApoE mimetic peptide can be Ac-Aha-hE18A- _NH2 or Ac-Aha-[R]hE18A- _NH2 .

Disclosed are methods for treating atherosclerosis, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein the synthetic ApoE mimetic peptide is administered as a composition comprising the synthetic ApoE mimetic peptide and a pharmaceutically acceptable carrier.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein binding of LDL to cells of the subject is enhanced.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any of the disclosed synthetic ApoE mimetic peptides, wherein degradation of LDL by cells of the subject is increased.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein LDL cholesterol in the subject is lowered.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein VLDL binding to cells of the subject is enhanced.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein degradation of VLDL by cells of the subject is increased.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein VLDL cholesterol in the subject is lowered.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein the total plasma concentration of cholesterol in the subject is reduced.

Disclosed are methods for treating atherosclerosis, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein the synthetic ApoE mimetic peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the ApoE mimetic peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range therebetween.

Disclosed are methods for treating atherosclerosis, comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein the subject suffers from coronary artery disease, rheumatoid arthritis, systemic lupus erythematosus, diabetes, Alzheimer's disease, PAD, cerebrovascular disease, diabetic-derived cardiovascular disease, macular degeneration, and/or congestive heart failure.

G. Methods of Treating Lipid Disorders

Disclosed are methods for treating a subject suffering from a lipid disorder, comprising administering to the subject an effective amount of any disclosed ApoE mimetic peptide or a composition thereof. The ApoE mimetic peptide can be a synthetic ApoE mimetic peptide comprising an ApoE receptor binding domain and a lipid-associating peptide, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha. For example, the synthetic ApoE mimetic peptide can be Ac-Aha-hE18A- _NH2 or Ac-Aha-[R]hE18A- _NH2 .

Disclosed are methods for treating a subject suffering from a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed ApoE mimetic peptides or a composition thereof, wherein the synthetic ApoE mimetic peptide is administered as a composition comprising the synthetic ApoE mimetic peptide and a pharmaceutically acceptable carrier.

Disclosed are methods of treating a subject having a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed ApoE mimetic peptides or compositions thereof, wherein LDL binding to cells of the subject is enhanced.

Disclosed are methods of treating a subject having a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed ApoE mimetic peptides or compositions thereof, wherein degradation of LDL by cells of the subject is increased.

Disclosed are methods of treating a subject having a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed ApoE mimetic peptides or compositions thereof, wherein the subject's LDL cholesterol is lowered.

Disclosed are methods of treating a subject having a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed ApoE mimetic peptides or compositions thereof, wherein VLDL binding to cells of the subject is enhanced.

Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE mimetic peptides, wherein degradation of VLDL by cells of the subject is increased.

Disclosed are methods of treating a subject having a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed ApoE mimetic peptides or compositions thereof, wherein the subject's VLDL cholesterol is reduced.

Disclosed are methods of treating a subject having a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed ApoE mimetic peptides or compositions thereof, wherein the total plasma concentration of cholesterol in the subject is reduced.

Disclosed are methods for treating a subject suffering from a lipid disorder, the methods comprising administering to the subject an effective amount of any one of the disclosed ApoE mimetic peptides or compositions thereof, wherein the synthetic ApoE mimetic peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the ApoE mimetic peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg or any range therebetween.

Disclosed are methods for treating a subject suffering from a lipid disorder, the method comprising administering to the subject an effective amount of any one of the disclosed ApoE mimetic peptides or compositions thereof, wherein the lipid disorder can be coronary artery disease, rheumatoid arthritis, systemic lupus erythematosus, diabetes, Alzheimer's disease, PAD, cerebrovascular disease, diabetic-derived cardiovascular disease, macular degeneration and/or congestive heart failure.

H. Monoclonal antibodies

Disclosed are monoclonal antibodies that specifically bind to any one of the synthetic ApoE mimetic peptides described herein.

I. Dosage Regimen

Disclosed is a dosing regimen comprising at least one treatment cycle of an effective amount of any disclosed Apo E mimetic peptide, followed by a rest period. The rest period of the dosing regimen is a period of time during which the Apo E mimetic peptide is not administered. The Apo E mimetic peptide can be, but is not limited to, Ac-Aha-hE18A- _NH2 or Ac-Aha-[R]hE18A- _NH2 .

Disclosed is a dosing regimen comprising at least one treatment cycle followed by a rest period, wherein the treatment cycle comprises administering an effective amount of an Apo E mimetic peptide to allow for a sustained therapeutic effect after the Apo E mimetic is withdrawn, wherein the Apo E mimetic peptide is not administered during the rest period. Not only does the effective amount of the Apo E mimetic peptide result in a sustained therapeutic effect, but it is also an amount sufficient to induce an acute beneficial effect. Thus, the effects of the Apo E mimetic peptide can be measured and observed during the treatment cycle, at the end of the treatment cycle, and during the rest period. A sustained therapeutic effect is a therapeutic effect that is observed even after the acute cholesterol-lowering effect has worn off.

Disclosed herein is a dosing regimen comprising at least one treatment cycle followed by a rest period, wherein the treatment cycle comprises administration of an effective amount of an Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic, wherein the Apo E mimetic peptide is not administered during the rest period, wherein the treatment cycle comprises administration of an effective amount of an Apo E mimetic peptide once a week for three months, or wherein the treatment cycle comprises administration of an effective amount of an Apo E mimetic peptide once every two weeks for up to 12 weeks.

Disclosed is a dosing regimen comprising at least one treatment cycle followed by a rest period, wherein the treatment cycle comprises administration of an effective amount of an Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic, wherein the Apo E mimetic peptide is not administered during the rest period, and wherein the dosing regimen further comprises a second treatment cycle after the rest period.

In one aspect, the dosing regimen can comprise at least one treatment cycle followed by a rest period, wherein the treatment cycle comprises administration of an effective amount of a synthetic ApoE mimetic peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein no Apo E mimetic peptide is administered during the rest period, wherein the synthetic ApoE mimetic peptide comprises Ac-Aha.

The dosing regimen can also include a second treatment cycle after the rest period. The second rest period can occur after the second treatment cycle. In some cases, a third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth treatment cycle can be administered, wherein each treatment cycle is followed by a rest period. In one aspect, the dosing regimen includes an unlimited number of treatment cycles, each followed by a rest period. For example, a dosing regimen can be prescribed to a subject that includes continuous treatment cycles for the duration of their life, followed by a rest period.

In one aspect, a second dosage regimen can be prescribed based on the recurrence of atherosclerotic lesions or other atherosclerotic factors. The second dosage regimen can be administered 1, 2, 3, 4, 5 years or more than 5 years after the initial dosage regimen is administered. The second dosage regimen can be the same as or different from the initial dosage regimen. For example, the initial dosage regimen can be a three-month treatment cycle followed by a one-year rest period. After the one-year rest period, the subject can be tested, and if atherosclerotic lesions accumulate again, a second dosage regimen consisting of another three-month treatment cycle, followed by a rest period, or a six-month treatment cycle, followed by a rest period can be administered. The dosage of the Apo E mimetic can vary between the initial dosage regimen and any other prescribed dosage regimen.

In some cases, a second administration can be administered based on vasoreactivity, the presence of isolated systolic hypertension, or exercise-induced angina measured in the subject after the first treatment. In some cases, the second dose can be administered based on the amount of plasma cholesterol. The frequency of administration can be varied based on the need to lower plasma cholesterol to minimize or eliminate the risk of any of the conditions disclosed herein.

1. Treatment cycle

The treatment cycle can include administering different doses of the ApoE mimetic peptide and administering it at different time points. The ApoE mimetic peptide can be administered for different amounts of time up to 6 months. In some cases, administration can occur for up to one, two, three, four, five, or six months. For example, the ApoE mimetic peptide can be administered once a week for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 weeks.

The length of time of each treatment cycle can vary according to the amount of ApoE mimetic peptide administered per dose. The treatment cycle can include administering the ApoE mimetic peptide once, twice, or three times a week. In some aspects, the ApoE mimetic peptide can be administered every day. In some aspects, the ApoE mimetic peptide can be administered once every two weeks or even once a month. In some cases, the Apo E mimetic can be administered every two weeks for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 weeks. For example, the treatment cycle can include administering the ApoE mimetic peptide once a week for four weeks or once every two weeks for up to six months. Therefore, each treatment cycle includes a determined time length for administration and a determined dosing regimen during that time frame.

In one aspect, more than one ApoE mimetic peptide can be administered during a treatment cycle. More than one ApoE mimetic peptide can be formulated together or as separate compositions. In some cases, one or more Apo E mimetics are administered in combination with one or more other therapeutic agents, such as cholesterol-lowering drugs.

2. Rest period

The disclosed dosing regimen can include at least one treatment cycle followed by a rest period. The rest period is a period of time during which the ApoE mimetic peptide is not administered, and the length of the period can vary. The length of the rest period depends on how long the sustained therapeutic effect of the Apo E mimetic administered during the treatment cycle lasts. In some cases, the rest period can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some cases, the rest period can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. For example, the rest period can be at least four weeks (one month).

A method of determining how long the rest period should last is to test the subject to determine the progress of the atherosclerotic load in the subject's artery. If the atherosclerotic load has progressed to the level that increases cardiovascular disease risk, then the second dosage regimen can be prescribed to the subject. If the atherosclerotic load is stable, then the rest period can be extended. The length of the reset period can also be based on VLDL reduction, LDL reduction, glucose reduction, inflammation alleviation, vascular reactivity, the existence of isolated systolic hypertension or the amount of exercise-induced angina or plasma cholesterol. The subject can be tested regularly. For example, the subject can be tested every 3, 6, 9, 12, 18, 24, 30 or 36 months.

In one aspect, the rest period can be reduced or extended depending on the dose of the ApoE mimetic peptide administered and the reduction in atherosclerosis achieved during the treatment cycle. For example, if the dose of the ApoE mimetic peptide is increased and the atherosclerotic burden is significantly reduced during the treatment cycle, the rest period can be extended. The length of the rest period can also vary based on the length of the treatment cycle. For example, if a subject receives a dose of an ApoE mimetic peptide once a week for three months, the rest period can be shorter than a subject who receives the same dose of an Apo E mimetic once a week for six months.

Although Apo E mimetics are not administered during the rest period, atherosclerosis therapeutic agents other than Apo E mimetics may be administered during the rest period. The atherosclerosis therapeutic agent other than Apo E mimetics may be a conventional lipid-lowering therapeutic agent, such as a statin, a bile acid sequestrant, or a fibrate, or a novel anti-atherosclerotic therapeutic agent such as a CETP inhibitor, a VLDL synthesis inhibitor, a PCSK9 inhibitor, and/or an arterial inflammation inhibitor. In other words, the atherosclerosis therapeutic agent other than Apo E mimetics may be a conventional LDL-lowering therapeutic agent or a HDL-raising therapeutic agent.

In some cases, the beneficial effects of the Apo E mimetic can persist in the subject even after the treatment cycle is complete. In one instance, the half-life of the Apo E mimetic is less than 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 days. In some cases, the Apo E mimetic is no longer detectable in the subject after the treatment cycle is complete. Thus, the long-term therapeutic effect is not due to residual Apo E mimetic.

3. Dosage

The administration or dosage of an ApoE mimetic peptide can vary depending on many factors, such as, but not limited to, the patient's age, condition, sex, and extent of disease, the route of administration, the length of the treatment cycle, or whether other drugs are included in the regimen, and can be determined by one skilled in the art.

The effective dose can be determined empirically, and making such a determination is within the skill of the art. The dosage range for administering the composition is a dosage range that is large enough to produce the desired effect for treating the disease. For example, the dosage can be an amount that is effective to provide a therapeutic effect and provides or allows for a sustained therapeutic effect even after the treatment (i.e., ApoE mimetic peptide) is withdrawn. The therapeutic effect can be, but is not limited to, a reduction in atherosclerotic lesions, a reduction in arterial hardness, a reduction in isolated systolic hypertension, an increase in vascular reactivity, or an improvement in cardiac function. The therapeutic effect can be measured by markers of arterial inflammation, such as, but not limited to, C-reactive protein. The therapeutic effect can be measured by atherosclerosis imaging techniques, including MRI, intravascular ultrasound, ultrafast imaging CT scan, B-mode ultrasound, virtual histology intravascular ultrasound, optical coherence tomography, or other known methods.

The dose should not be so large as to cause adverse side effects, such as undesirable cross-reactions, allergic reactions, etc. The dose can be adjusted by the individual physician in the event of any contraindications. The dose can vary and can be administered in one or more doses per day, for one or more days. Guidance on appropriate dosages for a given class of drug can be found in the literature.

