Peptides derived from fibronectin with improved bioactivity and reduced susceptibility to neutrophil elastase degradation
Polypeptides derived from fibronectin are presented that are neutrophil elastase-resistant and can bind to growth factors and/or enhance growth factor activity. These polypeptides are useful for enhancing wound healing in a patient.
1. A cyclized polypeptide consisting of Formula I:
(I):
(SEQ ID NO: 1)
H-X 1 -X 2 -K-Y-X 3 -X 4 -R-W-R-P-K-X 5 -X 6 -X 7
wherein X 1 is I or G or L,
X 2 is S or G,
X 3 is I or G or L,
X 4 is L or G,
X 5 is N or G,
X 6 is absent or S, and
X 7 is absent or V; and
wherein no two consecutive amino acids in the first 13 amino acids of the polypeptide differ from the sequence HISKYILRWRPKN (SEQ NO:9),
wherein the polypeptide is not a linear or branched multimer of Formula I.
2. The cyclized polypeptide of claim 1 , wherein the polypeptide is substituted with at least one of a lower acyl group at the N-terminus, a substituted or unsubstituted lower alkyl-, alkenyl-, alkynyl- or haloalkyl-amine group at the C-terminus and polyethylene glycol.
3. The cyclized polypeptide of claim 1 , selected from the group consisting of HISKYILRWRPKNSV (SEQ ID NO:10), HIGKYGLRWRPKNSV (SEQ ID NO:11), HIGKYGLRWRPKGSV (SEQ ID NO:12), HGSKYGLRWRPKNSV (SEQ ID NO:13), HIGKYIGRWRPKNSV (SEQ ID NO:14), HGSKYIGRWRPKNSV (SEQ ID NO:15), and HGSKYIGRWRPKGSV (SEQ ID NO:16).
4. The cyclized polypeptide of claim 3 , consisting of HIGKYGLRWRPKGSV (SEQ ID NO:12).
5. A composition comprising:
the cyclized polypeptide of claim 1 , and;
a pharmaceutically acceptable excipient, carrier or diluent,
wherein the composition is suitable for a route of administration selected from injection, intravenous administration and topical administration to a patient.
6. The composition of claim 5 , wherein the polypeptide is selected from the group consisting of HISKYILRWRPKNSV (SEQ ID NO:10), HIGKYGLRWRPKNSV (SEQ ID NO:11) HIGKYGLRWRPKGSV (SEQ ID NO:12), HGSKYGLRWRPKNSV (SEQ ID NO:13), HIGKYIGRWRPKNSV (SEQ ID NO:14), HGSKYIGRWRPKNSV (SEQ ID NO:15), and HGSKYIGRWRPKGSV (SEQ ID NO:16).
7. The composition of claim 6 , wherein the polypeptide is HIGKYGLRWRPKGSV (SEQ ID NO:12).
8. A method of treating a patient with a wound selected from the group consisting of a surgical incision or extirpation, a traumatic injury, a thermal burn, a chemical burn, a lesion or ulceration of the patient's skin, mucosa, connective tissue, fascia, ligament, tendon, cartilage, nerve or muscle and a wound to the patient's bone, the method comprising:
administering to the patient a therapeutically effective amount of a composition comprising a cyclized polypeptide consisting of Formula I:
(I):
(SEQ ID NO: 1)
H-X 1 -X 2 -K-Y-X 3 -X 4 -R-W-R-P-K-X 5 -X 6 -X 7
wherein X 1 is I or G or L,
X 2 is S or G,
X 3 is I or G or L,
X 4 is L or G,
X 5 is N or G,
X 6 is absent or S, and
X 7 is absent or V; and
wherein no two consecutive amino acids in the first 13 amino acids of the polypeptide differ from the sequence HISKYILRWRPKN (SEQ ID NO:9),
wherein the polypeptide is not a linear or branched multimer of Formula I.
9. The method of claim 8 , wherein the cyclized polypeptide is substituted with at least one of a lower acyl group at the N-terminus, a substituted or unsubstituted lower alkyl-, alkenyl-, alkynyl- or haloalkyl-amine group at the C-terminus and polyethylene glycol.
10. The method of claim 8 , wherein the wound is a thermal burn or a chemical burn.
11. The method of claim 10 , wherein the wound is a thermal burn.
12. The method of claim 8 , wherein the cyclized polypeptide is selected from the group consisting of HISKYILRWRPKNSV (SEQ ID NO:10), HIGKYGLRWRPKNSV (SEQ ID NO:11), HIGKYGLRWRPKGSV (SEQ ID NO:12), HGSKYGLRWRPKNSV (SEQ ID NO:13), HIGKYIGRWRPKNSV (SEQ ID NO:14), HGSKYIGRWRPKNSV (SEQ ID NO:15), and HGSKYIGRWRPKGSV (SEQ ID NO:16).
13. The method of claim 8 , wherein the cyclized polypeptide is HIGKYGLRWRPKGSV (SEQ ID NO:12).