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WO2003066672A1 - Peptides - Google Patents

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Publication number
WO2003066672A1
WO2003066672A1 PCT/JP2003/001333 JP0301333W WO03066672A1 WO 2003066672 A1 WO2003066672 A1 WO 2003066672A1 JP 0301333 W JP0301333 W JP 0301333W WO 03066672 A1 WO03066672 A1 WO 03066672A1
Authority
WO
WIPO (PCT)
Prior art keywords
peptide
amino acid
acid sequence
seq
active ingredient
Prior art date
Application number
PCT/JP2003/001333
Other languages
English (en)
Japanese (ja)
Inventor
Kenji Sakamoto
Original Assignee
Nakoshi, Hideo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nakoshi, Hideo filed Critical Nakoshi, Hideo
Priority to AU2003211501A priority Critical patent/AU2003211501A1/en
Priority to JP2003566043A priority patent/JPWO2003066672A1/ja
Publication of WO2003066672A1 publication Critical patent/WO2003066672A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4705—Regulators; Modulating activity stimulating, promoting or activating activity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to peptides. More specifically, the present invention relates to a peptide having an insulin production promoting effect, a gastric acid secretion suppressing effect, a growth hormone production promoting effect, a blood pressure lowering effect, a fat accumulation suppressing effect, an allergy suppressing effect, an analgesic effect, and a central nervous system function promoting effect.
  • An object of the present invention is to provide a peptide which is particularly useful as a medicine or food. Disclosure of the invention
  • the inventors of the present invention have conducted intensive studies to solve the above problems, and as a result, have found that a peptide having a specific amino acid sequence has excellent physiological activity and is particularly useful as a medicine or a food. Was completed.
  • the present invention relates to a peptide having the amino acid sequence represented by SEQ ID NO: 1 in the sequence listing, or substitution or deletion of one or more amino acids in the amino acid sequence, or substitution of one or more amino acids in the amino acid sequence.
  • a peptide having an insulin production promoting effect a peptide comprising the peptide as an active ingredient, an insulin production enhancer comprising these peptides, and an insulin production enhancer comprising the peptide as an active ingredient.
  • the present invention relates to a peptide having an amino acid sequence represented by SEQ ID NO: 2 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, or one or more amino acids are substituted in the amino acid sequence.
  • the present invention relates to a peptide having an amino acid sequence represented by SEQ ID NO: 3 in the sequence listing, or one or more amino acids in the amino acid sequence are substituted or deleted, or one or more amino acids are substituted in the amino acid sequence.
  • a medicament or a food such as a growth hormone production promoter containing the above-mentioned peptide as an active ingredient.
  • the present invention relates to a peptide having the amino acid sequence represented by SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, or 12 in the sequence listing, or 1 Or a peptide having an amino acid sequence in which a plurality of amino acids are substituted or deleted, or in which one or more amino acids are inserted or added to the amino acid sequence, and which has a blood pressure lowering effect.
  • Pharmaceuticals or foods such as a peptide containing the peptide as an active ingredient, a blood pressure lowering agent comprising these peptides, and a blood pressure lowering agent containing the peptide as an active ingredient.
  • the present invention relates to a peptide having the amino acid sequence represented by SEQ ID NO: 13, 14, 15, 15, 16, 17 or 18 in the sequence listing, A peptide having an amino acid sequence in which one or more amino acids in the amino acid sequence have been substituted or deleted, or an amino acid sequence in which one or more amino acids have been inserted or added to the amino acid sequence, and Pharmaceuticals or foods such as peptides having an antibacterial effect, peptides containing the peptides as active ingredients, fat accumulation inhibitors composed of these peptides, and fat accumulation inhibitors containing the peptides as active ingredients.
  • the present invention provides a peptide having an amino acid sequence represented by SEQ ID NO: 19 in the sequence listing, or a substitution or deletion of one or more amino acids in the amino acid sequence, or A peptide having an amino acid sequence in which one or more amino acids are inserted or added, wherein the peptide has an allergy-suppressing effect; Peptide to the peptide as an active ingredient, a pharmaceutical or a food such as those ⁇ les-saving one inhibitor consisting of peptides, and allele formic one inhibitor comprising the base peptide as an active ingredient.
  • the present invention relates to a peptide having an amino acid sequence represented by SEQ ID NO: 20, 21, or 22, or one or more amino acids in the amino acid sequence are substituted or deleted, or the amino acid A peptide having an amino acid sequence in which one or more amino acids are inserted or added to the sequence, the peptide having a blood pressure lowering effect, a peptide containing the peptide as an active ingredient, a blood pressure lowering agent comprising these peptides And a medicine or food, such as a hypotensive agent, containing the above-mentioned peptide as an active ingredient.
