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WO1992017499A1 - Hexapeptide particulier derive de la thrombospondine et utilisation de ce compose - Google Patents

Hexapeptide particulier derive de la thrombospondine et utilisation de ce compose Download PDF

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Publication number
WO1992017499A1
WO1992017499A1 PCT/US1992/002825 US9202825W WO9217499A1 WO 1992017499 A1 WO1992017499 A1 WO 1992017499A1 US 9202825 W US9202825 W US 9202825W WO 9217499 A1 WO9217499 A1 WO 9217499A1
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cys
acm
thrombospondin
thr
val
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PCT/US1992/002825
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English (en)
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Ralph L. Nachman
Adam S. Asch
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Cornell Research Foundation, Inc.
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Publication of WO1992017499A1 publication Critical patent/WO1992017499A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/20—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans from protozoa
    • C07K16/205—Plasmodium
    • 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
    • C07K14/44—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from protozoa
    • C07K14/445—Plasmodium
    • 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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Thrombospondin is a large multi-functional trimeric glycoprotein of approximately 450 Kd, and a major component of platelet alpha-granules secreted in response to thrombin or ionophore stimulation. When stimulated, thrombospondin is expressed on the activated platelet surface where it supports irreversible platelet aggregation. Thrombospondin has a broad biological distribution, is expressed by several cell types, and is incorporated into the extracellular matrix of growing cells in a regulated fashion.
  • Thrombospondin binds a variety of molecules including heparin, sulfated glycolipids, collagen, fibronectin, fibrinogen, histidine rich glycoprotein, plasminogen, tissue and urinary type plasminogen activators.
  • Thrombospondin is a trimeric glycoprotein composed of three identical, disulfide- linked glycopeptide chains which, in rotary shadowed images obtained by electron microscopy, resemble a bola with a central 9 ⁇
  • disulfide knot three linear domains, and three large globular domains at the ends.
  • thrombospondin In addition to its cytoadhesive activity, thrombospondin has several other functions. As a surface for macromolecular assembly, the molecule may mediate or modulate certain aspects of coagulation and fibrinolysis. Thrombospondin binds to the A- alpha and B-beta chains of fibrinogen. During fibrin formation, the molecule is incorporated into the growing clot and modulates the structure of the fibrin network, leading to a finer and more highly branched fibrin network. In the presence of coagulation factor XIII, thrombospondin may participate in an amide linkage and become crosslinked to other thrombospondin molecules or to fibrin via several reactive glutamyl and lysyl residues.
  • the molecule may regulate the strength of the fibrin clot by affecting fibrin filament thickness and may influence the efficiency of fibrinolysis.
  • the molecule can serve as a surface upon which plasminogen activation occurs, since it forms a ternary complex with plasminogen and tissue type plasminogen activator (t-PA).
  • t-PA tissue type plasminogen activator
  • t-PA tissue type plasminogen activator
  • a 40- fold increase in the catalytic efficiency of activation has been observed with plasminogen bound to thrombospondin as compared to plasminogen-t-PA complexes formed in the absence of thrombospondin.
  • formation of the thrombospondin- plasminogen complex is enhanced in the presence of t-PA or urinary-type plasminogen activator (u-PA) in a manner that b
  • thrombospondin plays an important role in the regulating of basic cellular functions. Most cell types examined in vitro - including endothelial, smooth muscle, glial, melanoma, type II pneumocytes, keratinocytes, and fibroblasts - synthesize thrombospondin and incorporate it into their extracellular matrices. In tissue sections, thrombospondin has been demonstrated in basement membranes of the dermis-epidermis, of renal peritubular connective tissues, in small blood vessels, in the subendothelium of the aorta, and in atherosclerotic lesions.
  • thrombospondin In the early development of mouse embryos, thrombospondin is deposited in the basement membrane of surface ectoderm, pharynx and neuroectoderm. Its observed distribution, and its interactions with several known matrix components such as thrombin, fibrinogen, fibronectin, histidine-rich glycoprotein, plasminogen, urokinase-type plasminogen activator, and collagen types l-V, suggests that it plays a major role in matrix biology. Thrombospondin may also affect matrix events by localizing and regulating plasmin in matrices which are undergoing rapid remodeling such as those found associated with wound healing, development, or neoplastic growth. The plasminogen-plasminogen activator complex bound to thrombospondin is relatively resistant to inhibition by protease inhibitors such as alpha-2 macroglobulin and PAI. Thrombospondin is a substrate for several 1
  • proteases including plasmin, and may be modified enzymatically in the matrix or by cells in the vicinity.