Suitable dosages include, but are not limited to, amounts between 0.01 mg/kg and 20 mg/kg. For example, the methods disclosed herein comprise administering to a subject one or more disclosed ApoE mimetic peptides, wherein the ApoE mimetic peptide is administered in an amount from about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the ApoE mimetic peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg.

The ApoE mimetic peptide dose can be administered as a bolus or as an infusion over one or more hours.

J. Methods of Treatment Using Dosing Regimens

Provided are methods for treating acute coronary syndrome (ACS) or atherosclerosis, comprising administering an effective amount of any one of the disclosed Apo E mimetic peptides for at least one treatment cycle, followed by a rest period. For example, the Apo E mimetic peptide can be Ac-Aha-hE18A- _NH2 or Ac-Aha-[R]hE18A- _NH2 . Thus, the disclosed methods involve administering the Apo E mimetic peptide using one or more of the disclosed dosing regimens. Thus, any disclosed treatment cycle or rest period can be used in the disclosed methods. The methods disclosed herein can allow for a prolonged therapeutic effect even in the absence of a therapeutic agent. The disclosed methods can comprise administering an effective amount of an Apo E mimetic. The effective amount of an Apo E mimetic can be an amount that allows for a sustained therapeutic effect after the Apo E mimetic is withdrawn.

Disclosed herein are methods for treating ACS comprising administering an effective amount of any one of the disclosed Apo E mimetic peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein the treatment cycle is followed by a rest period, wherein the Apo-E mimetic peptide is not administered during the rest period.

Disclosed herein are methods for treating ACS comprising administering an effective amount of any one of the disclosed Apo E mimetic peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein the treatment cycle is followed by a rest period, wherein the Apo-E mimetic peptide is not administered during the rest period, and wherein the rest period is at least four weeks.

Disclosed herein are methods for treating ACS, comprising administering an effective amount of any of the disclosed Apo E mimetic peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein the treatment cycle is followed by a rest period, wherein the Apo-E mimetic peptide is not administered during the rest period, and further comprising a second treatment cycle after the rest period. The second treatment cycle can be administered after a four-week rest period or one year after the initial treatment cycle.

Disclosed herein is a method for treating ACS, comprising administering an effective amount of any of the disclosed Apo E mimetic peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after the Apo E mimetic peptide is withdrawn, wherein the treatment cycle is followed by a rest period, wherein the Apo-E mimetic peptide is not administered during the rest period, and wherein an ACS therapy other than the Apo E mimetic peptide is administered during the rest period. The ACS therapy other than the Apo E mimetic peptide can be a conventional LDL-lowering therapy or a HDL-raising therapy. Conventional LDL-lowering therapy can be, but is not limited to, a statin. HDL-raising therapy can be, but is not limited to, an Apo A1-raising drug, a CETP inhibitor, a phospholipase A2 inhibitor, Apo A1 Milano, or an Apo A1 mimetic.

Disclosed herein are methods for treating atherosclerosis comprising administering to a subject an effective amount of an Apo E mimetic for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic, wherein the Apo E mimetic consists of an Ac-Aha-hE18A- _NH2 or Ac-Aha-[R]hE18A- _NH2 peptide, and wherein the treatment cycle is followed by a rest period, wherein the Apo E mimetic is not administered during the rest period.

Disclosed herein are methods for treating ACS, comprising administering an effective amount of any one of the disclosed Apo E mimetic peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein the treatment cycle is followed by a rest period, wherein the Apo-E mimetic peptide is not administered during the rest period, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide once a week for three months.

Disclosed methods of treatment can occur at different times according to the subject. In particular, treatment can occur in subjects who are considered to have a high or high residual risk of a cardiac or cerebrovascular event. In one case, treatment can be started after the subject has stabilized after an acute coronary event. In one case, treatment can be started immediately after the acute coronary event, or 3, 6, 9 or 12 months after the acute coronary event. Treatment can begin after acute interventional cardiac surgery such as coronary artery bypass grafting (CABG), percutaneous coronary intervention (angioplasty, PCI) or stent implantation in the coronary artery. Subjects considered to be high risk can be those individuals with homozygous familial hypercholesterolemia (FH), severe refractory FH, diabetes or acute coronary syndrome (ACS). In high-risk subjects, treatment can be extended.

1. Treatment cycle

The treatment cycle as previously described with respect to the dosing regimen can vary in length of time. The treatment cycle can be at least four weeks, but can last up to six months. In one case, the disclosed method has such a treatment cycle, which involves administering an effective amount of an ApoE mimetic peptide once a week for one month (four weeks), three months (12 weeks) or six months (24 weeks). The treatment cycle may include administering an ApoE mimetic peptide once a week, twice or three times a week. In some aspects, the ApoE mimetic peptide may be administered daily. In some aspects, the ApoE mimetic peptide may be administered once every two weeks or even monthly. In some cases, the ApoE mimetic peptide may be administered every two weeks for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 weeks. Each treatment cycle may include a determined length of time for administration and a determined dosing regimen during that time period.

The method can further include a second treatment cycle after the rest period. In one aspect, the second treatment cycle can be administered after a four-week rest period. In another aspect, the second treatment cycle can be administered at least one year after the initial treatment cycle.

2. Rest period

The rest period, as previously described with respect to the dosing regimen, can be at least four weeks, but can last for several years. The ApoE mimetic peptide is not administered during the rest period.

The length of the rest period depends on how long the sustained therapeutic effect of the ApoE mimetic peptide administered during the duration of the treatment cycle lasts. In some cases, the rest period can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some cases, the rest period can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. For example, the rest period can be at least four weeks (one month).

In one aspect, the rest period can be reduced or extended depending on the dose of the ApoE mimetic peptide administered during the treatment cycle. For example, if the dose of the ApoE mimetic peptide is increased during the treatment cycle, the rest period can be extended. The length of the rest period can also vary based on the length of the treatment cycle. For example, if a subject receives a certain dose of the ApoE mimetic peptide once a week for three months, the rest period can be shorter than a subject who receives the same dose of the ApoE mimetic peptide once a week for six months.

Although the ApoE mimetic peptide is not administered during the rest period, an atherosclerosis treatment other than the ApoE mimetic peptide can be administered during the rest period. The atherosclerosis treatment other than the ApoE mimetic can be a conventional lipid-lowering therapy, such as a statin or a bile acid sequestrant, and/or a treatment such as a PCSK9 inhibitor, a VLDL synthesis inhibitor, and/or a CETP inhibitor.

3. Atherosclerosis

The combination of LDL accumulation in the blood vessel wall and the inflammatory response to LDL is the cause of atherosclerosis. The LDL in the blood vessel wall is oxidized, damaging the blood vessel wall and triggering an immune response. Immune cells (such as macrophages) are unable to process the oxidized LDL and eventually rupture, resulting in more oxidized cholesterol in the artery wall. This cycle continues, which leads to more and more damage to the blood vessel wall. The increase in cholesterol leads to plaque, which ultimately leads to hardening and narrowing of the blood vessel wall. The disclosed method can be used to treat atherosclerosis and other lipid disorders.

K. Delivery

In the methods described herein, the ApoE mimetic peptides can be administered or delivered by a variety of mechanisms. As defined above, disclosed herein are methods of treatment, dosing regimens, and methods of treatment using those dosing regimens. Dosing regimens and methods include compositions containing any one or more polypeptides or nucleic acids described herein, which compositions may also include a carrier, such as a pharmaceutically acceptable carrier. For example, pharmaceutical compositions comprising the ApoE mimetic peptides disclosed herein and a pharmaceutically acceptable carrier are disclosed.

The disclosed ApoE mimetic peptides can be solutions or suspensions (e.g., incorporated into microparticles, liposomes, or cells). These compositions can be targeted to specific cell types through antibodies, receptors, or receptor ligands. Those skilled in the art know how to prepare and use such targeting agents using the disclosed compositions. Targeting agents can be vehicles, such as liposomes conjugated to antibodies; receptor-mediated DNA targeting through cell-specific ligands, and highly specific retroviral targeting of cells in vivo. Any such vehicle can be part of the compositions herein. For example, a targeting agent that directs the ApoE mimetic peptide to the blood vessel wall can be included in the composition.

Any suitable route of administration can be used for disclosed compositions.Suitable route of administration can for example include topical, enteral, local, systemic or parenteral.For example, administration can be epidermal, inhalation, enema, conjunctival, eye drops, ear drops, alveolar, nose, intranasal, enteral, oral, intraoral, per os, intestinal, rectal, rectal, rectal, injection, infusion, intravenous, intraarterial, intramuscular, intraventricular, intraventricular, intraventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavernous, intramedullary, intraocular, intracranial, percutaneous, through mucosa, through nose, inhalation, intracisternal, epidural, epidural, intravitreal etc.Disclosed compositions can be used for any other treatment and used together with any other treatment.

Unlike typical peptide formulations, the peptides of the present invention comprising D-amino acids can even be administered orally without protection from proteolysis by gastric acid or the like. However, in certain embodiments, peptide delivery can be enhanced by the protective excipients used. This is typically achieved by compounding the polypeptide with a composition so that it is resistant to acidic and enzymatic hydrolysis or by packaging the polypeptide in a suitable resistant carrier such as a liposome. Methods for protecting polypeptides for oral delivery are well known in the art (see, for example, U.S. Patent No. 5,391,377 describing lipid compositions for oral delivery of therapeutic agents).

The elevated serum half-life can be maintained by using a sustained-release protein "packaging" system. Such sustained-release systems are well known to those skilled in the art. In a preferred embodiment, the ProLease biodegradable microsphere delivery system for proteins and peptides (Tracy (1998) Biotechnol. Prog., 14: 108; Johnson et al. (1996) Nature Med. 2: 795; Herbert et al. (1998), Pharmaceut. Res. 15, 357) consists of a dry powder consisting of biodegradable polymer microspheres containing the active agent in a polymer matrix, which can be used as a dry formulation with or without other agents.

The ProLease microsphere manufacturing process is specifically designed to achieve high encapsulation efficiency while maintaining the integrity of the active agent. The process consists of: (i) preparing lyophilized drug particles in bulk by spraying a drug solution containing a stabilizing excipient, (ii) preparing a drug-polymer suspension followed by sonication or homogenization to reduce the drug particle size, (iii) producing frozen drug-polymer microspheres by atomization into liquid nitrogen, (iv) extracting the polymer solvent with ethanol, and (v) filtering and vacuum drying to produce the final dry powder product. The resulting powder contains the active agent in solid form, which is uniformly and rigidly dispersed within the porous polymer particles. The polymer most commonly used in this process, poly(lactide-co-glycolide) (PLG), is biocompatible and biodegradable.

Encapsulation can be achieved at low temperatures (e.g., -40°C). During encapsulation, the protein is maintained in a solid state in the absence of water, thereby minimizing water-induced conformational mobility of the protein, preventing protein degradation reactions involving water as a reactant, and avoiding organic-aqueous interfaces where the protein can undergo denaturation. Preferred methods use solvents in which most proteins are insoluble, resulting in high encapsulation efficiencies (e.g., greater than 95%).

In another embodiment, one or more components of the solution may be provided as a "concentrate," for example, in a storage container (eg, a pre-measured volume) ready for dilution, or in a dissolvable capsule ready to be added to a volume of water.

The foregoing formulations and methods of administration are intended to be illustrative and not limiting. It will be appreciated that other suitable formulations and modes of administration can be readily devised using the teachings provided herein.

1. Combination therapy

In one aspect of the disclosed method, the Apo E mimetic can be administered alone or in combination with one or more additional therapeutic agents. The additional therapeutic agent is selected based on the disease or symptom to be treated. Descriptions of various types of suitable pharmacological agents and drugs can be found in Goodman and Gilman, The Pharmacological Basis of Therapeutics, (11th edition, McGraw-Hill Publishing Co.) (2005). For example, a pharmaceutical composition containing an Apo E mimetic can be administered in combination with one or more therapeutic agents known to be used to treat atherosclerosis. Therapeutic agents used to treat atherosclerosis include, but are not limited to, cholesterol-lowering agents, HDL-raising agents, blood-thinning agents (i.e., drugs that prevent blood clots), anti-inflammatory agents, and anti-atherosclerotic agents. Examples of cholesterol-lowering agents include, but are not limited to, cholesterol absorption inhibitors, bile acid sequestrants, fibrates, PCSK9 inhibitors, microsomal triglyceride transfer protein inhibitors, apolipoprotein B synthesis inhibitors, or CETP inhibitors.

