Method of treating degenerative diseases
View Patent ↗Agonists of a non-proteolytically activated receptor can be used in methods for treating a disease or disorder in a subject. The methods comprise administering to the subject a therapeutically effective amount of an agonist, wherein the disease or disorder is scleroderma, macular degeneration, diabetic retinopathy, Huntington's disease, Parkinson's disease, closed head trauma, glaucoma, optic neuritis or allograft vasculopathy.
1. A method for treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of an agonist of a non-proteolytically activated thrombin receptor, wherein the disease or disorder is selected from the group consisting of: scleroderma, macular degeneration, diabetic retinopathy, closed head trauma, glaucoma, optic neuritis, and allograft vasculopathy.
2. The method of claim 1 , wherein the disease or disorder is glaucoma.
3. The method of claim 1 , wherein the disease or disorder is closed head trauma.
4. The method of claim 1 , wherein the disease or disorder is optic neuritis.
5. The method of claim 1 , wherein the disease or disorder is scleroderma.
6. The method of claim 1 , wherein the agonist is a thrombin peptide derivative comprising the amino acid sequence Asp-Ala-R, wherein R is a serine esterase conserved sequence; and wherein the thrombin peptide derivative comprises from about 12 to about 23 amino acid residues.
7. The method of claim 6 , wherein the thrombin peptide derivative comprises an N-terminus which is unsubstituted, and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 .
8. The method of claim 7 , wherein the thrombin peptide derivative comprises the polypeptide Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:1), wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val.
9. The method of claim 7 , wherein the thrombin peptide derivative comprises the polypeptide Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), an N-terminal truncated fragment of the thrombin peptide derivative having at least fourteen amino acid residues, or a C-terminal truncated fragment of the thrombin peptide derivative having at least eighteen amino acid residues, wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val.
10. The method of claim 1 , wherein the agonist is the polypeptide H-Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val-NH 2 (SEQ ID NO:3).
11. The method of claim 7 , wherein the thrombin peptide derivative comprises the polypeptide Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Xaa-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:5) or a fragment thereof comprising amino acids 10-18 of SEQ ID NO:5, wherein Xaa is alanine, glycine, serine or an S-protected cysteine; X 1 is Glu or Gln; and X 2 is Phe, Met, Leu, His or Val.
12. The method of claim 1 , wherein the agonist is a peptide dimer comprising two thrombin peptide derivatives 12 to 23 amino acid residues in length which, independently, comprise the polypeptide Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:10), wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val, or a C-terminal truncated fragment thereof having at least six amino acid residues, provided that zero, one, two, or three amino acid residues in the polypeptide differ from those residues in the corresponding position of SEQ ID NO:10; said thrombin peptide derivatives optionally comprising a C-terminal amide; and said thrombin peptide derivatives optionally comprising an acylated N-terminus; and
the dimer is essentially free of monomer;
the thrombin peptide derivatives are the same;
the thrombin peptide derivatives are covalently linked through a disulfide bond;
and the thrombin peptide derivatives consist of from about 12 to about 23 amino acids.
13. The method of claim 12 , wherein the thrombin peptide derivatives each comprise an N-terminus which is unsubstituted; and a C-terminus which is unsubstituted or a C-terminal amide represented by —C(O)NH 2 .
14. The method of claim 13 , wherein the thrombin peptide derivatives comprise the polypeptide Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val or a fragment thereof comprising amino acid residues 10-18 of SEQ ID NO:2.
15. The method of claim 13 , wherein the thrombin peptide derivatives comprise the polypeptide Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-X 1 -Gly-Asp-Ser-Gly-Gly-Pro-X 2 -Val (SEQ ID NO:2), wherein X 1 is Glu or Gln and X 2 is Phe, Met, Leu, His or Val.
16. The method of claim 1 , wherein the agonist is a peptide dimer of (SEQ ID NO: 3) represented by the following structural formula: