Compositions and methods for inhibiting cellular adhesion or directing diagnostic or therapeutic agents to RGD binding sites
Compounds comprising R-G-Cysteic Acid (i.e., R-G-NH—CH(CH 2 —SO 3 H)COOH or Arg-Gly-NH—CH(CH 2 —SO 3 H)COOH) and derivatives thereof, including pharmaceutically acceptable salts, hydrates, stereoisomers, multimers, cyclic forms, linear forms, drug-conjugates, pro-drugs and their derivatives. Also disclosed are methods for making and using such compounds including methods for inhibiting cellular adhesion to RGD binding sites or delivering other diagnostic or therapeutic agents to RGD binding sites in human or animal subjects.
1. A method of inhibiting adhesion of cells to RGD binding sites comprising administering to a subject in need thereof an effective amount of a cyclic or linear compound comprising either:
i) a peptide which comprises Glycinyl-Arginyl-Glycinyl-Cysteic-Threonyl-Proline-COOH or
ii) a peptide which has the formula:
X 1 —R-G-Cysteic Acid-X
where X and X 1 are selected from: Phe-Val-Ala, -Phe-Leu-Ala, -Phe-Val-Gly, -Phe-Leu-Gly, -Phe-Pro-Gly, -Phe-Pro-Ala, -Phe-Val; or from Arg, Gly, Cysteic, Phe, Val, Ala, Leu, Pro, Thr and salts thereof and any combinations of D-isomers and L-isomers thereof.
2. The method of claim 1 wherein the peptide is administered to the subject's eye and wherein said inhibition of adhesion of cells to RGD binding sites is effective to treat a disorder of the subject's eye.
3. The method of claim 2 wherein the peptide is administered by intravitreal injection.
4. The method of claim 2 wherein said inhibition of adhesion of cells to RGD binding sites is effective to treat a disorder of the subject's eye selected from: neovascularization, neovascular glaucoma, diabetic retinopa thy, retinal degeneration, dry macular degeneration, wet macular degeneration, corneal neovascularization and vitreo-macular traction.
5. The method of claim 1 wherein the peptide is administered systemically and wherein said inhibition of adhesion of cells to RGD binding sites is effective to treat a cancer which expresses an integrin that recognizes the RGD motif.
6. The method of claim 5 wherein the cancer comprises a vascularized solid tumor or metastatic lesions from a vascularized solid tumor.
7. The method of claim 1 wherein the peptide has the structural formula:
8. The method of claim 1 wherein the peptide has the structural formula:
where X′ is selected from: H, C1-C 6 alkyl, Ph or SO 3 H and Z is selected from H or Me; Y is selected from OH, NH 2 .
9. The method of claim 1 wherein the peptide comprises Glycine-Arginine-Glycine-Cysteic (Acid)-Threonine-Proline.
10. A method of antagonizing an RGD-binding integrin in a subject comprising administering to a subject in need thereof an effective amount of a cyclic or linear compound comprising either:
i) a peptide which comprises Glycinyl-Arginyl-Glycinyl-Cysteic-Threonyl-Proline-COOH or
ii) a peptide which has the formula:
X 1 —R-G-Cysteic Acid-X
where X and X 1 are selected from: Phe-Val-Ala, -Phe-Leu-Ala, -Phe-Val-Gly, -Phe-Leu-Gly, -Phe-Pro-Gly, -Phe-Pro-Ala, -Phe-Val; or from Arg, Gly, Cysteic, Phe, Val, Ala, Leu, Pro, Thr and salts thereof and any combinations of D-isomers and L-isomers thereof.
11. The method of claim 10 wherein the peptide is administered to the subject's eye and wherein said antagonizing of an RGD-binding integrin is effective to treat a disorder of the subject's eye.
12. The method of claim 11 wherein the peptide is administered by intravitreal injection.
13. The method of claim 11 wherein said antagonizing of an RGD-binding integrin is effective to treat a disorder of the subject's eye selected from: neovascularization, neovascular glaucoma, diabetic retinopathy, retinal degeneration, dry macular degeneration, wet macular degeneration, corneal neovascularization and vitreo-macular traction.
14. The method of claim 10 wherein said antagonizing of an RGD-binding integrin is effective to treat a cancer which expresses an integrin that recognizes the RGD motif.
15. The method of claim 14 wherein the cancer comprises a vascularized solid tumor or metastatic lesions from a vascularized solid tumor.
16. The method of claim 10 wherein the peptide has the structural formula:
17. The method of claim 10 wherein the peptide has the structural formula:
where X′ is selected from: H, C1-C 6 alkyl, Ph or SO 3 H and Z is selected from H or Me; Y is selected from OH, NH 2 .
18. The method of claim 10 wherein the peptide comprises Glycine-Arginine-Glycine-Cysteic (Acid)-Threonine-Proline.
19. A method of antagonizing an integrin in a subject comprising administering to a subject in need thereof a cyclic or linear compound comprising either:
i) a peptide which comprises Glycinyl-Arginyl-Glycinyl-Cysteic-Threonyl-Proline-COOH or
ii) a peptide which has the formula:
X 1 —R-G-Cysteic Acid-X
where X and X 1 are selected from: Phe-Val-Ala, -Phe-Leu-Ala, -Phe-Val-Gly, -Phe-Leu-Gly, -Phe-Pro-Gly, -Phe-Pro-Ala, -Phe-Val; or from Arg, Gly, Cysteic, Phe, Val, Ala, Leu, Pro, Thr and salts thereof and any combinations of D-isomers and L-isomers thereof, wherein said integrin is one which is subject to antagonism by an RGD peptide.
20. The method of claim 19 wherein the peptide is administered to the subject's eye and said antagonizing of an integrin is effective to treat a disorder of the subject's eye.
21. The method of claim 20 wherein the peptide is administered by intravitreal injection.
22. The method of claim 20 wherein the antagonizing of an integrin is effective to treat a disorder of the subject's eye selected from: neovascularization, neovascular glaucoma, diabetic retinopathy, retinal degeneration, dry macular degeneration, wet macular degeneration, corneal neovascularization and vitreo-macular traction.
23. The method of claim 19 wherein the peptide is administered systemically to treat a cancer which expresses an integrin that recognizes the RGD motif.
24. The method of claim 23 wherein the cancer comprises a vascularized solid tumor or metastatic lesions from a vascularized solid tumor.
25. The method of claim 19 wherein the peptide has the structural formula:
26. The method of claim 19 wherein the peptide has the structural formula:
where X′ is selected from: H, C1-C 6 alkyl, Ph or SO 3 H and Z is selected from H or Me; Y is selected from OH or NH 2 .
27. The method of claim 19 wherein the peptide comprises Glycine-Arginine-Glycine-Cysteic (Acid)-Threonine-Pro.