Apo E mimetics can be administered in combination with or after any of the other disclosed therapeutic agents.The treatment can be administered with or after LDL apheresis.

Combination therapy can include administering an Apo E mimetic and the other therapeutic agent during a treatment period of a dosing regimen. Combination therapy can also include administering an Apo E mimetic during a treatment period and administering the other therapeutic agent during a rest period.

Example

It should be understood that the disclosed methods and compositions are not limited to the specific methods, protocols and reagents described, as they may vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the present invention, which will be limited only by the appended claims.

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalent variations to the specific embodiments of the methods and compositions described herein. Such equivalent variations are intended to be encompassed by the appended claims.

Example 1: Preparation and Analysis of Synthetic ApoE Mimetic Peptide Analogs

The synthetic ApoE mimetic peptides used in the studies described in Figures 3 to 14 were prepared by standard Fmoc solid-phase peptide synthesis techniques. The various peptides and the principles of preparation are shown in Figure 1. Representative analytical HPLC profiles of the synthesized peptides are shown in Figures 2A-2G.

Example 2: Effects of AEM analogs in ApoE-null mice

Studies showing the effects of various synthetic ApoE mimetic peptides on plasma cholesterol levels are shown in Figures 3 to 14.

Example 3: Effects of AEM analogs in high sucrose-fed rats

Male Sprague-Dawley rats were purchased from Charles River and fed a diet containing 65% sucrose for two weeks. The lipoprotein profile ( FIG15 ) showed elevated triglycerides. At the time of peptide administration, the rats weighed 370 ± 20 g. The peptides administered (5 mg/kg via tail vein) were as follows: Ac-hE18A-NH ₂ , Ac-[R]hE18A-NH ₂ , and Ac-Aha-[R]hE18A-NH ₂ , where hE refers to LRKLRKRLLR (SEQ ID NO: 4), [R]hE refers to LRRLRRRLLR (SEQ ID NO: 6), and Aha refers to H ₂ N-(CH ₂ ) ₅ -COOH. Blood was drawn at the times indicated in the figures, and after cell separation, plasma was analyzed for cholesterol, triglyceride, and glucose levels. Plasma triglyceride levels at different time points are shown in FIG16 . Data on plasma triglyceride ( FIG. 17 ), cholesterol level ( FIG. 18 ), and plasma glucose level ( FIG. 19 ) were also obtained 48 hours after administration of the peptide.

Example 4: Preparation and analysis of fatty acid-containing peptides

The following peptides were prepared: (1) octanoyl-LRRLRRRLLR-18A-NH ₂ (SEQ ID NO: 625); (2) myristoyl-LRRLRRRLLR-18A-NH ₂ (SEQ ID NO: 628); (3) oleoyl-LRRLRRRLLR-18A-NH ₂ (SEQ ID NO: 634); (4) palmitoyl-LRRLRRRLLR-18A-NH ₂ (SEQ ID NO: 629); and (5) fish oil-LRRLRRRLLR-18A-NH ₂ (SEQ ID NO: 647), wherein fish oil is primarily a mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with other components in minor amounts.

Peptides were synthesized on Rink amide resin (using 5 mM functional groups present on 10 g of resin). The appropriate FMOC-amino acid derivative was added using the HBTu condensation method (for three couplings, three couplings of each amino acid of 5x, 3x and 2x). After adding the last amino acid leucine (L), the resin was weighed to approximately 40 g, indicating the quantitative yield of the amino acid coupling. Resin (2 g) of each fatty acid was taken and each fatty acid was added twice with 10X and 5X couplings using HBTu in DMF. The peptide was released from the resin using TFA:water:anisole:ethanedithiol (volume ratio of 95:2:2:1, 10 ml/G reagent) at room temperature for 3.5 hours. After filtering the resin, the peptide was precipitated by adding ether and washed three times by centrifugation with ether. The peptide was first dialyzed and then purified by HPLC. Since fish oil derivatives are known to contain mixtures that are very difficult to purify, they are not purified, but the ability of the peptide to reduce plasma cholesterol in apoE-invalid mice was compared with other dialyzed peptides. Purification of the peptide was achieved using a C18 silica column, and Figures 20A-20E show representative analytical HPLC profiles of the peptide (C-18 Vydac column - 250 x 4.6 mm; solvent system was a gradient of water/acetonitrile (0.1% TFA), 35-70% in 12 minutes).

Example 5: Effects of fatty acid-containing peptides in ApoE-null mice

The effects of synthetic ApoE mimetic peptides comprising a fatty acid moiety at the N-terminus of the peptide on plasma cholesterol are shown in Figures 21 to 31.

It will be apparent to those skilled in the art that various modifications and variations may be made to the present invention without departing from the scope or spirit of the invention. Other embodiments of the present invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the description and examples be considered exemplary only, with the true scope and spirit of the invention being indicated by the appended claims.

Sequence Listing

<110> LIPIMETIX DEVELOPMENT, LLC

Anantharamaiah, G.M.

Goldberg, Dennis

<120> APOE mimetic peptides and their higher efficacy in clearing plasma cholesterol

<130> 21085.0187P1

<150> 62/031,585

<151> 2014-07-31

<160> 661

<170> PatentIn version 3.5

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<210> 10

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; dog ApoE mimetic

<400> 10

Met Arg Lys Leu Arg Lys Arg Val Leu Arg

1 5 10

<210> 11

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; R-modified ApoE mimetic

<400> 11

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg

1 5 10

<210> 12

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; F-modified ApoE mimetic

<400> 12

Leu Arg Lys Leu Arg Lys Arg Phe Phe Arg

1 5 10

<210> 13

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; ApoB mimetics

<400> 13

Arg Leu Thr Arg Lys Arg Gly Leu Lys

1 5

<210> 14

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 14

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Phe

<210> 15

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 15

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 16

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 16

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 17

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 17

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 18

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 18

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Phe Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 19

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 19

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Phe Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 20

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 20

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Phe Phe

<210> 21

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 21

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Leu Lys Glu

1 5 10 15

Phe Phe

<210> 22

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 22

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 23

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 23

Glu Trp Leu Lys Leu Phe Tyr Glu Lys Val Leu Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 24

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 24

Glu Trp Leu Lys Ala Phe Tyr Ile Asp Lys Val Ala Glu Lys Phe Lys

1 5 10 15

Glu Ala Phe

<210> 25

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 25

Glu Glu Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys

1 5 10 15

Glu Phe Phe

<210> 26

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 26

Glu Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 27

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 27

Glu Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Leu Lys Glu

1 5 10 15

Phe Phe

<210> 28

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 28

Glu Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 29

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 29

Glu Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 30

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 30

Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

1 5 10

<210> 31

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 31

Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu Ala Phe

1 5 10

<210> 32

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 32

Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu Ala Phe

1 5 10

<210> 33

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 33

Ala Phe Tyr Asp Lys Phe Phe Glu Lys Phe Lys Glu Phe Phe

1 5 10

<210> 34

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 34

Ala Phe Tyr Asp Lys Phe Phe Glu Lys Phe Lys Glu Phe Phe

1 5 10

<210> 35

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 35

Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu Ala Phe

1 5 10

<210> 36

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 36

Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Phe Phe

1 5 10

<210> 37

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 37

Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu Ala Phe

1 5 10

<210> 38

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 38

Ala Phe Tyr Asp Lys Val Phe Glu Lys Leu Lys Glu Phe Phe

1 5 10

<210> 39

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 39

Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu Phe Phe

1 5 10

<210> 40

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 40

Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu Phe

1 5 10

<210> 41

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 41

Leu Phe Tyr Glu Lys Val Leu Glu Lys Phe Lys Glu Ala Phe

1 5 10

<210> 42

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 42

Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu Ala Phe

1 5 10

<210> 43

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 43

Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Phe Phe

1 5 10

<210> 44

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 44

Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu Ala Phe

1 5 10

<210> 45

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 45

Ala Phe Tyr Asp Lys Val Phe Glu Lys Leu Lys Glu Phe Phe

1 5 10

<210> 46

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 46

Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu Phe Phe

1 5 10

<210> 47

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 47

Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu Phe Phe

1 5 10

<210> 48

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 48

Asp Trp Leu Lys Ala Leu Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Leu

<210> 49

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 49

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Phe Phe

<210> 50

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 50

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Phe Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 51

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 51

Glu Trp Leu Lys Ala Leu Tyr Glu Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Leu

<210> 52

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 52

Glu Trp Leu Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Phe

<210> 53

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 53

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Phe Phe

<210> 54

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 54

Glu Trp Leu Lys Ala Phe Tyr Glu Lys Val Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 55

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 55

Glu Trp Leu Lys Ala Phe Tyr Glu Lys Phe Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 56

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 56

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Phe Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 57

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 57

Asp Phe Leu Lys Ala Trp Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Trp

<210> 58

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 58

Glu Phe Leu Lys Ala Trp Tyr Glu Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Trp

<210> 59

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 59

Asp Phe Trp Lys Ala Trp Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Trp Trp

<210> 60

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 60

Glu Phe Trp Lys Ala Trp Tyr Glu Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Trp Trp

<210> 61

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 61

Asp Lys Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Trp Ala Lys Glu

1 5 10 15

Ala Phe

<210> 62

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 62

Asp Lys Trp Lys Ala Val Tyr Asp Lys Phe Ala Glu Ala Phe Lys Glu

1 5 10 15

Phe Leu

<210> 63

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 63

Glu Lys Leu Lys Ala Phe Tyr Glu Lys Val Phe Glu Trp Ala Lys Glu

1 5 10 15

Ala Phe

<210> 64

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 64

Glu Lys Trp Lys Ala Val Tyr Glu Lys Phe Ala Glu Ala Phe Lys Glu

1 5 10 15

Phe Leu

<210> 65

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 65

Asp Trp Leu Lys Ala Phe Val Asp Lys Phe Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Tyr

<210> 66

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 66

Glu Lys Trp Lys Ala Val Tyr Glu Lys Phe Ala Glu Ala Phe Lys Glu

1 5 10 15

Phe Leu

<210> 67

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 67

Asp Trp Leu Lys Ala Phe Val Tyr Asp Lys Val Phe Lys Leu Lys Glu

1 5 10 15

Phe Phe

<210> 68

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 68

Glu Trp Leu Lys Ala Phe Val Tyr Glu Lys Val Phe Lys Leu Lys Glu

1 5 10 15

Phe Phe

<210> 69

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 69

Asp Trp Leu Arg Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Phe

<210> 70

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 70

Glu Trp Leu Arg Ala Phe Tyr Glu Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Phe

<210> 71

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 71

Asp Trp Leu Lys Ala Phe Tyr Asp Arg Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Phe

<210> 72

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 72

Glu Trp Leu Lys Ala Phe Tyr Glu Arg Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Phe

<210> 73

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 73

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Arg Leu Lys Glu

1 5 10 15

Ala Phe

<210> 74

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 74

Glu Trp Leu Lys Ala Phe Tyr Glu Lys Val Ala Glu Arg Leu Lys Glu

1 5 10 15

Ala Phe

<210> 75

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 75

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Arg Glu

1 5 10 15

Ala Phe

<210> 76

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 76

Glu Trp Leu Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Leu Arg Glu

1 5 10 15

Ala Phe

<210> 77

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 77

Asp Trp Leu Lys Ala Phe Tyr Asp Arg Val Ala Glu Arg Leu Lys Glu

1 5 10 15

Ala Phe

<210> 78

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 78

Glu Trp Leu Lys Ala Phe Tyr Glu Arg Val Ala Glu Arg Leu Lys Glu

1 5 10 15

Ala Phe

<210> 79

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 79

Asp Trp Leu Arg Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Arg Glu

1 5 10 15

Ala Phe

<210> 80

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 80

Glu Trp Leu Arg Ala Phe Tyr Glu Lys Val Ala Glu Lys Leu Arg Glu

1 5 10 15

Ala Phe

<210> 81

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 81

Asp Trp Leu Arg Ala Phe Tyr Asp Arg Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Phe

<210> 82

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 82

Glu Trp Leu Arg Ala Phe Tyr Glu Arg Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Phe

<210> 83

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 83

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Arg Leu Arg Glu

1 5 10 15

Ala Phe

<210> 84

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 84

Glu Trp Leu Lys Ala Phe Tyr Glu Lys Val Ala Glu Arg Leu Arg Glu

1 5 10 15

Ala Phe

<210> 85

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 85

Asp Trp Leu Arg Ala Phe Tyr Asp Lys Val Ala Glu Arg Leu Lys Glu

1 5 10 15

Ala Phe

<210> 86

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 86

Glu Trp Leu Arg Ala Phe Tyr Glu Lys Val Ala Glu Arg Leu Lys Glu

1 5 10 15

Ala Phe

<210> 87

<211> 37

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 87

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Phe Pro Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys

20 25 30

Leu Lys Glu Ala Phe

35

<210> 88

<211> 37

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 88

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Phe Phe Pro Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys

20 25 30

Leu Lys Glu Phe Phe

35

<210> 89

<211> 37

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 89

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu

1 5 10 15

Ala Phe Pro Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys

20 25 30

Leu Lys Glu Ala Phe

35

<210> 90

<211> 37

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 90

Asp Lys Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Trp Ala Lys Glu

1 5 10 15

Ala Phe Pro Asp Lys Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Trp

20 25 30

Leu Lys Glu Ala Phe

35

<210> 91

<211> 37

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 91

Asp Lys Trp Lys Ala Val Tyr Asp Lys Phe Ala Glu Ala Phe Lys Glu

1 5 10 15

Phe Leu Pro Asp Lys Trp Lys Ala Val Tyr Asp Lys Phe Ala Glu Ala

20 25 30

Phe Lys Glu Phe Leu

35

<210> 92

<211> 37

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 92

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe Pro Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys

20 25 30

Phe Lys Glu Ala Phe

35

<210> 93

<211> 37

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 93

Asp Trp Leu Lys Ala Phe Val Tyr Asp Lys Val Phe Lys Leu Lys Glu

1 5 10 15

Phe Phe Pro Asp Trp Leu Lys Ala Phe Val Tyr Asp Lys Val Phe Lys

20 25 30

Leu Lys Glu Phe Phe

35

<210> 94

<211> 37

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 94

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Phe Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe Pro Asp Trp Leu Lys Ala Phe Tyr Asp Lys Phe Ala Glu Lys

20 25 30

Phe Lys Glu Phe Phe

35

<210> 95

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 95

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 96

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 96

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe

1 5 10

<210> 97

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 97

Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10

<210> 98

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 98

Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10

<210> 99

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 99

Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10

<210> 100

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 100

Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10

<210> 101

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 101

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 102

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 102

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 103

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 103

Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu Ala Phe

1 5 10

<210> 104

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 104

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe

1 5 10

<210> 105

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 105

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 106

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 106

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 107

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 107

Glu Trp Leu Lys Ala Phe Tyr Glu Lys Val Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 108

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 108

Glu Trp Leu Lys Ala Phe Tyr Glu Lys Val Phe Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 109

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 109

Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu Phe Phe

1 5 10

<210> 110

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 110

Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu Phe Phe

1 5 10

<210> 111

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 111

Ala Phe Tyr Glu Lys Val Phe Glu Lys Phe Lys Glu Phe Phe

1 5 10

<210> 112

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 112

Ala Phe Tyr Glu Lys Val Phe Glu Lys Phe Lys Glu Phe Phe

1 5 10

<210> 113

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 113

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe

1 5 10

<210> 114

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 114

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe

1 5 10

<210> 115

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 115

Glu Trp Leu Lys Ala Phe Tyr Glu Lys Val Phe Glu Lys Phe

1 5 10

<210> 116

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 116

Glu Trp Leu Lys Ala Phe Tyr Glu Lys Val Phe Glu Lys Phe

1 5 10

<210> 117

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 117

Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu

1 5 10

<210> 118

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 118

Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu

1 5 10

<210> 119

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 119

Leu Lys Ala Phe Tyr Glu Lys Val Phe Glu Lys Phe Lys Glu

1 5 10

<210> 120

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A peptide

<400> 120

Leu Lys Ala Phe Tyr Glu Lys Val Phe Glu Lys Phe Lys Glu

1 5 10

<210> 121

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; modified class A peptides

<400> 121

Asp Lys Trp Lys Ala Val Tyr Asp Lys Phe Ala Glu Ala Phe Lys Glu

1 5 10 15

Phe Leu

<210> 122

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; modified class A peptides

<400> 122

Asp Lys Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Trp Ala Lys Glu

1 5 10 15

Ala Phe

<210> 123

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 123

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 124

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 124

Glu Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 125

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 125

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 126

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 126

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 127

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 127

Asp Phe Trp Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 128

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 128

Glu Phe Trp Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 129

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 129

Glu Phe Trp Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 130

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 130

Asp Phe Trp Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 131

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 131

Asp Phe Trp Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 132

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 132

Asp Trp Phe Lys Ala Tyr Phe Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 133

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 133

Glu Trp Phe Lys Ala Tyr Phe Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 134

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 134

Glu Trp Phe Lys Ala Tyr Phe Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 135

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 135

Asp Trp Phe Lys Ala Tyr Phe Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 136

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 136

Asp Trp Phe Lys Ala Tyr Phe Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 137

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 137

Asp Trp Phe Lys Ala Phe Val Asp Lys Tyr Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 138

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 138

Glu Trp Phe Lys Ala Phe Val Glu Lys Tyr Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 139

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 139

Glu Trp Phe Lys Ala Phe Val Asp Lys Tyr Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 140

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 140

Asp Trp Phe Lys Ala Phe Val Glu Lys Tyr Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 141

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 141

Asp Trp Phe Lys Ala Phe Val Glu Lys Tyr Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 142

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 142

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Ala Val Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 143

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 143

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Ala Val Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 144

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 144

Glu Trp Phe Lys Ala Phe Tyr Asp Lys Ala Val Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 145

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 145

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Ala Val Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 146

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 146

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Ala Val Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 147

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 147

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Ala Lys Glu

1 5 10 15

Ala Phe

<210> 148

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 148

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Phe Asp Lys Ala Lys Asp

1 5 10 15

Ala Phe

<210> 149

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 149

Glu Trp Phe Lys Ala Phe Tyr Asp Lys Val Phe Asp Lys Ala Lys Glu

1 5 10 15

Ala Phe

<210> 150

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 150

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Phe Asp Lys Ala Lys Glu

1 5 10 15

Ala Phe

<210> 151

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 151

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Phe Glu Lys Ala Lys Asp

1 5 10 15

Ala Phe

<210> 152

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 152

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Ala Lys Glu

1 5 10 15

Phe Phe

<210> 153

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 153

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Ala Lys Asp

1 5 10 15

Phe Phe

<210> 154

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 154

Glu Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Ala Lys Glu

1 5 10 15

Phe Phe

<210> 155

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 155

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Ala Lys Glu

1 5 10 15

Phe Phe

<210> 156

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 156

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Ala Lys Asp

1 5 10 15

Phe Phe

<210> 157

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 157

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe Ala

<210> 158

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 158

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Phe Ala

<210> 159

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 159

Glu Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Phe Ala

<210> 160

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 160

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Phe Ala

<210> 161

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 161

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Phe Ala

<210> 162

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 162

Asp Ala Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Trp Phe

<210> 163

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 163

Glu Ala Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Trp Phe

<210> 164

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 164

Glu Ala Phe Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Trp Phe

<210> 165

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 165

Asp Ala Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Trp Phe

<210> 166

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 166

Asp Ala Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Trp Phe

<210> 167

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 167

Asp Ala Phe Lys Ala Phe Tyr Asp Lys Val Trp Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 168

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 168

Glu Ala Phe Lys Ala Phe Tyr Glu Lys Val Trp Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 169

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 169

Glu Ala Phe Lys Ala Phe Tyr Asp Lys Val Trp Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 170

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 170

Asp Ala Phe Lys Ala Phe Tyr Glu Lys Val Trp Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 171

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 171

Asp Ala Phe Lys Ala Phe Tyr Glu Lys Val Trp Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 172

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 172

Asp Tyr Phe Lys Ala Phe Trp Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 173

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 173

Glu Tyr Phe Lys Ala Phe Trp Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 174

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 174

Glu Tyr Phe Lys Ala Phe Trp Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 175

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 175

Asp Tyr Phe Lys Ala Phe Trp Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 176

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 176

Asp Tyr Phe Lys Ala Phe Trp Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 177

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 177

Asp Trp Ala Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 178

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 178

Glu Trp Ala Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Phe Phe

<210> 179

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 179

Glu Trp Ala Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 180

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 180

Asp Trp Ala Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 181

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 181

Asp Trp Ala Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Phe Phe

<210> 182

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 182

Asp Trp Phe Lys Ala Ala Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 183

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 183

Glu Trp Phe Lys Ala Ala Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Phe Phe

<210> 184

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 184

Glu Trp Phe Lys Ala Ala Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 185

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 185

Asp Trp Phe Lys Ala Ala Tyr Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 186

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 186

Asp Trp Phe Lys Ala Ala Tyr Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Phe Phe

<210> 187

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 187

Asp Trp Phe Lys Ala Phe Ala Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Tyr Phe

<210> 188

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 188

Glu Trp Phe Lys Ala Phe Ala Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Tyr Phe

<210> 189

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 189

Glu Trp Phe Lys Ala Phe Ala Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Tyr Phe

<210> 190

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 190

Asp Trp Phe Lys Ala Phe Ala Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Tyr Phe

<210> 191

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 191

Asp Trp Phe Lys Ala Phe Ala Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Tyr Phe

<210> 192

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 192

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Ala Ala Glu Lys Phe Lys Glu

1 5 10 15

Val Phe

<210> 193

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 193

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Ala Ala Asp Lys Phe Lys Asp

1 5 10 15

Val Phe

<210> 194

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 194

Glu Trp Phe Lys Ala Phe Tyr Asp Lys Ala Ala Asp Lys Phe Lys Glu

1 5 10 15

Val Phe

<210> 195

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 195

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Ala Ala Asp Lys Phe Lys Glu

1 5 10 15

Val Phe

<210> 196

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 196

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Ala Ala Glu Lys Phe Lys Asp

1 5 10 15

Val Phe

<210> 197

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 197

Asp Trp Tyr Lys Ala Phe Phe Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 198

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 198

Glu Trp Tyr Lys Ala Phe Phe Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 199

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 199

Glu Trp Tyr Lys Ala Phe Phe Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 200

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 200

Asp Trp Tyr Lys Ala Phe Phe Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 201

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 201

Asp Trp Tyr Lys Ala Phe Phe Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 202

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 202

Asp Trp Val Lys Ala Phe Tyr Asp Lys Phe Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 203

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 203

Glu Trp Val Lys Ala Phe Tyr Glu Lys Phe Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 204

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 204

Glu Trp Val Lys Ala Phe Tyr Asp Lys Phe Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 205

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 205

Asp Trp Val Lys Ala Phe Tyr Glu Lys Phe Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 206

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 206

Asp Trp Val Lys Ala Phe Tyr Glu Lys Phe Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 207

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 207

Asp Trp Phe Lys Ala Phe Phe Asp Lys Val Ala Glu Lys Tyr Lys Glu

1 5 10 15

Ala Phe

<210> 208

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 208

Glu Trp Phe Lys Ala Phe Phe Glu Lys Val Ala Asp Lys Tyr Lys Asp

1 5 10 15

Ala Phe

<210> 209

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 209

Glu Trp Phe Lys Ala Phe Phe Asp Lys Val Ala Asp Lys Tyr Lys Glu

1 5 10 15

Ala Phe

<210> 210

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 210

Asp Trp Phe Lys Ala Phe Phe Glu Lys Val Ala Asp Lys Tyr Lys Glu

1 5 10 15

Ala Phe

<210> 211

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 211

Asp Trp Phe Lys Ala Phe Phe Glu Lys Val Ala Asp Lys Tyr Lys Glu

1 5 10 15

Ala Phe

<210> 212

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 212

Asp Trp Phe Lys Ala Phe Phe Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Tyr

<210> 213

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 213

Glu Trp Phe Lys Ala Phe Phe Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Tyr

<210> 214

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 214

Glu Trp Phe Lys Ala Phe Phe Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Tyr

<210> 215

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 215

Asp Trp Phe Lys Ala Phe Phe Glu Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Tyr

<210> 216

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 216

Asp Trp Phe Lys Ala Phe Phe Glu Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Tyr

<210> 217

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 217

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Phe Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Val

<210> 218

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 218

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Phe Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Val

<210> 219

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 219

Glu Trp Phe Lys Ala Phe Tyr Asp Lys Phe Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Val

<210> 220

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 220

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Phe Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Val

<210> 221

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 221

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Phe Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Val

