Claims
- 1. A peptide-based construct of 8-15 amino acid moieties in length having at least one of heparin binding, heparin neutralizing, endothelial cell proliferation inhibiting, or antiangiogenic properties comprising:
a sequence having the formula:α-χ-χ-α-χ-β-χ-α-Rwherein,
α is a hydrophilic basic amino acid moiety that is any one of lysine, arginine, histidine, ornithine, diaminobutyric acid, citrulline, or para-amino phenylalanine; β is a hydrophilic neutral amino acid moiety that is any one of asparagine, glutamine, serine, threonine, tyrosine, hydroxyproline, or 7-hydroxy-tetrahydroisoquinoline carboxylic acid; χ is a hydrophobic amino acid moiety that is any one of alanine, naphthylalanine, biphenylalanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, cyclohexylalanine, amino-isobutyric acid, norvaline, norleucine, tert-leucine, tetrahydroisoquinoline carboxylic acid, pipecolic acid, phenylglycine, homophenylalanine, cyclohexylglycine, dehydroleucine, 2,2-diethylglycine, 1-amino-1-cyclopentane carboxylic acid, 1-amino-1-cyclohexane carboxylic acid, amino-benzoic acid, amino-naphthoic acid, γ-amino butyric acid, beta-alanine, difluorophenylalanine, fluorophenylalanine, nipecotic acid, α-aminobutyric acid, thienyl-alanine, or t-butyl-glycine; and R is an amino acid moiety that is any one of -χ, -χ-α, -χ-α-χ, χ-α-χ-β, -χ-α-χ-β-χ, -χ-α-χ-β-χ-α, -χ-α-χ-β-χ-α-χ, -χ-α-χ-χ-α-χ, -NH2, -χ-NH2, -χ-α-NH2, -χ-α-χ-NH2, -χ-α-χ-β-NH2, -χ-α-χ-β-χ-NH2, -χ-α-χ-β-χ-α-NH2, -χ-α-χ-β-χ-α-χ-NH2, or -χ-α-χ-χ-α-χ-NH2.
- 2. A composition of 8-15 amino acid moieties consecutively linked by peptide bonds, said composition having one or more heparin binding properties and comprising a sequence of the formula:
- 3. The composition of claim 2 comprising two or more conservative substitutions of amino acid moieties.
- 4. The construct of claim 1 or composition of claim 2 having heparin neutralizing properties.
- 5. The construct of claim 1 or composition of claim 2 having endothelial cell proliferation inhibiting properties.
- 6. The construct of claim 1 or composition of claim 2 having anti-angiogenic properties.
- 7. The construct or composition of any one of claims 1 to 6 wherein the first two amino-terminal amino acid moieties are D-amino acid moieties and the last two carboxy-terminal amino acid moieties are D-amino acid moieties.
- 8. A method of neutralizing heparin in a mammal that has been administered an exogenous heparin compound comprising the step of administering to said mammal an amount of the construct of claim 1 or composition of claim 2 effective to neutralize the anticoagulant effect of the exogenous heparin compound.
- 9. The method of claim 8 wherein the clotting time of said mammal is returned to normal.
- 10. A method of inhibiting endothelial cell proliferation in a mammal in need thereof comprising the step of administering to said mammal an amount of the construct of claim 1 or composition of claim 2 effective to inhibit endothelial cell proliferation.
- 11. A method of inhibiting angiogenesis in a mammal in need thereof comprising the step of administering to said mammal an amount of the construct of claim 1 or composition of claim 2 effective to inhibit angiogenesis.
- 12. The method of claim 11 wherein said angiogenesis is in the eye.
- 13. A method of treating a mammal suffering from a disorder involving angiogenesis comprising the step of administering to said mammal an amount of the construct of claim 1 or composition of claim 2 effective to inhibit angiogenesis.
- 14. The method of claim 13 wherein said disorder involving angiogenesis is a chronic inflammatory disease.