  • Thrombospondin incorporation into the matrix of growing smooth muscle cells is also heparin-inhibitable.
  • Embryonic lung fibroblasts and bovine aortic smooth muscle cells endocytose thrombospondin in a heparin inhibitable fashion, and degrade it in a process which is saturable (Km of 6x10-8M with a V ma ⁇ of 1.4x10 5 molecules/cell/min). It is not presently clear whether this is a mechanism for the removal of matrix thrombospondin by growing or migrating cells, or whether processed thrombospondin may exhibit unique functions distinct from the intact molecule.
  • Thrombospondin incorporation into the matrix appears to be cell cycle dependent since recently-plated and rapidly proliferating subconfluent cells (aortic endothelial cells, smooth muscle cells and fibroblasts) synthesize and secrete more thrombospondin into the culture medium than senescent.density- arrested, cell cultures.
  • subconfluent cells aortic endothelial cells, smooth muscle cells and fibroblasts
  • the synthesis of thrombospondin by bovine aortic smooth muscle cells is enhanced by platelet- derived growth factor (PDGF).
  • PDGF-stimulated glial cells also show a 10-fold increase in levels of thrombospondin synthesis.
  • thrombospondin and epidermal growth factor act synergistically to stimulate mitogenesis in quiescent rat vascular smooth muscle cells and that antibodies to thrombospondin arrest proliferating smooth muscle cells in the G1 phase of the cell cycle.
  • thrombospondin mRNA can be rapidly induced by TGF-beta, FGF, and PDGF in several cell types including vascular smooth muscle cells and fibroblasts.
  • thrombospondin mRNA is superinduced by cycloheximide, as is expression of the c-fos and c-myc oncogene products. The similarities between expression of thrombospondin and oncogene products are indicative to shared growth factor-like functions between these materials.
  • Thrombospondin has an autocrine role in the regulation of smooth muscle cell proliferation through a synergistic effect with EGF; it is not known whether thrombospondin directly binds with EGF or other growth factors, but it has been suggested that thrombospondin reverses the inhibitory effect of heparin on smooth muscle cell growth by blocking heparin-smooth muscle cell interactions. Furthermore, monoclonal antibodies to thrombospondin inhibits smooth muscle cell growth. Together, this data indicates that thrombospondin is an important regulator of cell growth and further supports the concept that thrombospondin has growth factor-like properties.
  • thrombospondin is localized primarily at sites of active cell migration and proliferation; thrombospondin is more widely distributed in the matrices of wounded or actively developing tissues than in more stable fully differentiated tissues. Thrombospondin is also prevalent in human fetal skin and cartilage; in adult tissues e
  • thrombospondin is restricted to some basement membranes, loose connective tissues, and areas of injury, especially in the clefts of atherosclerotic blood vessels.
  • cytoadherence This process of attachment, called cytoadherence, is responsible for some of the fatal complications of infection with the causative organism, Plasmodium falciparum.
  • the Plasmodium organism is known to produce a malarial histidine rich protein which we speculated might interact with thrombospondin or a thrombospondin-like molecule.
  • thrombospondin As a multi-functional cell adhesive protein with growth factor-like characteristics, might possess the functional binding diversity needed by Plasmodium during its life cycle in the infected host to bind receptors on liver and endothelial cells.
  • the specific hexapeptide according to the present invention has the amino acid sequence [Seq ID No. 1]:
  • Cys-Ser-Val-Thr-Cys-Gly which corresponds to the region of homology of thrombospondin and the malarial circumsporozoite protein, and is found twice within each thrombospondin monomer at amino acid positions
  • Figure 1 is a dose responsive curve of the inhibition of the binding of histidine rich glycoprotein to insolubolized thrombospondin;
  • Figure 2 is a graphic representation of the metastatic potential of cells which express glycoprotein IV and those that do not express glycoprotein IV on their surfaces.
  • Figure 3 is a graphic representation of the profound inhibition of thrombospondin binding to U937 tumor cells by the peptide according to the present invention
  • Figure 4 is a graphic representation showing the peptide according to the present invention bound to glycoprotein IV on the surface of U937 cells.