<210> 222

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 222

Asp Lys Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Trp Glu

1 5 10 15

Ala Phe

<210> 223

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 223

Glu Lys Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Trp Asp

1 5 10 15

Ala Phe

<210> 224

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 224

Glu Lys Phe Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Phe Trp Glu

1 5 10 15

Ala Phe

<210> 225

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 225

Asp Lys Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Trp Glu

1 5 10 15

Ala Phe

<210> 226

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 226

Asp Lys Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Trp Asp

1 5 10 15

Ala Phe

<210> 227

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 227

Asp Lys Trp Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Phe Glu

1 5 10 15

Ala Phe

<210> 228

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 228

Glu Lys Trp Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Phe Asp

1 5 10 15

Ala Phe

<210> 229

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 229

Glu Lys Trp Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Phe Phe Glu

1 5 10 15

Ala Phe

<210> 230

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 230

Asp Lys Trp Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Phe Glu

1 5 10 15

Ala Phe

<210> 231

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 231

Asp Lys Trp Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Phe Asp

1 5 10 15

Ala Phe

<210> 232

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 232

Asp Lys Phe Lys Ala Phe Tyr Asp Lys Trp Ala Glu Val Phe Lys Glu

1 5 10 15

Ala Phe

<210> 233

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 233

Glu Lys Phe Lys Ala Phe Tyr Glu Lys Trp Ala Asp Val Phe Lys Asp

1 5 10 15

Ala Phe

<210> 234

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 234

Glu Lys Phe Lys Ala Phe Tyr Asp Lys Trp Ala Asp Val Phe Lys Glu

1 5 10 15

Ala Phe

<210> 235

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 235

Asp Lys Phe Lys Ala Phe Tyr Glu Lys Trp Ala Asp Val Phe Lys Glu

1 5 10 15

Ala Phe

<210> 236

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 236

Asp Lys Phe Lys Ala Phe Tyr Glu Lys Trp Ala Glu Val Phe Lys Asp

1 5 10 15

Ala Phe

<210> 237

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 237

Asp Lys Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Phe Trp Lys Glu

1 5 10 15

Ala Phe

<210> 238

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 238

Glu Lys Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Phe Trp Lys Asp

1 5 10 15

Ala Phe

<210> 239

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 239

Glu Lys Phe Cys Ala Phe Tyr Asp Lys Val Ala Asp Phe Trp Lys Glu

1 5 10 15

Ala Phe

<210> 240

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 240

Asp Lys Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Phe Trp Lys Glu

1 5 10 15

Ala Phe

<210> 241

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 241

Asp Lys Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Phe Trp Lys Asp

1 5 10 15

Ala Phe

<210> 242

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 242

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 243

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 243

Phe Ala Asp Lys Phe Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 244

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 244

Phe Ala Asp Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 245

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 245

Phe Ala Glu Lys Phe Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 246

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 246

Phe Ala Glu Lys Phe Lys Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 247

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 247

Phe Trp Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Ala Asp

<210> 248

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 248

Phe Trp Asp Lys Phe Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Ala Glu

<210> 249

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 249

Phe Ala Asp Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 250

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 250

Phe Ala Glu Lys Phe Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 251

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 251

Phe Ala Glu Lys Phe Lys Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 252

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 252

Phe Phe Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Ala

1 5 10 15

Trp Asp

<210> 253

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 253

Phe Phe Asp Lys Phe Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Ala

1 5 10 15

Trp Glu

<210> 254

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 254

Phe Phe Asp Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Ala

1 5 10 15

Trp Glu

<210> 255

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 255

Phe Phe Glu Lys Phe Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Ala

1 5 10 15

Trp Asp

<210> 256

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 256

Phe Phe Glu Lys Phe Lys Asp Ala Val Lys Asp Tyr Phe Ala Lys Ala

1 5 10 15

Trp Glu

<210> 257

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 257

Phe Ala Glu Lys Ala Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 258

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 258

Phe Ala Asp Lys Ala Lys Asp Phe Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 259

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 259

Phe Ala Asp Lys Ala Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 260

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 260

Phe Ala Glu Lys Ala Lys Asp Phe Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 261

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 261

Phe Ala Glu Lys Ala Lys Asp Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 262

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 262

Phe Ala Glu Lys Phe Lys Glu Val Ala Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 263

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 263

Phe Ala Asp Lys Phe Lys Asp Val Ala Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 264

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 264

Phe Ala Asp Lys Phe Lys Glu Val Ala Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 265

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 265

Phe Ala Glu Lys Phe Lys Asp Val Ala Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 266

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 266

Phe Ala Glu Lys Phe Lys Asp Val Ala Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 267

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 267

Phe Ala Asp Lys Phe Lys Glu Ala Tyr Lys Asp Val Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 268

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 268

Phe Ala Glu Lys Phe Lys Asp Ala Tyr Lys Glu Val Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 269

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 269

Phe Ala Glu Lys Phe Lys Asp Ala Tyr Lys Asp Val Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 270

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 270

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Phe Tyr Ala Lys Phe

1 5 10 15

Trp Asp

<210> 271

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 271

Phe Ala Asp Lys Phe Lys Asp Ala Val Lys Glu Phe Tyr Ala Lys Phe

1 5 10 15

Trp Glu

<210> 272

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 272

Phe Ala Asp Lys Phe Lys Glu Ala Val Lys Asp Phe Tyr Ala Lys Phe

1 5 10 15

Trp Glu

<210> 273

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 273

Phe Ala Glu Lys Phe Lys Asp Ala Val Lys Glu Phe Tyr Ala Lys Phe

1 5 10 15

Trp Asp

<210> 274

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 274

Phe Ala Glu Lys Phe Lys Asp Ala Val Lys Asp Phe Tyr Ala Lys Phe

1 5 10 15

Trp Glu

<210> 275

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 275

Phe Ala Glu Lys Phe Trp Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Asp

<210> 276

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 276

Phe Ala Asp Lys Phe Trp Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 277

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 277

Phe Ala Asp Lys Phe Trp Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 278

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 278

Phe Ala Glu Lys Phe Trp Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Lys Asp

<210> 279

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 279

Phe Ala Glu Lys Phe Trp Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 280

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 280

Ala Phe Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 281

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 281

Ala Phe Asp Lys Phe Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 282

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 282

Ala Phe Asp Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 283

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 283

Ala Phe Glu Lys Phe Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 284

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 284

Ala Phe Glu Lys Phe Lys Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 285

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 285

Val Ala Glu Lys Phe Lys Glu Ala Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 286

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 286

Val Ala Asp Lys Phe Lys Asp Ala Phe Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 287

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 287

Val Ala Asp Lys Phe Lys Glu Ala Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 288

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 288

Val Ala Glu Lys Phe Lys Asp Ala Phe Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 289

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 289

Val Ala Glu Lys Phe Lys Asp Ala Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 290

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 290

Tyr Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Phe Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 291

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 291

Tyr Ala Asp Lys Phe Lys Asp Ala Val Lys Glu Phe Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 292

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 292

Tyr Ala Asp Lys Phe Lys Glu Ala Val Lys Asp Phe Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 293

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 293

Tyr Ala Glu Lys Phe Lys Asp Ala Val Lys Glu Phe Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 294

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 294

Tyr Ala Glu Lys Phe Lys Asp Ala Val Lys Asp Phe Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 295

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 295

Ala Ala Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 296

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 296

Ala Ala Asp Lys Phe Lys Asp Phe Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 297

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 297

Ala Ala Asp Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 298

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 298

Ala Ala Glu Lys Phe Lys Asp Phe Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 299

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 299

Ala Ala Glu Lys Phe Lys Asp Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 300

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 300

Phe Phe Glu Lys Ala Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 301

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 301

Phe Phe Asp Lys Ala Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 302

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 302

Phe Phe Asp Lys Ala Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 303

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 303

Glu Lys Ala Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe Trp Asp

1 5 10 15

<210> 304

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 304

Glu Lys Ala Lys Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe Trp Glu

1 5 10 15

<210> 305

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 305

Phe Tyr Glu Lys Phe Lys Glu Ala Val Lys Asp Ala Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 306

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 306

Phe Tyr Asp Lys Phe Lys Asp Ala Val Lys Glu Ala Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 307

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 307

Phe Tyr Asp Lys Phe Lys Glu Ala Val Lys Asp Ala Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 308

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 308

Phe Tyr Glu Lys Phe Lys Asp Ala Val Lys Glu Ala Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 309

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 309

Phe Tyr Glu Lys Phe Lys Asp Ala Val Lys Asp Ala Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 310

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 310

Phe Val Glu Lys Phe Lys Glu Ala Ala Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 311

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 311

Phe Val Asp Lys Phe Lys Asp Ala Ala Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 312

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 312

Phe Val Asp Lys Phe Lys Glu Ala Ala Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 313

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 313

Phe Val Glu Lys Phe Lys Asp Ala Ala Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 314

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 314

Phe Val Glu Lys Phe Lys Asp Ala Ala Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 315

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 315

Phe Ala Glu Lys Tyr Lys Glu Ala Val Lys Asp Phe Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 316

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 316

Phe Ala Asp Lys Tyr Lys Asp Ala Val Lys Glu Phe Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 317

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 317

Phe Ala Asp Lys Tyr Lys Glu Ala Val Lys Asp Phe Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 318

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 318

Phe Ala Glu Lys Tyr Lys Asp Ala Val Lys Glu Phe Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 319

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 319

Phe Ala Glu Lys Tyr Lys Asp Ala Val Lys Asp Phe Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 320

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 320

Phe Ala Glu Lys Val Lys Glu Ala Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 321

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 321

Phe Ala Asp Lys Val Lys Asp Ala Phe Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 322

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 322

Phe Ala Asp Lys Val Lys Glu Ala Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 323

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 323

Phe Ala Glu Lys Val Lys Asp Ala Phe Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 324

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 324

Phe Ala Glu Lys Val Lys Asp Ala Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 325

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 325

Phe Ala Glu Lys Phe Lys Glu Tyr Val Lys Asp Ala Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 326

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 326

Phe Ala Asp Lys Phe Lys Asp Tyr Val Lys Glu Ala Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 327

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 327

Phe Ala Asp Lys Phe Lys Glu Tyr Val Lys Asp Ala Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 328

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 328

Phe Ala Glu Lys Phe Lys Asp Tyr Val Lys Glu Ala Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 329

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 329

Phe Ala Glu Lys Phe Lys Asp Tyr Val Lys Asp Ala Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 330

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 330

Phe Ala Glu Lys Phe Lys Glu Ala Phe Lys Asp Tyr Val Ala Lys Phe

1 5 10 15

Trp Asp

<210> 331

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 331

Phe Ala Asp Lys Phe Lys Asp Ala Phe Lys Glu Tyr Val Ala Lys Phe

1 5 10 15

Trp Glu

<210> 332

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 332

Phe Ala Asp Lys Phe Lys Glu Ala Phe Lys Asp Tyr Val Ala Lys Phe

1 5 10 15

Trp Glu

<210> 333

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 333

Phe Ala Glu Lys Phe Lys Asp Ala Phe Lys Glu Tyr Val Ala Lys Phe

1 5 10 15

Trp Asp

<210> 334

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 334

Phe Ala Glu Lys Phe Lys Asp Ala Phe Lys Asp Tyr Val Ala Lys Phe

1 5 10 15

Trp Glu

<210> 335

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 335

Phe Ala Glu Lys Phe Lys Glu Ala Phe Lys Asp Tyr Phe Ala Lys Val

1 5 10 15

Trp Asp

<210> 336

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 336

Phe Ala Asp Lys Phe Lys Asp Ala Phe Lys Glu Tyr Phe Ala Lys Val

1 5 10 15

Trp Glu

<210> 337

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 337

Phe Ala Asp Lys Phe Lys Glu Ala Phe Lys Asp Tyr Phe Ala Lys Val

1 5 10 15

Trp Glu

<210> 338

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 338

Phe Ala Glu Lys Phe Lys Asp Ala Phe Lys Glu Tyr Phe Ala Lys Val

1 5 10 15

Trp Asp

<210> 339

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 339

Phe Ala Glu Lys Phe Lys Asp Ala Phe Lys Asp Tyr Phe Ala Lys Val

1 5 10 15

Trp Glu

<210> 340

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 340

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Phe Phe Ala Lys Tyr

1 5 10 15

Trp Asp

<210> 341

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 341

Phe Ala Asp Lys Phe Lys Asp Ala Val Lys Glu Phe Phe Ala Lys Tyr

1 5 10 15

Trp Glu

<210> 342

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 342

Phe Ala Asp Lys Phe Lys Glu Ala Val Lys Asp Phe Phe Ala Lys Tyr

1 5 10 15

Trp Glu

<210> 343

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 343

Phe Ala Glu Lys Phe Lys Asp Ala Val Lys Glu Phe Phe Ala Lys Tyr

1 5 10 15

Trp Asp

<210> 344

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 344

Phe Ala Glu Lys Phe Lys Asp Ala Val Lys Asp Phe Phe Ala Lys Tyr

1 5 10 15

Trp Glu

<210> 345

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 345

Trp Ala Glu Lys Phe Phe Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Asp

<210> 346

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 346

Trp Ala Asp Lys Phe Phe Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 347

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 347

Trp Ala Asp Lys Phe Phe Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 348

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 348

Trp Ala Glu Lys Phe Phe Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Lys Asp