  • the present invention provides a peptide having the amino acid sequence represented by SEQ ID NO: 23 or 24, or substitution or deletion of one or more amino acids in the amino acid sequence, or Or a peptide having an amino acid sequence in which a plurality of amino acids are inserted or added, the peptide having an analgesic effect, a peptide containing the peptide as an active ingredient, an analgesic comprising the peptide, and the aforementioned It is a drug or food such as an analgesic containing a peptide as an active ingredient.
  • the present invention relates to a peptide having the amino acid sequence represented by SEQ ID NO: 25, 26, 27, 28, 29, 30, 31 or 32, or 1 Or a peptide having an amino acid sequence in which a plurality of amino acids are substituted or deleted, or in which one or more amino acids are inserted or added to the amino acid sequence, and which has a central nervous system function promoting effect.
  • Pharmaceuticals or foods such as a peptide, a peptide containing the peptide as an active ingredient, a central nervous system function promoter comprising the peptide, and a central nervous system function promoter containing the peptide as an active ingredient.
  • the peptide according to the first invention of the present invention is a peptide having an amino acid sequence represented by SEQ ID NO: 1 in the sequence listing. Since the peptide has a function of promoting insulin production, it is useful as an insulin production promoter and is applied to medicines, foods, and the like. For example, the peptide according to the first invention is blended as an active ingredient, and is applied to medicines, foods, etc., such as insulin production promoters. Among these, the insulin production promoter as a medicament can be used for the treatment and prevention of diabetes, and its application as a therapeutic agent for diabetes is also included in the category of the insulin production promoter of the present invention.
  • a peptide having a physiological activity has a small number of amino acid sequences substituted or deleted in the amino acid sequence, or a small number of amino acid sequences inserted or added to the amino acid sequence. It is well known to those skilled in the art that the physiological activity may be maintained. Therefore, one or more amino acids in the amino acid sequence shown in SEQ ID NO: 1 are substituted or deleted, or a peptide having an amino acid sequence in which one or more amino acids are inserted or added to the amino acid sequence. Further, peptides having an insulin production promoting effect are also included in the scope of the peptides according to the first invention of the present invention.
  • the amino acid sequence of such a peptide is shown in SEQ ID NO: It is preferred that it has 70% or more, more preferably 90% or more homology with the amino acid sequence represented by 1.
  • the insulin production promoting agent as the medicament according to the first invention is administered orally administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, or rectal administration.
  • a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, or rectal administration.
  • the dosage is determined appropriately based on the condition of the patient, the molecular weight of the active ingredient, and the like.
  • the body weight is preferably 1 kg and the daily dose is preferably about 0.1 mg to 0.1 mg.
  • the weight is preferably about 1 kg and about 0.1 mg to 1 Omg per day.
  • the insulin production promoter comprising the peptide according to the first invention can be appropriately formulated by a conventional method.
  • the insulin production promoter is dissolved in physiological saline in a concentration range of 30 mg / l to 300 mg Z1. Can be used.
  • oral administration it can be added to beverages to form a so-called drink.
  • the peptide according to the second invention of the present invention is a peptide having an amino acid sequence represented by SEQ ID NO: 2 in the sequence listing. Since the peptide has a function of suppressing gastric acid secretion, it is useful as a gastric acid secretion inhibitor and is applied to medicines, foods, and the like.
  • the peptide according to the second invention is blended as an active ingredient and applied to medicines, foods and the like such as gastric acid secretion inhibitors.
  • the gastric acid secretion inhibitor as a medicament can be used for treatment and prevention of gastric ulcer and duodenal ulcer, and the application as a gastrointestinal drug is also included in the scope of the gastric acid secretion inhibitor of the present invention.
  • one or more amino acids in the amino acid sequence shown in SEQ ID NO: 2 are substituted or deleted, or one or more amino acids are inserted in the amino acid sequence, or Peptides having an added amino acid sequence and having a gastric acid secretion inhibitory effect are also included in the scope of the peptides according to the second invention of the present invention. It is preferable that the amino acid sequence of such a peptide has 70% or more, more preferably 90% or more homology with the amino acid sequence represented by SEQ ID NO: 2.
  • the gastric acid secretion inhibitor as a medicament according to the second invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, or rectal administration, or orally.
  • the dosage is determined appropriately based on the condition of the patient, the molecular weight of the active ingredient, and the like.
  • the body weight is preferably 1 kg and the daily dose is preferably about 0.01 mg to 1 mg.
  • the body weight is preferably 1 kg, and about 0.1 to 10 mg per day is preferable.
  • the gastric acid secretion inhibitor comprising the peptide according to the second invention can be appropriately formulated by a conventional method, for example, a concentration of 30 mgZl to 300 mg / l in physiological saline. It is possible to use those dissolved within the range.
  • a so-called drink can be added to a beverage.