  • Figure 5 is a graphic representation of thrombospondin binding to salivary protein
  • Figure 6 is a graphic representation of the inhibition of platelet thrombospondin expression by the peptide according to the present invention in which 6A1 and 6A2 depict the results of flow cytometry, and 6B-1 and 6B-2 depict platelet aggregometry of platelet rich plasma.
  • HRGP histidine rich glycoprotein
  • Thrombospondin was prepared from human platelets by a conventional technique. Briefly, outdated normal human platelets were washed free of contaminating plasma proteins by three centrifugations in saline containing buffer. The platelets were then stimulated with 10 micromolar ionophore A23187 to cause the platelets to release intracellular stores of thrombospondin. The released thrombospondin was further purified by affinity chromatography on heparin-Sepharose followed by high performance liquid chromatography using Mono-Q Sepharose. Thrombospondin was coated in wells of a conventional 96 well
  • HRGP was prepared from normal human plasma by heparin affinity chromatography, and varying concentrations of HRGP in a total volume of 200 ⁇ l were added alone (or in the presence of the indicated concentrations of the hexapeptide Cys-Ser-Val-Thr-Cys-Gly according to the present invention) to thrombospondin-coated wells, and the binding was determined by an ELISA system using monospecific antibody to HRGP followed by alkaline phosphatase conjugated goat anti-rabbit IgG and para-nitrophenylphosphate was used as a colorimetric substrate. Color generation was quantitated using a Titertex spectrophotometer at 405 nanometers.
  • the hexapeptide was prepared containing a carboxy terminus aminocaprolylcysteine amide (ACM) which provided the cysteine residues protection from oxidation and allowed for the selective conjugation to the carboxy terminus cysteine residue as well as a spacer for presenting the peptide from the Keyhole limpet hemocyanin (KLH) carrier backbone. In addition, this prevented intra- and inter-chain disulfide bond formation.
  • ACM carboxy terminus aminocaprolylcysteine amide
  • KLH Keyhole limpet hemocyanin
  • the hexapeptide according to the present invention, or congeners coupled to the proper immunogenic carrier may function as a potential vaccine (or a potential treatment) to prevent infection with the malarial organism in mammals including man.
  • Cogeners may include tandem repeats of the peptide sequence up to 40 amino acid residues in length, or the protein coupled to a branching carboxyterminal polysine network.
  • the carrier for immunizing patients using such a protocol would most likely to be a conventional tetanus toxoid or another immunogenic vaccine carrier.
  • the optimal ratio of peptide to carrier in such uses has yet to be determined, however, it is likely to be in the ratio of approximately 20-50 peptide:1 carrier.
  • the peptides according to the present invention also have potential for the inhibition of tumor cell metastasis.
  • thrombospondin The function of thrombospondin on carcinoma cells appears, in part, to mediate adhesion of the cells to endothelial or subendothelial metastatic sites.
  • Experimental evidence suggests that antibodies to thrombospondin can inhibit the metastasis of human tumor cells in animal models.
  • Our own data generated in making the present invention demonstrates that the adhesion of tumor cells to surfaces rich in thrombospondin is mediated by interaction with tumor cell glycoprotein IV.
  • the adhesion of human melanoma cell line (C-32) to human endothelial cells is mediated by a receptor on the latter cells identified as glycoprotein IV, and the metastatic potential of cells that express glycoprotein IV is markedly greater than that of cells that do not (figure 2).
  • the tail veins of male nude mice were injected with 1 x 10 6 glycoprotein IV-rich or glycoprotein IV-poor C32 human melanoma cells. After three months the animals were sacrificed, the lungs were insufflated with 15% India ink solution followed by bleaching with Fekete's solution, and the pulmonary nodules were counted. Glycoprotein IV-rich innocula resulted in a 14-fold increase in the number of pulmonary metastasis as compared to those found when glycoprotein IV-poor innocula was used.
  • thrombospondin The homology between thrombospondin and the proteins expressed by malaria that mediate malarial adhesion to endothelium, tumor cells, and possibly to hepatic cells which resulted from our experiments suggest that an agent such as the peptide according to the present invention might potentially interfere with thrombospondin's interaction with glycoprotein IV and thus may be useful to inhibit tumor cell metastatic behavior.
  • an agent such as the peptide according to the present invention might potentially interfere with thrombospondin's interaction with glycoprotein IV and thus may be useful to inhibit tumor cell metastatic behavior.
  • Utilizing cell line U937 inhibition of thrombospondin binding to cell line U937 was studied, as described in the following Example II, to confirm that the peptide would interfere with thrombospondin's interaction with glycoprotein IV.
