Use of thrombin-derived peptides for the therapy of chronic dermal ulcers
Disclosed is a method of promoting healing of a chronic dermal skin ulcer, such as a diabetic ulcer, on a subject. The method comprises the step of contacting the chronic dermal skin ulcer with an effective amount of an agonist of the non-proteolytically activated thrombin receptor.
1. A method of treating a chronic skin ulcer in a subject, said method comprising administering to the chronic skin ulcer an effective amount of a polypeptide of between 14 to 23 amino acids in length, wherein the polypeptide comprises a thrombin receptor binding domain of the sequence Arg-Gly-Asp-Ala (SEQ ID NO.: 7) and a serine esterase conserved sequence, wherein the polypeptide is administered to the chronic skin ulcer for a duration sufficient to achieve at least 80% closure of the chronic skin ulcer, and wherein the polypeptide is administered to the chronic skin ulcer alone or in combination with an antimicrobial, a disinfectant, an antibiotic, an analgesic or an anti-inflammatory agent.
2. The method of claim 1 wherein said serine esterase conserved sequence comprises Asp-X 1 -Cys-X 2 -Gly-Asp-Ser-Gly-Gly-Pro-X 3 -Val (SEQ ID NO.: 9), wherein X 1 is either Ala or Ser; X 2 is either Glu or Gln; and X 3 is either Phe, Met, Leu, His, or Val.
3. The method of claim 2 wherein said serine esterase conserved sequence comprises Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val (SEQ ID NO.: 8).
4. The method of claim 3 wherein said polypeptide is represented by R1-Ala-Gly -Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val-R2 (SEQ ID NO.: 5), wherein:
R1 is —H or R3-C(O)—;
R2 is —OH or —NR4R5;
R3 is —H or a C1–C6 alkyl group; and
R4 and R5 are independently —H, a C1–C6 alkyl group or, taken together with the nitrogen atom to which they are bonded, a non-aromatic heterocyclic group.
5. The method of claim 4 wherein R1 is —H and R2 is —NH2.
6. The method of claim 4 wherein R1 is —H and R2 is —OH.
7. A method of treating a chronic skin ulcer in a subject, said method comprising administering to the chronic skin ulcer an effective amount of a polypeptide 23 amino acids in length, wherein the polypeptide comprises the sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val- (SEQ ID NO.: 1), wherein the polypeptide is administered to the chronic skin ulcer for a duration sufficient to achieve at least 80% closure of the chronic skin ulcer, and wherein the polypeptide is administered to the chronic skin ulcer alone or in combination with an antimicrobial, a disinfectant, an antibiotic, an analgesic or an anti-inflammatory agent.
8. A method of treating a diabetic ulcer in a subject, said method comprising administering to the diabetic ulcer an effective amount of the polypeptide 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.: 6), wherein the polypeptide is administered to the diabetic ulcer for a duration sufficient to achieve at least 80% closure of the diabetic ulcer, and wherein the polypeptide is administered to the diabetic ulcer alone or in combination with an antimicrobial, a disinfectant, an antibiotic, an analgesic or an anti-inflammatory agent.
9. A method of treating a decubitus ulcer in a subject, said method comprising administering to the decubitus ulcer an effective amount of the polypeptide 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.: 6), wherein the polypeptide is administered to the decubitus ulcer for a duration sufficient to achieve at least 80% closure of the decubitus ulcer, and wherein the polypeptide is administered to the decubitus ulcer alone or in combination with an antimicrobial, a disinfectant, an antibiotic, an analgesic or an anti-inflammatory agent.
10. A method of treating a venous stasis ulcer in a subject, said method comprising administering to the venous stasis ulcer an effective amount of the polypeptide 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.: 6), wherein the polypeptide is administered to the venous stasis ulcer for a duration sufficient to achieve at least 80% closure of the venous stasis ulcer, and wherein the polypeptide is administered to the venous stasis ulcer alone or in combination with an antimicrobial, a disinfectant, an antibiotic, an analgesic or an anti-inflammatory agent.
11. A method of treating a arterial ulcer in a subject, said method comprising administering to the arterial ulcer an effective amount of the polypeptide Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val-NH2 (SEQ ID NO.: 6), wherein the polypeptide is administered to the arterial ulcer for a duration sufficient to achieve at least 80% closure of the arterial ulcer, and wherein the polypeptide is administered to the arterial ulcer alone or in combination with an antimicrobial, a disinfectant, an antibiotic, an analgesic or an anti-inflammatory agent.