  • the peptide according to the third invention of the present invention is a peptide having an amino acid sequence represented by SEQ ID NO: 3 in the sequence listing. Since the peptide has a function of promoting the production of growth hormone, it is useful as a growth hormone production promoter and is applied to medicines, foods, and the like.
  • the above-mentioned peptide according to the third aspect of the present invention is blended as an active ingredient and applied to pharmaceuticals such as growth hormone production promoters, foods and the like.
  • the growth hormone production promoter as a medicine can be used for treating dwarfism.
  • amino acids in the amino acid sequence shown in SEQ ID NO: 3 are substituted or deleted, or one or more amino acids are inserted into the amino acid sequence or Peptides having an added amino acid sequence and having a growth hormone production promoting effect are also included in the scope of the peptide according to the third invention of the present invention. It is preferable that the amino acid sequence of such a peptide has 70% or more, more preferably 90% or more homology with the amino acid sequence represented by SEQ ID NO: 3.
  • the growth hormone production promoter as a medicament according to the third invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, or rectal administration, or orally. Also, the dose depends on the patient It is appropriately determined based on the condition of the individual, the molecular weight of the active ingredient, etc., but in general, the body weight is preferably 1 kg for parenteral administration and about 0.01 to 1 mg per day, and the weight for oral administration. 1 kg, about 0.1 mg to 10 mg per day is preferable. Further, the growth hormone production promoter comprising the peptide according to the third invention can be appropriately formulated by a conventional method, for example, in a concentration range of 30 mgZl to 300 mgZ1 in physiological saline. A dissolved one can be used. In the case of oral administration, a so-called drink can be added to a beverage.
  • a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, or rectal administration, or orally.
  • the peptide according to the fourth invention of the present invention is a peptide having an amino acid sequence represented by SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, or 12 in the sequence listing. Since the peptide has a function of lowering blood pressure, it is useful as a blood pressure lowering agent, and is applied to medicines, foods, and the like.
  • the above-mentioned peptide according to the fourth aspect of the present invention is blended as an active ingredient, and is applied to medicines, foods and the like such as antihypertensive agents.
  • the antihypertensive agent as a medicament can be used for treatment and prevention of hypertension, and its application as an antihypertensive agent is also included in the category of the antihypertensive agent of the present invention.
  • amino acids in the amino acid sequence shown in SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, or 12 are substituted.
  • a peptide having an amino acid sequence in which the amino acid sequence is deleted or deleted, or one or more amino acids are inserted or added in the amino acid sequence, and which has a blood pressure lowering effect is also a fourth invention of the present invention.
  • the amino acid sequence of such a peptide has at least 70%, more preferably at least 90%, the amino acid sequence represented by SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, or 12. Preferably, they have homology.
  • the antihypertensive agent as a medicament according to the fourth aspect of the present invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration or oral administration. Dosage may vary depending on patient condition and It is determined as appropriate based on the molecular weight of the active ingredient, etc., but in general, parenteral administration is preferably lkg in body weight, and 0.0 lmg per day or more: about Lmg is preferable. About 0.1 to 10 mg per day is preferred.
  • the antihypertensive agent comprising the peptide according to the fourth aspect of the present invention can be appropriately formulated by a conventional method.
  • a solution obtained by dissolving in a physiological saline solution in a concentration range of 30 mg / l to 300 OmgZl is used.
  • a so-called drink can be added to a beverage.
  • the peptide according to the fifth invention of the present invention is a peptide having an amino acid sequence represented by SEQ ID NO: 13, 14, 15, 16, 17 or 18 in the sequence listing. Since the peptide has a function of suppressing fat accumulation (fat accumulation suppressing effect), it is useful as a fat accumulation inhibitor, and is applied to medicines, foods, and the like.
  • the peptide according to the fifth aspect of the present invention is blended as an active ingredient, and is applied to medicines, foods and the like such as fat accumulation inhibitors.
  • the fat accumulation inhibitor as a medicament can be used for the treatment and prevention of hypolipidemia
  • the fat accumulation inhibitor of the present invention can be used as an agent for hyperlipidemia, a therapeutic agent for obesity, and an agent for preventing obesity. It is included in the category of accumulation inhibitors.
  • a peptide having a physiological activity has a small number of amino acid sequences substituted or deleted in the amino acid sequence, or a small number of amino acid sequences inserted or added to the amino acid sequence. It is well known to those skilled in the art that the physiological activity may be maintained. Therefore, one or more amino acids in the amino acid sequence shown in SEQ ID NO: 13, 14, 15, 15, 16, 17 or 18 are substituted or deleted, or one or more amino acids are added to the amino acid sequence.
  • Peptides having an amino acid sequence in which the amino acid is inserted or added and having an effect of suppressing fat accumulation are also included in the scope of the peptide according to the fifth invention of the present invention.
  • the amino acid sequence of such a peptide is at least 70%, more preferably at least 90%, the amino acid sequence represented by SEQ ID NOS: 13, 14, 15, 16, 17 or 18. It is preferable to have the above homology.
  • the fat accumulation inhibitor as a medicament according to the fifth invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, or rectal administration, or orally.
  • the dosage is determined appropriately based on the condition of the patient, the molecular weight of the active ingredient, and the like.
  • the body weight is preferably 1 kg and the daily dose is preferably about 0.01 mg to 1 mg.
  • the body weight is preferably 1 kg and about 0.1 to 10 mg per day.
  • the fat accumulation inhibitor comprising the peptide according to the fifth invention can be appropriately formulated by a conventional method.For example, 30 mg / l to 300 mg / l of physiological saline can be used. Those dissolved in the concentration range can be used.
  • a so-called drink can be added to a beverage.
  • the peptide according to the sixth invention of the present invention is a peptide having an amino acid sequence represented by SEQ ID NO: 19 in the sequence listing. Since the peptide has a function of suppressing allergy (allergy suppressing effect), it is useful as an allergy inhibitor and is applied to medicines, foods, and the like.
  • the peptide according to the sixth aspect of the present invention is blended as an active ingredient and applied to medicines, foods and the like such as allergic inhibitors.
  • allergy inhibitors as medicines can be used for the treatment of allergic diseases such as atopic dermatitis, bronchial asthma, allergic rhinitis, etc ..
  • the application of is also included in the category of the allergy suppressant of the present invention.
  • the fat accumulation inhibitor As in the case of the fat accumulation inhibitor, one or more amino acids in the amino acid sequence shown in SEQ ID NO: 19 are substituted or deleted, or one or more amino acids are inserted in the amino acid sequence.
  • a peptide having an added or added amino acid sequence and having an allergy suppressing effect is also included in the scope of the peptide according to the sixth invention of the present invention. It is preferable that the amino acid sequence of such a peptide has 70% or more, more preferably 90% or more homology with the amino acid sequence represented by SEQ ID NO: 19.
  • the allergy inhibitor as a medicament according to the sixth aspect of the present invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, or rectal administration, or orally.
  • the dosage is appropriately determined based on the condition of the patient, the molecular weight of the active ingredient, and the like.
  • the body weight is preferably 1 kg and the daily dose is preferably about 0.1 mg to 0.1 mg.
  • the body weight is preferably about 1 kg, and about 0.1 to 10 mg per day.
  • the allergy inhibitor comprising the peptide according to the sixth invention can be appropriately formulated by a conventional method.For example, a drug dissolved in physiological saline in a concentration range of S OmgZl SOO OmgZl can be used. Can be used. In the case of oral administration, a so-called drink can be added to a beverage.
  • the peptide according to the seventh invention of the present invention is a peptide having an amino acid sequence represented by SEQ ID NO: 20, 21 or 22. Since the peptide has a function of lowering blood pressure (blood pressure lowering effect), it is useful as a blood pressure lowering agent, and is applied to medicines, foods and the like.
  • the above-mentioned peptide according to the seventh aspect of the present invention is blended as an active ingredient, and is applied to medicines, foods and the like such as antihypertensive agents.
  • the antihypertensive agent as a medicament can be used for treatment and prevention of hypertension.
  • one or more amino acids in the amino acid sequence shown in SEQ ID NO: 20, 21, or 22 are replaced or deleted, or one or more amino acids are substituted in the amino acid sequence.
  • a peptide having an amino acid sequence in which the amino acid is inserted or added and having a blood pressure lowering effect is also included in the scope of the peptide according to the seventh aspect of the present invention.
  • the amino acid sequence of such a peptide preferably has 70% or more, more preferably 90% or more homology with the amino acid sequence shown in SEQ ID NO: 20, 21 or 22 ⁇ Seventh Invention
  • the antihypertensive agent as a medicament according to the present invention is preferably administered by parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration or oral administration.
  • the dosage is determined appropriately based on the condition of the patient, the molecular weight of the active ingredient, and the like.
  • the body weight is preferably about lkg, and about 0.01 mg to 1 mg per day, and for oral administration, about 1 kg, about 0.1 to 10 mg per day is preferable.
  • the antihypertensive comprising the peptide according to the seventh aspect of the present invention can be appropriately formulated by a conventional method.
  • the antihypertensive was dissolved in physiological saline in a concentration range of 30 mg / l to 300 mg / l.
  • a so-called drink can be added to a beverage.
  • the peptide according to the eighth invention of the present invention is a peptide having the amino acid sequence represented by SEQ ID NO: 23 or 24. Since the peptide has a function of relieving pain (analgesic effect), it is useful as an analgesic and is applied to medicines, foods and the like.
  • the peptide according to the eighth aspect of the present invention is blended as an active ingredient and applied to medicines such as analgesics, foods and the like.