  • Thrombospondin was labelled to a specific activity of 8 x ⁇ cpm/ ⁇ g for these studies, and cell binding was performed in triplicate in Tris-buffered saline with 2 mM CaCl2 utilizing 5 x 10 5 cells in a total volume of 0.2 ml at 4° C for 40 minutes. Cell bound radioactivity was determined by centrifuging the cells through silicone oil, and removing and counting the cell pellets in a gamma counter. Nonspecific binding was determined by cold inhibition studies. The data collected from this example is graphically represented in figure 3 and illustrates the profound inhibition of thrombospondin binding to U937 cells by the hexapeptide according to the present invention.
  • the peptide itself is capable of binding to glycoprotein IV on these cells as measured by radioactive binding studies as depicted in figure 4.
  • the peptide according to the present invention was radiolabelled to a specific activity of 4.6 x 10 4 cpm/ ⁇ g and the direct binding measured as described previously.
  • hexapeptide according to the present invention or its congeners may be useful as anti metastatic agents. These agents would function by blocking the binding of tumor cells to thrombospondin at metastatic sites within the body, or by serving as an immunogen for the development of antibodies that serve the same purpose and inhibit thrombospondin-tumor cell interactions.
  • thrombospondin is also found in inflammatory tissues such as those that would be present in various wounds. Based upon the investigational findings collected during the making of the present invention, it would be reasonable to assume that thrombospondin may also be present in inflammatory oral lesions such as those found in acute gingivitis. To test this premise, formalin fixed sections of normal and inflamed gingiva were subjected to immunohistochemical identification using monospecific antisera to thrombospondin. The inflamed gingiva /
  • thrombospondin contained significant deposits of thrombospondin in the acutely inflamed regions and in the adjacent mucosal epitheliuim. No thrombospondin was identified in normal gingival tissue.
  • a major defense mechanism in the oral cavity for clearance of bacterial from gingival surfaces and in saliva is a salivary agglutinin that clumps bacteria and leads to clearance of aggregated bacteria by phagocytes and leukocytes.
  • salivary agglutinin that clumps bacteria and leads to clearance of aggregated bacteria by phagocytes and leukocytes.
  • thrombospondin in inflamed tissue would interact with the salivary protein.
  • thrombospondin containing the hexapeptide of the present invention plays an important role in determining the binding functions of this adhesive salivary glycoprotein.
  • thrombospondin present in inflamed tissues such as those which might be seen in peridontal disease, interferes with the normal antibacterial agglutinating function of salivary protein.
  • thrombospondin could potentiate bacterial growth on inflamed gingiva.
  • the thrombospondin present in such tissues can be blocked by the hexapeptide according to the present invention.
  • This peptide (Cys-Ser-Val-Thr-Cys-Gly) if provided a dental patient in a mouthwash and/or toothpaste formulation could potentially prevent gingival infection and limit the development of periodontal disease.
  • thrombospondin serves to support the secretion-dependent phase of aggregation by stabilizing the interaction of fibrinogen with its receptor complex on the activated platelet surface.
  • Our studies into thrombospondin demonstrated the endogenous thrombospondin binding to the platelet surface is mediated by glycoprotein IV.
  • an agent such as the hexapeptide according to the present invention, which inhibits expression of thrombospondin on the activated platelet surface, and thereby inhibits platelet aggregation (see figure 6), might be useful as a therapeutic anti-platelet agent.
  • figures 6A-1 and 6A-2 depict the results of flow cytometry data and reveal normal thrombospondin expression on the platelet surface following stimulation with the calcium ionophore A23187 in the presence of a control peptide of the formula Thr-Val-Ser-Gly-Cys-Cys at 200 ⁇ M, and inhibition of thrombospondin surface expression in the presence of the peptide according to the present invention, Cys-Ser-Val-Thr-Cys-Gly, at 200 ⁇ M.
  • Figures 6B-1 and 6B-2 depicts data generated by platelet aggregometry of platelet rich plasma, and reveals a diminished response to A23187 in the presence of 200 ⁇ M of the peptide according to the present invention, compared with the control aggregation in the presence of 200 ⁇ M of the same control peptide used for the flow cytometry tests.
  • the peptide according to the present invention when coupled to a conjugate, such a albumin, may be useful as a clinical agent to inhibit platelet aggregation in patients undergoing coronary bypass, or post-transluminal angioplasty.