<210> 349

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 349

Trp Ala Glu Lys Phe Phe Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 350

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 350

Phe Ala Glu Lys Trp Phe Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Asp

<210> 351

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 351

Phe Ala Asp Lys Trp Phe Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 352

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 352

Phe Ala Asp Lys Trp Phe Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 353

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 353

Phe Ala Glu Lys Trp Phe Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Lys Asp

<210> 354

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 354

Phe Ala Glu Lys Trp Phe Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 355

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 355

Phe Ala Glu Lys Phe Val Glu Ala Trp Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Asp

<210> 356

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 356

Phe Ala Asp Lys Phe Val Asp Ala Trp Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 357

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 357

Phe Ala Asp Lys Phe Val Glu Ala Trp Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 358

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 358

Phe Ala Glu Lys Phe Val Asp Ala Trp Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Lys Asp

<210> 359

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 359

Phe Ala Glu Lys Phe Val Asp Ala Trp Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 360

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 360

Phe Tyr Glu Lys Phe Ala Glu Ala Val Lys Asp Trp Phe Ala Lys Phe

1 5 10 15

Lys Asp

<210> 361

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 361

Phe Tyr Asp Lys Phe Ala Asp Ala Val Lys Glu Trp Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 362

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 362

Phe Tyr Asp Lys Phe Ala Glu Ala Val Lys Asp Trp Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 363

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 363

Phe Tyr Glu Lys Phe Ala Asp Ala Val Lys Glu Trp Phe Ala Lys Phe

1 5 10 15

Lys Asp

<210> 364

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Class A amphipathic helical peptide

<400> 364

Phe Tyr Glu Lys Phe Ala Asp Ala Val Lys Asp Trp Phe Ala Lys Phe

1 5 10 15

Lys Glu

<210> 365

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; Class A or Class Y amphipathic helical peptides

<220>

<221> misc

<222> (1)..(1)

<223> D can be Asp or Glu

<220>

<221> misc

<222> (2)..(3)

<223> Xaa can be Leu, norLeu, Val, Ile, Trp, Phe, Tyr, β-Nal or

α-Nal

<220>

<221> misc

<222> (5)..(5)

<223> Y can be Ala, His, Ser, Gln, Asn or Thr

<220>

<221> misc

<222> (6)..(7)

<223> Xaa can be Leu, norLeu, Val, Ile, Trp, Phe, Tyr, β-Nal or

α-Nal

<220>

<221> misc

<222> (8)..(8)

<223> D can be Asp or Glu

<220>

<221> misc

<222> (10)..(10)

<223> Xaa can be Leu, norLeu, Val, Ile, Trp, Phe, Tyr, β-Nal or

α-Nal

<220>

<221> misc

<222> (11)..(11)

<223> Y can be Ala, His, Ser, Gln, Asn or Thr

<220>

<221> misc

<222> (12)..(12)

<223> D can be Asp or Glu

<220>

<221> misc

<222> (14)..(14)

<223> Xaa can be Leu, norLeu, Val, Ile, Trp, Phe, Tyr, β-Nal or

α-Nal

<220>

<221> misc

<222> (16)..(16)

<223> D can be Asp or Glu

<220>

<221> misc

<222> (17)..(17)

<223> Y can be Ala, His, Ser, Gln, Asn or Thr

<220>

<221> misc

<222> (18)..(18)

<223> Xaa can be Leu, norLeu, Val, Ile, Trp, Phe, Tyr, β-Nal or

α-Nal

<400> 365

Asp Xaa Xaa Lys Tyr Xaa Xaa Asp Lys Xaa Tyr Asp Lys Xaa Lys Asp

1 5 10 15

Tyr Xaa

<210> 366

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 366

Asp Trp Phe Lys His Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 367

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 367

Glu Trp Phe Lys His Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 368

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 368

Glu Trp Phe Lys His Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 369

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 369

Asp Trp Phe Lys His Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 370

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 370

Asp Trp Phe Lys His Phe Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 371

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 371

Asp Trp Phe Lys His Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 372

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 372

Asp Trp His Lys Phe Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 373

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 373

Glu Trp His Lys Phe Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 374

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 374

Glu Trp His Lys Phe Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 375

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 375

Asp Trp His Lys Phe Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 376

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 376

Asp Trp His Lys Phe Phe Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 377

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 377

Asp Trp His Lys Phe Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 378

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 378

Asp Trp Phe Lys Phe His Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 379

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 379

Glu Trp Phe Lys Phe His Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 380

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 380

Glu Trp Phe Lys Phe His Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 381

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 381

Asp Trp Phe Lys Phe His Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 382

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 382

Asp Trp Phe Lys Phe His Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 383

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 383

Asp Trp Phe Lys Phe His Tyr Asp Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 384

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 384

Asp Trp Phe Lys Val Phe Tyr Asp Lys His Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 385

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 385

Glu Trp Phe Lys Val Phe Tyr Glu Lys His Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 386

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 386

Glu Trp Phe Lys Val Phe Tyr Asp Lys His Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 387

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 387

Asp Trp Phe Lys Val Phe Tyr Glu Lys His Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 388

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 388

Asp Trp Phe Lys Val Phe Tyr Asp Lys His Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 389

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 389

Asp Trp Phe Lys Val Phe Tyr Asp Lys His Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 390

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 390

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

His Phe

<210> 391

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 391

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

His Phe

<210> 392

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 392

Glu Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

His Phe

<210> 393

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 393

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

His Phe

<210> 394

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 394

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

His Phe

<210> 395

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 395

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

His Phe

<210> 396

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 396

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe His

<210> 397

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 397

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Phe His

<210> 398

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 398

Glu Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe His

<210> 399

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 399

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe His

<210> 400

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 400

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe His

<210> 401

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 401

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe His

<210> 402

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 402

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Phe His

<210> 403

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 403

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 404

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 404

Phe His Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 405

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 405

Phe His Glu Lys Phe Lys Glu Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 406

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 406

Phe His Asp Lys Phe Lys Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 407

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 407

Phe His Asp Lys Phe Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 408

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 408

Phe His Asp Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 409

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 409

Phe His Glu Lys Phe Lys Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 410

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 410

Phe His Glu Lys Phe Lys Glu Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 411

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 411

Phe His Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 412

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 412

His Phe Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 413

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 413

His Phe Asp Lys Phe Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 414

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 414

His Phe Glu Lys Phe Lys Glu Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 415

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 415

His Phe Asp Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 416

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 416

His Phe Glu Lys Phe Lys Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 417

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 417

His Phe Glu Lys Phe Lys Glu Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 418

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 418

His Phe Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 419

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 419

Phe Phe Glu Lys His Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 420

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 420

Phe Phe Asp Lys His Lys Asp Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 421

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 421

Phe Phe Glu Lys His Lys Glu Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 422

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 422

Phe Phe Asp Lys His Lys Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 423

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 423

Phe Phe Asp Lys His Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 424

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 424

Phe Phe Glu Lys His Lys Glu Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 425

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 425

Phe Phe Glu Lys His Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 426

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 426

Phe Val Glu Lys Phe Lys Glu Ala His Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 427

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 427

Phe Val Asp Lys Phe Lys Asp Ala His Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 428

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 428

Phe Val Glu Lys Phe Lys Glu Ala His Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 429

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 429

Phe Val Asp Lys Phe Lys Asp Ala His Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 430

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 430

Phe Val Asp Lys Phe Lys Glu Ala His Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 431

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 431

Phe Val Glu Lys Phe Lys Asp Ala His Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 432

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 432

Phe Val Glu Lys Phe Lys Glu Ala His Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 433

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 433

Phe Val Glu Lys Phe Lys Glu Ala His Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 434

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 434

Phe Ala Glu Lys Phe Lys Glu His Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 435

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 435

Phe Ala Asp Lys Phe Lys Asp His Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 436

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 436

Phe Ala Glu Lys Phe Lys Glu His Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 437

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 437

Phe Ala Asp Lys Phe Lys Asp His Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 438

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 438

Phe Ala Asp Lys Phe Lys Glu His Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 439

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 439

Phe Ala Glu Lys Phe Lys Asp His Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 440

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 440

Phe Ala Glu Lys Phe Lys Glu His Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 441

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 441

Phe Ala Glu Lys Phe Lys Glu His Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 442

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 442

Phe Ala Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr His Ala Lys Phe

1 5 10 15

Trp Asp

<210> 443

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 443

Phe Ala Asp Lys Phe Lys Asp Phe Val Lys Glu Tyr His Ala Lys Phe

1 5 10 15

Trp Glu

<210> 444

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 444

Phe Ala Asp Lys Phe Lys Glu Phe Val Lys Asp Tyr His Ala Lys Phe

1 5 10 15

Trp Asp

<210> 445

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 445

Phe Ala Glu Lys Phe Lys Asp Phe Val Lys Asp Tyr His Ala Lys Phe

1 5 10 15

Trp Asp

<210> 446

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 446

Phe Ala Asp Lys Phe Lys Asp Phe Val Lys Asp Tyr His Ala Lys Phe

1 5 10 15

Trp Asp

<210> 447

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 447

Phe Ala Glu Lys Phe Lys Glu Phe Val Lys Glu Tyr His Ala Lys Phe

1 5 10 15

Trp Glu

<210> 448

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 448

Phe Ala Glu Lys Phe Lys Glu Phe Val Lys Glu Tyr His Ala Lys Phe

1 5 10 15

Trp Asp

<210> 449

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 449

Phe Ala Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr His Ala Lys Phe

1 5 10 15

Trp Glu

<210> 450

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 450

Phe Ala Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys His

1 5 10 15

Trp Asp

<210> 451

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 451

Phe Ala Asp Lys Phe Lys Asp Phe Val Lys Glu Tyr Phe Ala Lys His

1 5 10 15

Trp Glu

<210> 452

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 452

Phe Ala Glu Lys Phe Lys Glu Phe Val Lys Glu Tyr Phe Ala Lys His

1 5 10 15

Trp Glu

<210> 453

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 453

Phe Ala Asp Lys Phe Lys Asp Phe Val Lys Asp Tyr Phe Ala Lys His

1 5 10 15

Trp Asp

<210> 454

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 454

Phe Ala Asp Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys His

1 5 10 15

Trp Asp

<210> 455

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 455

Phe Ala Glu Lys Phe Lys Asp Phe Val Lys Asp Tyr Phe Ala Lys His

1 5 10 15

Trp Asp

<210> 456

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 456

Phe Ala Glu Lys Phe Lys Glu Phe Val Lys Glu Tyr Phe Ala Lys His

1 5 10 15

Trp Asp

<210> 457

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 457

Phe Ala Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys His

1 5 10 15

Trp Glu

<210> 458

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 458

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 459

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 459

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 460

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 460

Glu Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 461

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 461

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 462

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 462

Glu Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 463

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 463

Asp Trp Phe Lys Ala Phe Tyr Glu Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 464

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 464

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Asp Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 465

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 465

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Asp

1 5 10 15

Ala Phe

<210> 466

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 466

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 467

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 467

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 468

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 468

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 469

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 469

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 470

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 470

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 471

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (3)..(3)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (6)..(6)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (14)..(14)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (18)..(18)

<223> Phenyl containing p-nitro moiety

<400> 471

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 472

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (1)..(1)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (5)..(5)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (13)..(13)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (16)..(16)

<223> Phenyl containing p-nitro moiety

<400> 472

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 473

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (1)..(1)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (5)..(5)

<223> Phenyl containing p-nitro moiety

<400> 473

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 474

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (13)..(13)

<223> Phenyl containing p-nitro moiety

<220>

<221> misc

<222> (16)..(16)

<223> Phenyl containing p-nitro moiety

<400> 474

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 475

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (1)..(1)

<223> Phenyl containing p-nitro moiety

<400> 475

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 476

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (5)..(5)

<223> Phenyl containing p-nitro moiety

<400> 476

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 477

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (13)..(13)

<223> Phenyl containing p-nitro moiety

<400> 477

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 478

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct, Nph peptide mimetic

<220>

<221> misc

<222> (16)..(16)

<223> Phenyl containing p-nitro moiety

<400> 478

Phe Ala Glu Lys Glu Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 479

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 479

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 480

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 480

Phe Ala Asp Lys Phe Lys Asp Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 481

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 481

Phe Ala Glu Arg Phe Arg Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 482

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 482

Phe Ala Glu Lys Phe Arg Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 483

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 483

Phe Ala Glu Lys Phe Lys Glu Ala Val Arg Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 484