  • analgesics as medicines can be used for treatment of headache, menstrual pain and the like.
  • one or more amino acids in the amino acid sequence shown in SEQ ID NO: 23 or 24 are substituted or deleted, or one or more amino acids are added to the amino acid sequence.
  • a peptide having an amino acid sequence into which is inserted or added and having an analgesic effect is also included in the scope of the peptide according to the eighth invention of the present invention.
  • the amino acid sequence of such a peptide preferably has 70% or more, more preferably 90% or more homology with the amino acid sequence represented by SEQ ID NO: 23 or 24.
  • the analgesic as a medicament according to the eighth invention is preferably administered by a parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, rectal administration, or oral administration.
  • the dosage is appropriately determined based on the condition of the patient, the molecular weight of the active ingredient, and the like.
  • the body weight is preferably 1 kg and the daily dose is preferably about 0.0 to 1 mg.
  • the body weight is preferably 1 kg, 0.1 mg per day;
  • the analgesic comprising the peptide according to the eighth invention can be appropriately formulated by a conventional method.
  • a solution dissolved in water at a concentration range of 30 mg / l to 300 Omg / 1 can be used.
  • a so-called drink can be added to a beverage.
  • the peptide according to the ninth invention of the present invention is a peptide having an amino acid sequence represented by SEQ ID NOS: 25, 26, 27, 28, 29, 30, 31 or 32. Since the peptide has a function of promoting central nervous system function (central nervous system function promoting effect), it is useful as a central nervous system function promoter and is applied to medicines, foods, and the like.
  • the above-mentioned peptide according to the ninth aspect of the present invention is blended as an active ingredient, and is applied to pharmaceuticals such as central nervous system function promoters, foods and the like.
  • central nervous system function promoters can be used to prevent cerebral nerve dysfunction due to cerebral ischemic injury or to improve cerebral nerve dysfunction (recovery treatment), etc.
  • the therapeutic agent for improving cerebral nerve dysfunction and application as a drug for central nervous system are also included in the category of the central nervous system function promoter of the present invention.
  • one or more amino acids in the amino acid sequence shown in SEQ ID NO: 25, 26, 27, 28, 29, 30, 31 or 32 are the same.
  • Peptides having an amino acid sequence in which one or more amino acids are substituted or deleted, or one or more amino acids are inserted or added to the amino acid sequence, and which have a central nervous system function promoting effect are also included in the present invention. Included in the range of peptides according to the nine inventions.
  • the amino acid sequence of such a peptide is at least 70%, more preferably 90%, the amino acid sequence represented by SEQ ID NOS: 25, 26, 27, 28, 29, 30, 31 or 32. It is preferable to have the above homology.
  • the agent for promoting central nervous system function as a medicament according to the ninth invention is preferably administered by parenteral route such as intravenous injection, subcutaneous injection, intramuscular injection, or rectal administration, or orally. .
  • the dosage is determined as appropriate based on the condition of the patient, the molecular weight of the active ingredient, and the like.In general, for parenteral administration, the body weight is 1 kg, and the dose is 0.01 mg to 1 mg per day. In the case of oral administration, the body weight is preferably 1 kg and about 0.1 mg to 10 mg per day.
  • the central nervous system function promoter comprising the peptide according to the ninth invention can be appropriately formulated by a conventional method. For example, 30 mg / l to 300 mg Z 1 of physiological saline can be used. Those dissolved in the concentration range can be used. In the case of oral administration, a so-called drink can be added to a beverage.
  • the peptide having the amino acid sequence represented by SEQ ID NOS: 1 to 32 in the sequence listing according to the present invention can be easily synthesized by a well-known peptide chemical synthesis method using a commercially available peptide synthesizer.
  • the synthesis method includes a solid phase method and a liquid phase method.
  • the synthesized peptide is purified according to a usual method. Examples of the purification method include ion exchange chromatography, reverse phase liquid chromatography, affinity chromatography and the like.
  • the peptide of the present invention can also be produced by incorporating a gene corresponding to the amino acid sequence of the peptide of the present invention and an expression promoter into Escherichia coli, yeast and the like by using a gene modification technique.
  • the obtained peptide is analyzed and confirmed with a mass spectrometer or a protein sequencer.
  • the present invention will be described specifically with reference to examples.
  • Example 1 Insulin production promoting action
  • the peptide having the amino acid sequence represented by SEQ ID NO: 1 was synthesized, purified, and confirmed in the following manner by consignment to CSBIO LTD. (Ca1ifornia, U.S.A.). That is, it is synthesized by the solid phase method, the purity is assayed using reversed-phase liquid chromatography (Vy dac C18 column, trifluoroacetic acid Zacetonitrile solvent system), and the molecular weight of the product is analyzed using a mass spectrometer. It was confirmed.