- 15. The method of claim 14 wherein said chronic inflammatory disease is rheumatoid or reactive arthritis.
- 16. The method of claim 13 wherein said disorder involving angiogenesis is proliferation or metastasis of tumor cells.
- 17. A derivatized peptide-based construct of 8-15 amino acid moieties in length having heparin binding, heparin neutralizing, endothelial cell proliferation inhibiting, or antiangiogenic properties comprising:
a sequence having the formula:R1-α-χ-χ-α-χ-β-χ-α-Rwherein,
α is a hydrophilic basic amino acid moiety that is any one of lysine, arginine, histidine, ornithine, diaminobutyric acid, citrulline, or para-amino phenylalanine; β is a hydrophilic neutral amino acid moiety that is any one of asparagine, glutamine, serine, threonine, tyrosine, hydroxyproline, or 7-hydroxy-tetrahydroisoquinoline carboxylic acid; χ is a hydrophobic amino acid moiety that is any one of alanine, naphthylalanine, biphenylalanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, cyclohexylalanine, amino-isobutyric acid, norvaline, norleucine, tert-leucine, tetrahydroisoquinoline carboxylic acid, pipecolic acid, phenylglycine, homophenylalanine, cyclohexylglycine, dehydroleucine, 2,2-diethylglycine, 1-amino-1-cyclopentane carboxylic acid, 1-amino-1-cyclohexane carboxylic acid, amino-benzoic acid, amino-naphthoic acid, γ-amino butyric acid, beta-alanine, difluorophenylalanine, fluorophenylalanine, nipecotic acid, α-aminobutyric acid, thienyl-alanine, or t-butyl-glycine; R is an amino acid moiety that is any one of -χ, -χ-α, -χ-α-χ, χ-α-χ-β, -χ-α-χ-β-χ, -χ-α-χ-β-χ-α, -χ-α-χ-β-χ-α-χ, -χ-αχ-χ-α-χ, -NH2, -χ-NH2, -χ-α-NH2, -χ-α-χ-NH2, -χ-α-χ-β-NH2, -χ-α-χ-β-χ-NH2, -χ-α-χ-β-χ-α-NH2, -χ-α-χ-β-χ-α-χ-NH2, or -χ-α-χ-χ-α-χ-NH2; and wherein,
R1 is any one of R2—CH2—, R2—CH2—CO—, R2—CO—, R2—SOy—, or R2—POz—; wherein,
y=0-3, z=1-4; R2 is a hydrophobic moiety that is any one of a cyclic molecule having at least 3 carbon atoms, a heterocyclic molecule having at least 3 atoms, a functionalized cyclic molecule having at least 3 carbon atoms, or a functionalized heterocyclic molecule having at least 3 atoms.
- 18. A composition of 8-15 amino acid moieties consecutively linked by peptide bonds, said composition having one or more heparin binding properties and comprising a sequence of the formula:
- 19. The composition of claim 18 comprising two or more conservative substitutions of amino acid moieties.
- 20. The construct of claim 17 or composition of claim 18 having heparin neutralizing properties.
- 21. The construct of claim 17 or composition of claim 18 having endothelial cell proliferation inhibiting properties.
- 22. The construct of claim 17 or composition of claim 18 having anti-angiogenic properties.
- 23. The construct or compositon of any one of claims 17 to 22 wherein the first two amino-terminal amino acid moieties are D-amino acid moieties and the last two carboxy-terminal amino acid moieties are D-amino acid moieties.
- 24. A method of neutralizing heparin in a mammal that has been administered an exogenous heparin compound comprising the step of administering to said mammal an amount of the construct of claim 17 or composition of claim 18 effective to neutralize the anticoagulant effect of the exogenous heparin compound.
- 25. The method of claim 24 wherein the clotting time of said mammal is returned to normal.