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 484

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Arg Phe

1 5 10 15

Trp Asp

<210> 485

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 485

Phe Ala Glu Lys Phe Arg Glu Ala Val Lys Asp Tyr Glu Ala Lys Phe

1 5 10 15

Trp Asp

<210> 486

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 486

Leu Phe Glu Lys Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 487

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 487

Leu Phe Glu Arg Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 488

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 488

Leu Phe Glu Lys Phe Ala Glu Ala Phe Arg Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 489

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 489

Leu Phe Glu Lys Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Arg Trp

1 5 10 15

Lys Asp

<210> 490

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 490

Leu Phe Glu Lys Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Arg Asp

<210> 491

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 491

Leu Phe Glu Lys Phe Ala Glu Ala Phe Lys Glu Tyr Val Ala Lys Trp

1 5 10 15

Lys Glu

<210> 492

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 492

Leu Phe Asp Lys Phe Ala Asp Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 493

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 493

Leu Phe Asp Lys Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 494

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 494

Leu Phe Glu Lys Phe Ala Asp Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 495

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 495

Leu Phe Glu Lys Phe Ala Glu Ala Phe Lys Glu Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 496

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 496

Leu Phe Glu Lys Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Glu

<210> 497

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 497

Phe Ala Glu Lys Ala Trp Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Lys Asp

<210> 498

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 498

Phe Ala Glu Arg Ala Trp Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Lys Asp

<210> 499

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 499

Phe Ala Glu Lys Ala Trp Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Lys Asp

<210> 500

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 500

Phe Ala Glu Lys Ala Trp Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Lys Asp

<210> 501

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 501

Phe Ala Glu Lys Ala Trp Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Arg Asp

<210> 502

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 502

Phe Ala Glu Lys Ala Trp Glu Phe Val Lys Glu Tyr Phe Ala Lys Leu

1 5 10 15

Lys Glu

<210> 503

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 503

Phe Ala Asp Lys Ala Trp Asp Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Lys Asp

<210> 504

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 504

Phe Ala Asp Lys Ala Trp Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Lys Asp

<210> 505

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 505

Phe Ala Glu Lys Ala Trp Asp Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Lys Asp

<210> 506

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 506

Phe Ala Glu Lys Ala Trp Glu Phe Val Lys Glu Tyr Phe Ala Lys Leu

1 5 10 15

Lys Asp

<210> 507

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 507

Phe Ala Glu Lys Ala Trp Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Lys Glu

<210> 508

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 508

Phe Phe Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 509

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 509

Phe Phe Glu Lys Phe Lys Glu Phe Val Lys Glu Tyr Phe Ala Lys Leu

1 5 10 15

Trp Glu

<210> 510

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 510

Phe Phe Asp Lys Phe Lys Asp Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 511

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 511

Phe Phe Glu Arg Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 512

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 512

Phe Phe Glu Lys Phe Arg Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 513

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 513

Phe Phe Glu Lys Phe Lys Glu Phe Val Arg Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 514

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 514

Phe Phe Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Arg Leu

1 5 10 15

Trp Asp

<210> 515

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 515

Phe Phe Asp Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 516

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 516

Phe Phe Glu Lys Phe Lys Asp Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 517

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 517

Phe Phe Glu Lys Phe Lys Glu Phe Val Lys Glu Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 518

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 518

Phe Phe Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Glu

<210> 519

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 519

Phe Leu Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 520

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 520

Phe Leu Glu Lys Phe Lys Glu Phe Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 521

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 521

Phe Leu Asp Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 522

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 522

Phe Leu Asp Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 523

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 523

Phe Leu Glu Lys Phe Lys Asp Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 524

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 524

Phe Leu Glu Lys Phe Lys Glu Phe Val Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 525

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 525

Phe Leu Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 526

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 526

Phe Leu Glu Arg Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 527

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 527

Phe Leu Glu Lys Phe Arg Glu Phe Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 528

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 528

Phe Leu Glu Lys Phe Lys Glu Phe Val Arg Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 529

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 529

Phe Leu Glu Lys Phe Lys Glu Phe Val Lys Asp Tyr Phe Ala Arg Phe

1 5 10 15

Trp Asp

<210> 530

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 530

Phe Phe Glu Lys Phe Lys Glu Phe Phe Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 531

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 531

Phe Phe Glu Lys Phe Lys Glu Phe Phe Lys Glu Tyr Phe Ala Lys Leu

1 5 10 15

Trp Glu

<210> 532

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 532

Phe Phe Asp Lys Phe Lys Asp Phe Phe Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 533

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 533

Phe Phe Glu Arg Phe Lys Glu Phe Phe Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 534

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 534

Phe Phe Glu Lys Phe Arg Glu Phe Phe Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 535

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 535

Phe Phe Glu Lys Phe Lys Glu Phe Phe Arg Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 536

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 536

Phe Phe Glu Arg Phe Lys Glu Phe Phe Lys Asp Tyr Phe Ala Arg Leu

1 5 10 15

Trp Asp

<210> 537

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 537

Phe Phe Asp Lys Phe Lys Glu Phe Phe Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 538

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 538

Phe Phe Glu Lys Glu Lys Asp Phe Phe Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 539

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 539

Phe Phe Glu Lys Phe Lys Glu Phe Phe Lys Glu Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 540

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 540

Phe Phe Glu Lys Phe Lys Glu Phe Phe Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Glu

<210> 541

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 541

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 542

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 542

Asp Lys Trp Lys Ala Val Tyr Asp Lys Phe Ala Glu Ala Phe Lys Glu

1 5 10 15

Phe Phe

<210> 543

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 543

Glu Lys Trp Lys Ala Val Tyr Glu Lys Phe Ala Glu Ala Phe Lys Glu

1 5 10 15

Phe Phe

<210> 544

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 544

Asp Lys Trp Lys Ala Val Tyr Asp Lys Phe Ala Asp Ala Phe Lys Asp

1 5 10 15

Phe Phe

<210> 545

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 545

Asp Arg Trp Lys Ala Val Tyr Asp Lys Phe Ala Glu Ala Phe Lys Glu

1 5 10 15

Phe Phe

<210> 546

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 546

Asp Lys Trp Arg Ala Val Tyr Asp Lys Phe Ala Glu Ala Phe Lys Glu

1 5 10 15

Phe Phe

<210> 547

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 547

Asp Lys Trp Lys Ala Val Tyr Asp Arg Phe Ala Glu Ala Phe Lys Glu

1 5 10 15

Phe Phe

<210> 548

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 548

Asp Lys Trp Lys Ala Val Tyr Asp Lys Phe Ala Glu Ala Phe Arg Glu

1 5 10 15

Phe Phe

<210> 549

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 549

Phe Phe Glu Lys Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 550

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 550

Phe Phe Glu Lys Phe Ala Glu Ala Phe Lys Glu Tyr Val Ala Lys Trp

1 5 10 15

Lys Glu

<210> 551

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 551

Phe Phe Asp Lys Phe Ala Asp Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 552

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 552

Phe Phe Glu Arg Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 553

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 553

Glu Phe Glu Arg Phe Ala Glu Ala Phe Arg Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 554

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 554

Phe Phe Glu Lys Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Arg Trp

1 5 10 15

Lys Asp

<210> 555

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 555

Phe Phe Glu Arg Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Arg Asp

<210> 556

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 556

Phe Phe Asp Lys Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 557

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 557

Phe Phe Glu Lys Phe Ala Asp Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 558

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 558

Phe Phe Glu Arg Phe Ala Glu Ala Phe Lys Glu Tyr Val Ala Lys Trp

1 5 10 15

Lys Asp

<210> 559

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 559

Phe Phe Glu Arg Phe Ala Glu Ala Phe Lys Asp Tyr Val Ala Lys Trp

1 5 10 15

Lys Glu

<210> 560

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 560

Phe Phe Glu Lys Phe Lys Glu Phe Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 561

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 561

Phe Phe Asp Lys Phe Lys Asp Phe Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 562

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 562

Phe Phe Glu Lys Phe Lys Glu Phe Phe Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 563

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 563

Phe Phe Glu Arg Phe Lys Glu Phe Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 564

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 564

Phe Phe Glu Lys Phe Arg Glu Phe Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 565

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 565

Phe Phe Glu Lys Phe Lys Glu Phe Phe Arg Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 566

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 566

Phe Phe Glu Lys Phe Lys Glu Phe Phe Lys Asp Tyr Phe Ala Arg Phe

1 5 10 15

Trp Asp

<210> 567

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 567

Phe Phe Asp Lys Phe Lys Glu Phe Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 568

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 568

Phe Phe Glu Lys Phe Lys Asp Phe Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 569

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 569

Phe Phe Glu Lys Phe Lys Glu Phe Phe Lys Glu Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 570

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 570

Phe Phe Glu Lys Phe Lys Glu Phe Phe Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Glu

<210> 571

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-methyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is delta-methylated

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is delta-methylated

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is delta-methylated

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is delta-methylated

<400> 571

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 572

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-methyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is delta-methylated

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is delta-methylated

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is delta-methylated

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is delta-methylated

<400> 572

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 573

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-dimethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 and δ-N-dimethyl-Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-dimethyl-Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 9 is δ-N-dimethyl-Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 9 is δ-N-dimethyl-Lys

<400> 573

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 574

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-dimethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 and δ-N-dimethyl-Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-dimethyl-Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is δ-N-dimethyl-Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a δ-N-dimethyl-Lys

<400> 574

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 575

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-dimethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 and δ-N-dimethyl-Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-dimethyl-Lys

<400> 575

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 576

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-dimethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 and δ-N-dimethyl Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-dimethyl Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is δ-N-dimethyl Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a δ-N-dimethyl Lys

<400> 576

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 577

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-dimethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 and δ-N-dimethyl Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-dimethyl Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is δ-N-dimethyl Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a δ-N-dimethyl Lys

<400> 577

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 578

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-dimethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 and δ-N-dimethyl Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-dimethyl Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is δ-N-dimethyl Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 15 is a δ-N-dimethyl Lys

<400> 578

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 579

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-monomethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 and δ-N-monomethyl-Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-monomethyl-Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is δ-N-monomethyl-Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a δ-N-monomethyl-Lys

<400> 579

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 580

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-monomethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 and δ-N-monomethyl-Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-monomethyl-Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is δ-N-monomethyl-Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a δ-N-monomethyl-Lys

<400> 580

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 581

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-monomethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 and δ-N-monomethyl-Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-monomethyl-Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is δ-N-monomethyl-Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a δ-N-monomethyl-Lys

<400> 581

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 582

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-ethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys and δ-N-ethyl-Lys at position 4

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-ethyl-Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is δ-N-ethyl-Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is δ-N-ethyl-Lys

<400> 582

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 583

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-ethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys and δ-N-ethyl-Lys at position 4

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-ethyl-Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is δ-N-ethyl-Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is δ-N-ethyl-Lys

<400> 583

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 584

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; δ-N-ethyl Lys analog

<220>

<221> misc

<222> (4)..(4)

<223> Lys and δ-N-ethyl-Lys at position 4

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is δ-N-ethyl-Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is δ-N-ethyl-Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is δ-N-ethyl-Lys

<400> 584

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 585

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a homologous Lys

<400> 585

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 586

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a homologous Lys

<400> 586

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 587

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 13 is a homologous Lys

<400> 587

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 588

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a homologous Lys

<400> 588

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 589

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a homologous Lys

<400> 589

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 590

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a homologous Lys

<400> 590

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 591

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a homologous Lys

<400> 591

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 592

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a homologous Lys

<400> 592

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 593

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a homologous Lys

<400> 593

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 594

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a homologous Lys

<400> 594

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 595

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; homologous Lys analogs

<220>

<221> misc

<222> (4)..(4)

<223> Lys at position 4 is a homologous Lys

<220>

<221> misc

<222> (9)..(9)

<223> Lys at position 9 is a homologous Lys

<220>

<221> misc

<222> (13)..(13)

<223> Lys at position 13 is a homologous Lys

<220>

<221> misc

<222> (15)..(15)

<223> Lys at position 15 is a homologous Lys

<400> 595

Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 596

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-dimethyl-ornithine

<400> 596

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 597

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-dimethyl-ornithine

<400> 597

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 598

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-dimethyl-ornithine

<400> 598

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 599

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-dimethyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-dimethyl-ornithine

<400> 599

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 600

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-diethyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-diethyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-diethyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-diethyl-ornithine

<400> 600

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 601

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-methyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-methyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-methyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-methyl-ornithine

<400> 601

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 602

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-methyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-methyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-methyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-methyl-ornithine

<400> 602

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 603

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-methyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-methyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-methyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-methyl-ornithine

<400> 603

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 604

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-ethyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-ethyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-ethyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-ethyl-ornithine

<400> 604

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 605

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-ethyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-ethyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-ethyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-ethyl-ornithine

<400> 605

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 606

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ornithine analog

<220>

<221> misc

<222> (4)..(4)