  • HIT cells which are hamster kidney cells that produce insulin (Manufactured by Dainippon Pharmaceutical Co., Ltd.) in RPMI 1640 medium containing 10% fetal bovine serum (source: Dainippon Pharmaceutical Co., Ltd.), and humidified in 5% carbon dioxide gas at 37 nC Nurtured. 1 ⁇ 10 4 wells (we 11) were seeded on a 96-well culture plate by trypsin treatment, and when the culture became confluent, the medium was replaced with a serum-free F12 medium and cultured for 8 hours.
  • the peptide having the amino acid sequence shown in SEQ ID NO: 1 of the present invention synthesized in (1) was dissolved in serum-free RPMI 1640 medium, and added to we11 while changing the dose of HIT cells. The culture was continued for another 12 hours. After the culture, the effect of the peptide on promoting the production of insulin by the cells was measured by insulin immunoassay, and the effect of promoting the production on the non-treated group was determined. In addition, the calculation of the insulin immunoassay and insulin production promotion rates was specifically performed as follows.
  • the cell culture solution supernatant was added to the anti-insulin antibody-fixed well and reacted with the anti-insulin antibody solution while changing the dose.
  • biotin labeled with the antibody was reacted with streptavidin-conjugated peroxidase, and the color development by peroxidase was measured.
  • Insulin concentration was calculated from a standard curve of insulin.
  • the insulin production promotion rate was as follows when the control group without addition of the peptide was set to 100% and the insulin production promotion rate of the group to which the dose was changed was obtained. Table 1 shows the results.
  • the peptide having the amino acid sequence shown in SEQ ID NO: 1 of the present invention acts on hamster-derived insulin-producing cells in a manner that promotes insulin production. Therefore, the peptide having the amino acid sequence shown in SEQ ID NO: 1 of the present invention promotes insulin production, has a function as an insulin production promoter, and is useful as a therapeutic agent for diabetes (insulin production promoter). It can be seen that It can also be seen that it can be used for foods that have an insulin production promoting function.
  • Example 2 Gastric acid secretion inhibitory action
  • the gastric acid secretion inhibitory effect was evaluated by using a rat (Wistar sp.) By combining a peptide having the amino acid sequence represented by SEQ ID NO: 2 of the present invention synthesized in (1) with gastrin that promotes gastric acid secretion in physiological saline. The dissolved solution was injected subcutaneously and evaluated by measuring gastric acid secretion 10 minutes later. Gastrin was administered to the peptide, and the peptide having the amino acid sequence shown in SEQ ID NO: 2 was administered to give 10 g Zkg. Gastric acid secretion was evaluated by fixing the rat to a fixator, inserting a probe into the stomach through the mouth, collecting gastric juice, and measuring the pH. The results are shown in Table 2 below. The control is a result of a control group to which the peptide was not administered.
  • the peptide having the amino acid sequence shown in SEQ ID NO: 2 of the present invention acts on rats to inhibit gastric acid secretion. Therefore, the peptide of the present invention having the amino acid sequence represented by SEQ ID NO: 2 suppresses gastric acid secretion, has a function as a gastric acid secretion inhibitor, and is useful as a therapeutic agent for gastric ulcer and duodenal ulcer (gastric acid secretion inhibitor). You can see that there is. It can also be seen that it can be used for foods that have a gastric acid secretion inhibitory function.
  • Example 3 Growth hormone production promoting action
  • Hamster-derived GH3 cells which are pituitary cells that produce growth hormone (obtained from: IFO (Accession No. 5105)), and F12 medium containing 15% fetal bovine serum (obtained from Dainippon Japan) Pharmaceuticals) and cultivated in a 5% CO2 humidified 37 incubator.
  • IFO Accession No. 5105
  • F12 medium containing 15% fetal bovine serum obtained from Dainippon Japan
  • 1 x 10 4 Z wells were seeded on a 96-well culture plate by trypsin treatment and confluent. The medium was replaced with a 15% serum F12 medium when cultivated for 12 hours, and then the peptide having the amino acid sequence shown in SEQ ID NO: 3 of the present invention synthesized in (1) was replaced with 1%.
  • the dose was changed and added to we11, and the culture was continued for another 3 days.
  • the effect of the peptide on promoting growth hormone production of cells by the growth hormone Imnoassay was examined.
  • the production promoting effect on the untreated group was determined.
  • Growth hormone immunoassay was performed by a standard sandwich ELISA method, in which the cell culture supernatant was added to the anti-growth hormone antibody-fixed well at varying doses and reacted at room temperature for 180 minutes. After washing, a peroxidase-labeled anti-growth hormone antibody was further added, and the mixture was allowed to react at room temperature for 60 minutes. It was measured by degree measurement.
  • Growth hormone concentration was determined based on a standard curve obtained by performing the same sandwich ELISA using a known concentration of growth hormone.