  • peptide, peptide-conjugates or peptide antibodies need to be more particularly defined in clinical trials.
  • in vitro experimental data suggests that significant inhibition of thrombospondin binding occurs at peptide concentrations less than 200 micromolar. It is also likely that peptide conjugates, because of their relative large size, will be more potent clinical agents than the purified peptide alone.
  • the determination of the dosage levels for the various uses that the peptide according to the present invention may be ⁇ ⁇
  • the hexapeptide according to the present invention is potentially useful as a pharmaceutical for treating warm-blooded animals suffering from many different pathologic conditions when administered in amounts sufficient to treat or correct the specific targeted condition.
  • the specific amounts of the peptide given in such instances may be adapted to provide the optimum therapeutic response sought. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic solution.
  • the peptide may be administered in the form of the free peptide, a conjugated peptide, or as a nontoxic pharmaceutically acceptable salt thereof (collectively referred to as "its modifications").
  • hexapeptide or its modifications may be administered parenterally, e.g. by subcutaneous, intramuscular, or intravenous 11 injection. Solutions or suspensions of the active hexapeptide or its modifications can be prepared in water suitably mixed with a surfactant such as hydroxyproplycellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • these preparations Under ordinary conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms. As the hexapeptide or its modifications have a natural tendency to adhere to glass or plastic surfaces, these preparations may also contain an agent, such as gelatin or albumin, to competitively inhibit this effect.
  • an agent such as gelatin or albumin
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the carrier may be a solvent or dispersion medium containing, for example, water, polyol (for example, glycerol, proplylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • Compositions suitable for intramuscular or subcutaneous injection may also contain minor amounts of salts, acids, buffers, and bases. Suitable pharmaceutically acceptable buffering and tonicity agents are readily determinable by persons skilled in the art. ⁇ Lt>
  • the hexapeptide and its modifications according to the present invention may also be suitable for oral administration, for example with an inert diluent or with an assimilable edible carrier, or it may be encapsulated within a hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the hexapeptide or its modification may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, mouthwashes, wafers and the like.
  • the tablets, troches, pills, and the like may also contain binders such as gum tragacanth, acacia, corn starch or gelatin; colorants; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid and the like; lubricating agents such as magnesium stearate; sweetening agents such as sucrose lactose or saccharin; and flavoring agents such as peppermint, oil of wintergreen or cherry flavorings.
  • binders such as gum tragacanth, acacia, corn starch or gelatin
  • colorants such as dicalcium phosphate
  • disintegrating agents such as corn starch, potato starch, alginic acid and the like
  • lubricating agents such as magnesium stearate
  • sweetening agents such as sucrose lactose or saccharin
  • flavoring agents such as peppermint, oil of wintergreen or cherry flavorings.

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Abstract

Hexapeptide particulier présentant la séquence d'acides aminés Cys-Ser-Val-Thr-Cys-Gly, anticorps contre cet hexapeptide, et utilisation de cet hexapeptide et de son anticorps.
PCT/US1992/002825 1991-04-08 1992-04-07 Hexapeptide particulier derive de la thrombospondine et utilisation de ce compose WO1992017499A1 (fr)

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US68071091A 1991-04-08 1991-04-08
US680,710 1991-04-08

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0554670A3 (en) * 1992-02-07 1994-07-13 Behringwerke Ag Specific antibodies against activated platelets, their production and applications in diagnostics and therapeutics
US5399667A (en) * 1993-03-05 1995-03-21 Washington University Thrombospondin receptor binding peptides