<223> Xaa at position 4 is Δ-N-ethyl-ornithine

<220>

<221> misc

<222> (9)..(9)

<223> Xaa at position 9 is Δ-N-ethyl-ornithine

<220>

<221> misc

<222> (13)..(13)

<223> Xaa at position 13 is Δ-N-ethyl-ornithine

<220>

<221> misc

<222> (15)..(15)

<223> Xaa at position 15 is Δ-N-ethyl-ornithine

<400> 606

Asp Trp Phe Xaa Ala Phe Tyr Asp Xaa Val Ala Glu Xaa Phe Xaa Glu

1 5 10 15

Ala Phe

<210> 607

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE receptor binding domain

<400> 607

Arg Leu Leu Arg Lys Arg Leu Lys Arg Leu

1 5 10

<210> 608

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE receptor binding domain

<400> 608

Arg Met Leu Arg Lys Arg Met Lys Arg Leu

1 5 10

<210> 609

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE receptor binding domain

<400> 609

Arg Leu Leu Arg Lys Pro Leu Lys Arg Leu

1 5 10

<210> 610

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE receptor binding domain

<400> 610

Arg Val Leu Arg Lys Arg Val Asn Arg Leu

1 5 10

<210> 611

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE receptor binding domain

<400> 611

Arg Leu Val Arg Lys Arg Leu Lys Arg Met

1 5 10

<210> 612

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE receptor binding domain

<400> 612

Arg Leu Leu Arg Arg Arg Leu Arg Arg Leu

1 5 10

<210> 613

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE receptor binding domain

<400> 613

Arg Phe Phe Arg Lys Arg Leu Lys Arg Leu

1 5 10

<210> 614

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; lipid-associated peptide

<400> 614

Phe Ala Glu Lys Leu Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Leu

1 5 10 15

Trp Asp

<210> 615

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; lipid-associated peptide

<400> 615

Phe Ala Glu Lys Phe Lys Glu Ala Val Lys Asp Tyr Phe Ala Lys Phe

1 5 10 15

Trp Asp

<210> 616

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 616

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Lys Phe Lys Glu

1 5 10 15

Ala Phe

<210> 617

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic constructs; peptide mimetics

<400> 617

Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu

1 5 10 15

Phe Phe

<210> 618

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; lipid-associated peptide

<400> 618

Asp Trp Leu Arg Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Arg Glu

1 5 10 15

Ala Phe

<210> 619

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; lipid-associated peptide

<400> 619

Asp Trp Leu Arg Ala Leu Tyr Asp Lys Val Ala Glu Lys Leu Arg Glu

1 5 10 15

Ala Leu

<210> 620

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; lipid-associated peptide

<400> 620

Asp Leu Leu Arg Ala Leu Tyr Asp Lys Val Ala Glu Lys Leu Arg Glu

1 5 10 15

Ala Trp

<210> 621

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; rat ApoE mimetic

<400> 621

Leu Arg Arg Met Arg Arg Arg Leu Met Arg

1 5 10

<210> 622

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; rat ApoE mimetic

<400> 622

Arg Leu Thr Arg Arg Arg Gly Lys

1 5

<210> 623

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE-mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal butyryl

<400> 623

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 624

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal hexanoyl

<400> 624

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 625

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal octanoyl

<400> 625

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 626

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal decanoyl

<400> 626

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 627

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal lauroyl

<400> 627

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 628

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal myristoyl group

<400> 628

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 629

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal palmitoyl

<400> 629

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 630

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal stearoyl

<400> 630

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 631

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal palmitoyl

<400> 631

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 632

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal arachidonic acid

<400> 632

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 633

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal behenoyl

<400> 633

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 634

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal oleoyl

<400> 634

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 635

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal ricinoleyl

<400> 635

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 636

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal linolenoyl

<400> 636

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 637

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal octadecanoyl

<400> 637

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 638

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal cod oleoyl

<400> 638

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 639

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal erucyl group

<400> 639

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 640

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal cetoleoyl

<400> 640

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 641

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal neuryl

<400> 641

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 642

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal adrenoyl

<400> 642

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 643

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal α-linolenoyl

<400> 643

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 644

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal γ-linolenoyl

<400> 644

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 645

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal EPA

<400> 645

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 646

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal DHA

<400> 646

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 647

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal fish oil

<400> 647

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 648

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 4-amino-butyryl

<400> 648

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 649

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 6-amino-hexanoyl

<400> 649

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 650

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 8-amino-octanoyl

<400> 650

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 651

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 10-amino-decanoyl

<400> 651

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 652

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 12-amino-lauroyl

<400> 652

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 653

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 14-amino-cinnamoyl

<400> 653

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 654

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 16-amino-palmitoyl

<400> 654

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 655

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal-16-amino-palmitoleyl

<400> 655

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 656

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 18-amino-stearyl

<400> 656

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 657

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 18-amino-oleoyl

<400> 657

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 658

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 18-amino-linolenoyl

<400> 658

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 659

<211> 28

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; ApoE mimetic peptide

<220>

<221> MISC_Features

<222> (1)..(1)

<223> N-terminal 20-amino-arachidonoyl

<400> 659

Leu Arg Arg Leu Arg Arg Arg Leu Leu Arg Asp Trp Leu Lys Ala Phe

1 5 10 15

Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu Ala Phe

20 25

<210> 660

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; lipid-associated peptide

<400> 660

Lys Ala Phe Glu Glu Val Leu Ala Lys Lys Phe Tyr Asp Lys Ala Leu

1 5 10 15

Trp Asp

<210> 661

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic construct; Apo E receptor binding domain

<400> 661

Leu Arg Leu Leu Arg Lys Leu Lys Arg Arg

1 5 10

Claims (54)

1. A synthetic apolipoprotein E (ApoE) mimetic peptide, which is Aha-[R]he18A-NH ₂ ; Ac-Aha-[R]he18A-NH ₂ ; octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 625); myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 628); oleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 634); or palmitoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH ₂ (SEQ ID NO: 629); [R]he refers to the peptide LRRLRRRLLR (SEQ ID NO: 11), 18A refers to the peptide DWLKAFYDKVAEKLKEAF (SEQ ID NO: 5), and Aha refers to aminohexanoic acid. 2 . The peptide according to claim 1 , wherein the synthetic ApoE mimetic peptide is Aha-[R]he18A-NH ₂ . 3. The peptide according to claim 1, wherein the synthetic ApoE mimetic peptide is Ac-Aha-[R]he18A- _NH2 . 4. The peptide of claim 1, wherein the synthetic ApoE mimetic peptide is octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 625). 5. The peptide of claim 1, wherein the synthetic ApoE mimetic peptide is myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 628). 6. The peptide of claim 1, wherein the synthetic ApoE mimetic peptide is oleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 634). 7. The peptide of claim 1, wherein the synthetic ApoE mimetic peptide is palmitoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- _NH2 (SEQ ID NO: 629). 8 . A pharmaceutical composition comprising the synthetic apolipoprotein E mimetic peptide according to claim 1 and a pharmaceutically acceptable carrier. 9. Use of the synthetic apolipoprotein E mimetic peptide according to any one of claims 1 to 7 for the preparation of a medicament for affecting plasma LDL, plasma VLDL or both in a subject. 10 . The use according to claim 9 , wherein the drug comprises the synthetic apolipoprotein E mimetic peptide and a pharmaceutically acceptable carrier. 11. The use according to claim 9, wherein the medicament is used to enhance the binding of LDL to cells of the subject. 12. The use according to claim 9, wherein the medicament is used to increase the degradation of LDL by cells of the subject. 13. The use according to claim 9, wherein the medicament is for lowering LDL cholesterol in the subject. 14. The use according to claim 9, wherein the medicament is used to enhance the binding of VLDL to cells of the subject. 15. The use according to claim 9, wherein the medicament is used to increase the degradation of VLDL by cells of the subject. 16. The use according to claim 9, wherein the medicament is for lowering VLDL cholesterol in the subject. 17. The use according to claim 9, wherein the medicament is for lowering the total plasma concentration of cholesterol in the subject. 18. Use of the synthetic apolipoprotein E mimetic peptide according to any one of claims 1 to 7 for the preparation of a medicament for treating a disease in a subject, wherein the disease comprises coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebrovascular disease, diabetic cardiovascular disease, macular degeneration, congestive heart failure and/or systemic lupus erythematosus. 19. Use of the synthetic apolipoprotein E mimetic peptide according to any one of claims 1 to 7 for the preparation of a medicament for lowering plasma cholesterol in a subject. 20. The use according to claim 19, wherein the medicament comprises the synthetic apolipoprotein E mimetic peptide and a pharmaceutically acceptable carrier. 21. The use according to claim 19, wherein the medicament is used to enhance the binding of LDL to cells of the subject. 22. The use according to claim 19, wherein the medicament is used to increase the degradation of LDL by cells of the subject. 23. The use of claim 19, wherein the medicament is for lowering LDL cholesterol in the subject. 24. The use according to claim 19, wherein the medicament is for enhancing the binding of VLDL to cells of the subject. 25. The use according to claim 19, wherein the medicament is used to increase the degradation of VLDL by cells of the subject. 26. The use of claim 19, wherein the medicament is for lowering VLDL cholesterol in the subject. 27. The use according to claim 19, wherein the medicament is for lowering the total plasma concentration of cholesterol in the subject. 28. Use of the synthetic apolipoprotein E mimetic peptide according to any one of claims 1 to 7 for the preparation of a medicament for treating atherosclerosis in a subject. 29. The use according to claim 28, wherein the medicament is for enhancing the binding of LDL to cells of the subject. 30. The use according to claim 28, wherein the medicament is used to increase the degradation of LDL by cells of the subject. 31. The use of claim 28, wherein the medicament is for lowering LDL cholesterol in the subject. 32. The use according to claim 28, wherein the medicament is for enhancing the binding of VLDL to cells of the subject. 33. The use according to claim 28, wherein the medicament is for increasing the degradation of VLDL by cells of the subject. 34. The use of claim 28, wherein the medicament is for lowering VLDL cholesterol in the subject. 35. The use according to claim 28, wherein the medicament is for lowering the total plasma concentration of cholesterol in the subject. 36. Use of the synthetic apolipoprotein E mimetic peptide of any one of claims 1 to 7 for the preparation of a medicament for treating a lipid disorder in a subject. 37. The use according to claim 36, wherein the medicament is for enhancing the binding of LDL to cells of the subject. 38. The use according to claim 36, wherein the medicament is used to increase the degradation of LDL by cells of the subject. 39. The use of claim 36, wherein the medicament is for lowering LDL cholesterol in the subject. 40. The use according to claim 36, wherein the medicament is for enhancing the binding of VLDL to cells of the subject. 41. The use according to claim 36, wherein the medicament is for increasing the degradation of VLDL by cells of the subject. 42. The use of claim 36, wherein the medicament is for lowering VLDL cholesterol in the subject. 43. The use according to claim 36, wherein the medicament is for lowering the total plasma concentration of cholesterol in the subject. 44. Use of the synthetic apolipoprotein E mimetic peptide of any one of claims 1 to 7 for the preparation of a medicament for treating a lipid disorder in a subject for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein the treatment cycle is followed by a rest period in which the Apo E mimetic peptide is not administered. 45. The use according to claim 44, wherein the treatment cycle further comprises a second treatment cycle after the rest period. 46. Use of the synthetic apolipoprotein E mimetic peptide of any one of claims 1 to 7 for the preparation of a medicament for treating acute coronary syndrome (ACS) in a subject for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of the Apo E mimetic peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic peptide, wherein the treatment cycle is followed by a rest period in which the Apo E mimetic peptide is not administered. 47. The use according to claim 46, wherein the rest period is at least four weeks. 48. The use according to claim 46, wherein the rest period is followed by a second treatment cycle. 49. The use of claim 48, wherein the second treatment cycle is administered after a four-week rest period. 50. The use of claim 48, wherein the second treatment cycle is administered one year from the start of the initial treatment cycle. 51. The use according to claim 46, wherein an ACS therapeutic agent other than the Apo E mimetic peptide is administered during the rest period. 52. The use according to claim 51, wherein the ACS therapeutic agent other than the Apo E mimetic peptide is a conventional LDL-lowering therapy or HDL-raising therapy. 53. The use according to claim 52, wherein the conventional LDL-lowering therapy is a statin. 54. The use according to claim 52, wherein the HDL-raising therapy is an Apo A1-raising drug, a CETP inhibitor, a phospholipase A2 inhibitor, Apo A1 Milano or an Apo A1 mimetic.