  • the growth hormone production promotion rate was as follows when the control group to which no peptide was added was set to 100%, and the growth hormone production promotion rate of the group to which the dose was changed was calculated. Table 3 shows the results.
  • the peptide having the amino acid sequence shown in SEQ ID NO: 3 of the present invention is a growth hormone-producing cell for growth hormone-producing cells. It was confirmed that it acts to promote production. Therefore, the peptide of the present invention having the amino acid sequence represented by SEQ ID NO: 3 promotes growth hormone production, has a function as a growth hormone production promoter, and is used as a therapeutic agent for dwarf disease (growth hormone production promotion). It is found to be useful as an agent. Also, it can be seen that it can be used for foods that have a growth hormone production promoting function.
  • Example 4 Blood pressure lowering effect
  • SEQ ID NO: 4 5 6, 7, 8, 9, 10, 10, 11 or 12 of the present invention synthesized in (1) was added.
  • a peptide having the amino acid sequence shown was intraperitoneally administered to give 10 jug Z kg, and physiological saline was similarly administered as a control instead of the above peptide solution.
  • the tail artery blood pressure before and 1 hour after administration was measured using a rat tail artery blood pressure / pulse meter (KN-210, manufactured by Natsume Seisakusho). Table 4 shows the results.
  • Adipocytes that accumulate fat were cultured in a 37 ° C. incubator with 5% carbon dioxide gas humidified using an RPM 1 1640 medium containing 10% fetal bovine serum (source: Dainippon Pharmaceutical). 1 ⁇ 10 4 Z holes (we 11) were seeded on a 96-well culture plate, and when confluent, the medium was replaced with a serum-free F 12 medium and cultured for 8 hours. Thereafter, the peptide having the amino acid sequence shown in SEQ ID NOS: 13 and 14 of the present invention synthesized in (1) was dissolved in serum-free RPMI 11640 medium, and added to wel 1 while changing the dose. The culture was continued for another 24 hours.
  • the fat accumulation of the cells by the peptide was determined by the presence or absence of fat granules, The fat accumulation rate for the group was determined.
  • the fat accumulation rate was determined by counting the number of fat accumulated cells in each group by microscopic observation, and expressed as a percentage of the number of fat accumulated cells in the control group to which the peptide was not added. Table 5 shows the results.
  • Rats (Wistar, male, 6 weeks old) were allowed to freely ingest a high-fat diet, and the amino acid sequence represented by SEQ ID NOS: 15, 16, 16, 17 and 18 of the present invention synthesized in the above (1) was obtained every day. 4 weeks after intraperitoneal administration of peptide having Immediately afterwards, blood was collected and the level of triglyceride (TG) in the blood was measured. Each peptide of the present invention was dissolved in physiological saline and injected into the abdominal cavity at a dose of 10 ag / kg. For the control group, physiological saline was similarly injected intraperitoneally. Table 6 shows the results.
  • the peptide of the present invention having the amino acid sequence represented by SEQ ID NOS: 15, 16, 17, and 18 suppresses fat accumulation, is useful as a fat accumulation inhibitor, and It can be seen that it can be used as a medicament for hyperlipidemia as a medicament, an agent for treating fat accumulation, an agent for treating obesity, an agent for preventing obesity, and a food having an inhibitory function on fat accumulation.
  • SEQ ID NOS: 15, 16, 17, and 18 suppresses fat accumulation
  • the peptide of the present invention having an amino acid sequence represented by SEQ ID NO: 19 has a high inhibitory rate of / 3-hexosaminidase release, which is an indicator of histamine release inhibition, and has an allergic inhibitory action ( Function). Therefore, the peptide of the present invention having the amino acid sequence represented by SEQ ID NO: 19 is useful as an allergy inhibitor, and is formulated by mixing the peptide as an active ingredient, as an allergy drug for medicine, a histamine release inhibitor, It can be seen that it can be used for allergy suppressants such as anti-inflammatory agents and foods with allergy suppression function.
  • Example 7 Blood pressure lowering effect
  • a peptide having the amino acid sequence shown in SEQ ID NOS: 20, 21 and 22 of the present invention synthesized in (1) was added to 1 0 zg / kg in the abdominal cavity. Saline was administered. The blood pressure of the tail artery was measured before and 1 hour after administration using a rat tail artery blood pressure / pulse meter (KN-210, manufactured by Natsume Seisakusho). Table 8 shows the results.
  • cerebral ischemia is created by holding the artery for 10 minutes, and the next day, the patient is placed in an eight-way maze to measure the degree of spatial recognition memory. Of the first eight attempts to reach the bait location at each aisle end, the number of correctly reached bait locations is referred to as the ⁇ positive selection number ''. The number of times it reached was defined as the “number of errors” and counted. An increase in the number of positive selections for the control and / or a decrease in the number of errors indicate that the cerebral ischemia has an effect of alleviating the disorder or an early recovery from the disorder. The results are shown in Table 10.