WO1996033218A1 (fr) * 1995-04-21 1996-10-24 Allelix Biopharmaceuticals Inc. Peptides anti-hemorragiques
WO1996036349A1 (fr) * 1995-05-17 1996-11-21 Manitoba Cancer Treatment And Research Foundation ACTIVATION POST-TRANSLATIVE DU FACTEUR DE CROISSANCE TRANSFORMANT BETA1 (TGFβ1) FAISANT INTERVENIR LE RECEPTEUR CD36 DU TSP-1
WO1996038480A1 (fr) * 1995-06-02 1996-12-05 Allelix Biopharmaceuticals, Inc. Peptides anti-inflammatoires derives de la thrombospondine
US5627265A (en) * 1993-03-05 1997-05-06 Washington University Receptor for cell-binding domain of thrombospondins
US5648461A (en) * 1990-02-22 1997-07-15 W.R. Grace & Co.-Conn Synthetic analogs of thrombospondin and therapeutic use thereof
WO1999026649A1 (fr) * 1997-11-25 1999-06-03 Cornell Research Foundation, Inc. Compositions inhibant l'infectiosite du virus vih et entravant l'activite de la chemokine et methodes afferentes
US6239110B1 (en) 1990-02-22 2001-05-29 W.R. Grace & Co. -Conn. Synthetic analogs of thrombospondin and therapeutic use thereof
US6339062B1 (en) 1998-11-23 2002-01-15 Inkine Pharmaceutical Company, Inc. Retroinverso polypeptides that mimic or inhibit thrombospondin activity
WO2000078359A3 (fr) * 1999-06-21 2002-01-24 George Tuszynski Compositions pour traiter des cellules tumorales resistant a la chimiotherapie et compositions de chimiotherapie ciblee
US6380161B1 (en) 1999-06-21 2002-04-30 Inkine Pharmaceutical Company, Inc. Compositions for treating chemotherapy-resistant tumor cells and targeted chemotherapy compositions
US6964763B1 (en) 1997-11-25 2005-11-15 Cornell Research Foundation, Inc. Methods and compositions for inhibiting HIV infectivity and blocking chemokine activity

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HARLOWE et al., "Antibodies: A Laboratory Manual", published 1988 by COLD SPRING HARBOR LABORATORY (N.Y.), see pages 72-76. *
JOURNAL OF BIOLOGICAL CHEMISTRY, Volume 265, No. 5, 15 February 1990, HOLT et al., "Properdin Binds to Sulfate (Gal(3-S04)B1-1Cer) and has a Sequence Homology with other Proteins that Bind Sulfated Glyconjugates", pages 2852-2855. *
NATURE, Volume 335, issued 01 September 1988, ROBSON et al., "A highly conserved amino acid sequence in thrombospondin, properdin and in proteins from sporozoites and blood stages of a human malaria parasite", see pages 79-81. *
STEWART et al., "Solid Phase Peptide Synthesis", published 1984 by PIERCE CHEMICAL COMPANY (ROCKFORD, ILLINOIS), see pages 26-27. *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6239110B1 (en) 1990-02-22 2001-05-29 W.R. Grace & Co. -Conn. Synthetic analogs of thrombospondin and therapeutic use thereof
US5648461A (en) * 1990-02-22 1997-07-15 W.R. Grace & Co.-Conn Synthetic analogs of thrombospondin and therapeutic use thereof
EP0554670A3 (en) * 1992-02-07 1994-07-13 Behringwerke Ag Specific antibodies against activated platelets, their production and applications in diagnostics and therapeutics
US5686583A (en) * 1992-02-07 1997-11-11 Behringwerke Aktiengesellschaft Specific antibodies against activated platelets, the preparation thereof and the use thereof in diagnosis and therapy
US6469138B1 (en) 1993-03-05 2002-10-22 Washington University Thrombospondin receptor binding peptides
US5627265A (en) * 1993-03-05 1997-05-06 Washington University Receptor for cell-binding domain of thrombospondins
US5399667A (en) * 1993-03-05 1995-03-21 Washington University Thrombospondin receptor binding peptides
WO1996033218A1 (fr) * 1995-04-21 1996-10-24 Allelix Biopharmaceuticals Inc. Peptides anti-hemorragiques
WO1996036349A1 (fr) * 1995-05-17 1996-11-21 Manitoba Cancer Treatment And Research Foundation ACTIVATION POST-TRANSLATIVE DU FACTEUR DE CROISSANCE TRANSFORMANT BETA1 (TGFβ1) FAISANT INTERVENIR LE RECEPTEUR CD36 DU TSP-1
WO1996038480A1 (fr) * 1995-06-02 1996-12-05 Allelix Biopharmaceuticals, Inc. Peptides anti-inflammatoires derives de la thrombospondine
WO1999026649A1 (fr) * 1997-11-25 1999-06-03 Cornell Research Foundation, Inc. Compositions inhibant l'infectiosite du virus vih et entravant l'activite de la chemokine et methodes afferentes
US6964763B1 (en) 1997-11-25 2005-11-15 Cornell Research Foundation, Inc. Methods and compositions for inhibiting HIV infectivity and blocking chemokine activity
US6339062B1 (en) 1998-11-23 2002-01-15 Inkine Pharmaceutical Company, Inc. Retroinverso polypeptides that mimic or inhibit thrombospondin activity
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