Collagen-binding synthetic peptidoglycans, preparation, and methods of use
This invention relates to collagen-binding synthetic peptidoglycans and engineered collagen matrices comprising a collagen matrix and a collagen-binding synthetic peptidoglycan where the collagen-binding synthetic peptidoglycan can be aberrant or can have amino acid homology with a portion of the amino acid sequence of a protein or a proteoglycan that regulates collagen fibrillogenesis. The invention also relates to kits, compounds, compositions, and engineered graft constructs comprising such collagen-binding synthetic peptidoglycans or engineered collagen matrices and methods for their preparation and use.
1. A synthetic peptidoglycan (PL)xG wherein
G is heparin;
x is 2 to 10;
L is a linker having a molecular weight of 20 to 500 Daltons which covalently links each “P” to “G”;
P is a collagen-binding synthetic peptide of 5 to 40 amino acids comprising an amino acid sequence selected from the group consisting of:
RRANAALKAGELYKSILYGC (SEQ ID NO: 1),
KELNLVYTGC (SEQ ID NO: 12),
GSITTIDVPWNVGC (SEQ ID NO: 14),
RLDGNEIKRGC (SEQ ID NO: 2),
AHEEISTTNEGVMGC (SEQ ID NO: 3),
NGVFKYRPRYFLYKHAYFYPPLKRFPVOGC (SEQ ID NO: 4),
CQDSETRTFY (SEQ ID NO: 5),
TKKTLRTGC (SEQ ID NO: 6),
GLRSKSKKFRRPDIQYPDATDEDITSHMGC (SEQ ID NO: 7) and
SQNPVQPGC (SEQ ID NO: 8); or an amino acid sequence having at least 80% sequence identity thereto.
2. The synthetic peptidoglycan of claim 1 , wherein the linker comprises from 2 to 20 carbon atoms.
3. The synthetic peptidoglycan of claim 1 , wherein x is 5.
4. The synthetic peptidoglycan of claim 1 , wherein P is RRANAALKAGELYKSILY (SEQ ID NO: 19).
5. A pharmaceutical composition comprising the peptidoglycan of claim 1 and a pharmaceutically acceptable excipient or diluent, or a combination thereof.
6. A composition comprising a plurality of synthetic peptidoglycans (PL)xG, wherein
G is heparin;
L is a linker having a molecular weight of 20 to 500 Daltons which covalently links “P” and “G”; and the average value of x in the composition is greater than 1 and less than 10;
P is a collagen-binding synthetic peptide of up to 40 amino acids comprising an amino acid sequence selected from the group consisting of:
RRANAALKAGELYKSILYGC (SEQ ID NO: 1),
KELNLVYTGC (SEQ ID NO: 12),
GSITTIDVPWNVGC (SEQ ID NO: 14),
RLDGNEIKRGC (SEQ ID NO: 2),
AHEEISTTNEGVMGC (SEQ ID NO: 3),
NGVFKYRPRYFLYKHAYFYPPLKRFPVOGC (SEQ ID NO: 4),
CQDSETRTFY (SEQ ID NO: 5),
TKKTLRTGC (SEQ ID NO: 6),
GLRSKSKKFRRPDIQYPDATDEDITSITMGC (SEQ ID NO: 7) and
SQNPVQPGC (SEQ ID NO: 8); or an amino acid sequence having at least 80% sequence identity thereto.
7. The composition of claim 6 , wherein P is RRANAALKAGELYKSILY (SEQ ID NO: 19).
8. The composition of claim 6 , wherein the linker has from 2 to 20 carbon atoms.
9. The composition of claim 6 , wherein the average value of x in the composition is 5.
10. A pharmaceutical composition comprising the composition of claim 6 and a pharmaceutically acceptable excipient or diluent, or a combination thereof.
11. A method of decreasing average fibril diameter in a patient in need thereof, comprising administering to the patient the synthetic peptidoglycan of claim 1 .
12. A method of decreasing average fibril diameter in a patient in need thereof, comprising administering to the patient the composition of claim 6 .
13. A method of inhibiting platelet aggregation in a patient in need thereof, comprising administering to the patient the synthetic peptidoglycan of claim 1 .
14. A method of inhibiting platelet aggregation in a patient in need thereof, comprising administering to the patient the composition of claim 6 .
15. A method of inhibiting platelet activation in a patient in need thereof, comprising administering to the patient the synthetic peptidoglycan of claim 1 .
16. A method of inhibiting platelet activation in a patient in need thereof, comprising administering to the composition of claim 6 .