  • SEQ ID NOs: 25, 26, 27, 28, 29, 3 Peptides having the amino acid sequences represented by 0, 31 and 32 are useful as central nervous system function promoters, and are used as prophylactic and therapeutic agents for brain nerve dysfunction as pharmaceuticals by incorporating the peptides as active ingredients. It can be seen that it can be used for central nervous system function promoters such as therapeutic agents for improving cerebral nerve dysfunction, drugs for the central nervous system, cerebral nerve function protectants (drugs), and foods that have the function of promoting central nervous system function.
  • a peptide particularly useful as a medicine or food can be obtained.
  • Peptides having the amino acid sequences represented by SEQ ID NOs: 1 to 32 in the sequence listing of the present invention are particularly useful as insulin production promoters, gastric acid secretion inhibitors, growth hormone production promoters, hypotensive agents, and fat accumulation inhibitors.
  • An allergy inhibitor, an analgesic, a central nervous system function promoter, etc., and a novel amino acid sequence represented by SEQ ID NOS: 1 to 32 in the sequence listing of the present invention, Drugs, foods, etc. can be obtained.

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Abstract

Cette invention porte sur des peptides qui sont particulièrement utiles comme médicaments et aliments. On utilise des peptides comportant des séquences d'acides aminés spécifiques qui ont pour effet de promouvoir la production d'insuline, de réguler la sécrétion de suc gastrique, de promouvoir la production de l'hormone de croissance, de réduire la pression sanguine, d'inhiber l'accumulation des graisses, de lutter contre l'allergie, de soulager la douleur et de renforcer les fonctions du système nerveux central. L'utilisation de ces peptides permet de produire de nouveaux médicaments, aliments, etc. présentant les fonctions susmentionnées.
PCT/JP2003/001333 2002-02-08 2003-02-07 Peptides WO2003066672A1 (fr)

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WO1995019568A1 (fr) * 1994-01-14 1995-07-20 Matthias Rath Oligopeptides signaux hydrophiles et leurs procedes d'utilisation a des fins therapeutiques
WO1998014479A1 (fr) * 1996-10-02 1998-04-09 Kenji Sakamoto Procede de recherche de substances physiologiquement actives et procede de production de telles substances
WO1999051627A1 (fr) * 1998-04-04 1999-10-14 Nakoshi, Hideo Methode de recherche de substances physiologiquement actives, procede de production de ces substances et medicaments decouverts par la methode de recherche
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WO2001040265A2 (fr) * 1999-12-02 2001-06-07 V.I. Technologies, Inc. Procede d'identification d'un ligand destine a une molecule cible
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984003506A1 (fr) * 1983-03-08 1984-09-13 Commw Serum Lab Commission Sequences d'acides amines antigeniquement actives
WO1994009828A1 (fr) * 1992-11-03 1994-05-11 Synaptic Pharmaceutical Corporation Adn codant un recepteur de serotonine humain (5-ht4b) et ses utilisations
WO1995019568A1 (fr) * 1994-01-14 1995-07-20 Matthias Rath Oligopeptides signaux hydrophiles et leurs procedes d'utilisation a des fins therapeutiques
US6030804A (en) * 1995-06-06 2000-02-29 Human Genome Sciences, Inc. Polynucleotides encoding G-protein parathyroid hormone receptor HLTDG74 polypeptides
WO1998014479A1 (fr) * 1996-10-02 1998-04-09 Kenji Sakamoto Procede de recherche de substances physiologiquement actives et procede de production de telles substances
WO1999051627A1 (fr) * 1998-04-04 1999-10-14 Nakoshi, Hideo Methode de recherche de substances physiologiquement actives, procede de production de ces substances et medicaments decouverts par la methode de recherche
JP2001098000A (ja) * 1999-09-29 2001-04-10 Kenji Sakamoto 新規ペプチド及びその医薬用途
WO2001040265A2 (fr) * 1999-12-02 2001-06-07 V.I. Technologies, Inc. Procede d'identification d'un ligand destine a une molecule cible
WO2001077172A2 (fr) * 2000-04-07 2001-10-18 Arena Pharmaceuticals, Inc. Recepteurs connus couples a la proteine g non endogenes a activation constitutive
JP2001335596A (ja) * 2000-05-24 2001-12-04 Kenji Sakamoto 新規ペプチド及びその医薬用途

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LOMASNEY JON W. ET AL.: "Expansion of the alpha2-adrenergic receptor family: cloning and characterization of a human alpha2-adrenergic receptor subtype, the gene for which is located on chromo some 2", PROC. NATL. ACAD. SCI. USA, vol. 87, 1990, pages 5094 - 5098, XP002158508 *

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