- 26. A method of inhibiting endothelial cell proliferation in a mammal in need thereof comprising the step of administering to said mammal an amount of the construct of claim 17 or composition of claim 18 effective to inhibit endothelial cell proliferation.
- 27. A method of inhibiting angiogenesis in a mammal in need thereof comprising the step of administering to said mammal an amount of the construct of claim 17 or composition of claim 18 effective to inhibit angiogenesis.
- 28. The method of claim 27 wherein said angiogenesis is in the eye.
- 29. A method of treating a mammal suffering from a disorder involving angiogenesis comprising the step of administering to said mammal an amount of the construct of claim 17 or composition of claim 18 effective to inhibit angiogenesis.
- 30. The method of claim 29 wherein said disorder involving angiogenesis is a chronic inflammatory disease.
- 31. The method of claim 30 wherein said chronic inflammatory disease is rheumatoid or reactive arthritis.
- 32. The method of claim 29 wherein said disorder involving angiogenesis is proliferation or metastasis of tumor cells.
- 33. The construct of claim 17 or composition of claim 18, wherein said R2 is a hydrophobic moiety that is any one of (a) an optionally substituted carbocyclic ring, saturated or partially or fully unsaturated containing 3 to 8, preferably 5 or 6, carbon atoms; (b) an optionally substituted heterocyclic ring, saturated or partially or fully unsaturated, containing 3 to 8, preferably 5 or 6, atoms, wherein at least one atom is a heteroatom that is any one of oxygen, nitrogen, or sulfur; or (c) an optionally substituted bicyclic ring
- 34. The construct of claim 17 or composition of claim 18, wherein said R2 is a hydrophobic moiety that is any one of biotin, 2-biphenylene, 2-anthraquinone, 2-benzofuran, 2-indole, 1-isoquinoline, hydroxyphenyl, 2-quinoline, 1-[3-(3,4-dihydroxycinnamoyl)-1,3,4,5-tetrahydroxycyclohexyl], 1-(3,5-dichloro-2-hydroxyphenyl), 1-(3,5-diiodo-2-hydroxyphenyl), 1-(3,5-dinitro-2-hydroxyphenyl), 1-(4-azido-2-hydroxyphenyl), 4-biphenyl, 2-biphenyl, 1-naphthyl, 2-naphthyl, 3-amino-2-naphthyl, 3-chloro-2-nitrophenyl, 3,4-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2-chloro-3-nitrophenyl, 5-azido-2-nitrophenyl, 3-amino-2-pyrazyl, 2-benzyloxycarbonyl-ethyl, 2-thienyl, 2-(3,4-dihydroxyphenyl)ethylene, 5-bromo-3-indolemethylene, 2-(4-hydroxy-3-methoxyphenyl)ethylene, 2-(3-chlorophenyl)ethylene, 2-pyrazyl, 4-imidazolyl, 2-imino-1-imidazolidyl, pyridyl, 3-piperidyl, 4-piperidyl, fluorescein, 2-(4-amino-3,5,6-trichloro-pyridyl), 3-(2-chloro-6-fluorophenyl)-5-methylisoxazolyl, or 4-azido-phenyl.
Parent Case Info
[0001] This is a continuation-in-part of U.S. application Ser. No. 09/344,219 and U.S. application Ser. No. 09/344,827, each filed Jun. 25, 1999, each hereby incorporated by reference in their entirety.
Continuations (2)
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Number |
Date |
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Parent |
09789941 |
Feb 2001 |
US |
Child |
10209621 |
Jul 2002 |
US |
Parent |
09602811 |
Jun 2000 |
US |
Child |
09789941 |
Feb 2001 |
US |
Continuation in Parts (2)
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Number |
Date |
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Parent |
09344219 |
Jun 1999 |
US |
Child |
09602811 |
Jun 2000 |
US |
Parent |
09344827 |
Jun 1999 |
US |
Child |
09602811 |
Jun 2000 |
US |