Extracellular matrix-binding synthetic peptidoglycans

Abstract

This disclosure provides extracellular matrix-binding synthetic peptidoglycans comprised of one or more synthetic peptides conjugated to a glycan and methods of their use.

What is claimed is: 
     
         1 . A method of treating and/or preventing osteoarthritis in a joint of a patient, comprising injecting to the joint an extracellular matrix-binding synthetic peptidoglycan comprising:
 a) a glycan;   b) from about 1 to about 80 collagen binding peptide(s); and   c) from about 1 to about 80 hyaluronic acid binding peptide(s);   wherein the peptides of b) and c) are covalently bonded to the glycan.   
     
     
         2 . The method of  claim 1 , wherein the glycan is dextran, chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparan, heparin, keratin, keratan sulfate, or hyaluronic acid. 
     
     
         3 . The method of  claim 1 , wherein the glycan is dermatan sulfate. 
     
     
         4 . The method of  claim 1 , wherein the glycan is chondroitin sulfate. 
     
     
         5 . The method of  claim 1 , wherein the glycan is hyaluronic acid. 
     
     
         6 . The method of  claim 1 , wherein the peptides are covalently bonded to the glycan via a linker. 
     
     
         7 . The method of  claim 6 , wherein the linker is N-[β-maleimidopropionic acid]hydrazide (BMPH). 
     
     
         8 . The method of  claim 1 , wherein the synthetic peptidoglycan comprises a total of less than about 50 peptides. 
     
     
         9 . The method of  claim 1 , wherein the synthetic peptidoglycan comprises a total of from about 10 to about 40 peptides. 
     
     
         10 . The method of  claim 1 , wherein the synthetic peptidoglycan comprises a total of about 22 peptides. 
     
     
         11 . The method of  claim 1 , wherein the collagen binding peptide has binding affinity to one or more of collagen types I, II, III, or IV. 
     
     
         12 . The method of  claim 1 , wherein the collagen binding peptide comprises at least one collagen binding peptide that binds to type I collagen and at least one collagen binding peptide that binds to type II collagen. 
     
     
         13 . The method of  claim 1 , wherein the collagen binding peptide comprises an amino acid sequence selected from the group consisting of:
 i) WYRGRLGC (SEQ ID NO: 81), RRANAALKAGELYKSILYGC (SEQ ID NO: 68), RLDGNEIKRGC (SEQ ID NO: 69), AHEEISTTNEGVMGC (SEQ ID NO: 70), GCGGELYKSILY (SEQ ID NO: 71), NGVFKYRPRYFLYKHAYFYPPLKRFPVQGC (SEQ ID NO: 72), CQDSETRTFY (SEQ ID NO: 60), TKKTLRTGC (SEQ ID NO: 74), GLRSKSKKFRRPDIQYPDATDEDITSHMGC (SEQ ID NO: 75), SQNPVQPGC (SEQ ID NO: 76), SYIRIADTNITGC (SEQ ID NO: 77), SYIRIADTNIT (SEQ ID NO: 64), KELNLVYT (SEQ ID NO: 65), KELNLVYTGC (SEQ ID NO: 78), GSITTIDVPWNV (SEQ ID NO: 67), GELYKSILYGC (SEQ ID NO: 80) and GSITTIDVPWNVGC (SEQ ID NO: 66), or   ii) any peptide sequence comprising a sequence with at least about 80% sequence identity to the amino acid sequence of i).   
     
     
         14 . The method of  claim 1 , wherein the collagen binding peptide is WYRGRLGC (SEQ ID NO: 81), RRANAALKAGELYKSILYGC (SEQ ID NO: 68), RLDGNEIKRGC (SEQ ID NO: 69), AHEEISTTNEGVMGC (SEQ ID NO: 70), GCGGELYKSILY (SEQ ID NO: 71), NGVFKYRPRYFLYKHAYFYPPLKRFPVQGC (SEQ ID NO: 72), CQDSETRTFY (SEQ ID NO: 60), TKKTLRTGC (SEQ ID NO: 74), GLRSKSKKFRRPDIQYPDATDEDITSHMGC (SEQ ID NO: 75), SQNPVQPGC (SEQ ID NO: 76), SYIRIADTNITGC (SEQ ID NO: 77), SYIRIADTNIT (SEQ ID NO: 64), KELNLVYT (SEQ ID NO: 65), KELNLVYTGC (SEQ ID NO: 78), GSITTIDVPWNV (SEQ ID NO: 67), GELYKSILYGC (SEQ ID NO: 80) or GSITTIDVPWNVGC (SEQ ID NO: 66). 
     
     
         15 . The method of  claim 1 , wherein the collagen binding peptide is WYRGRLGC (SEQ ID NO: 81), or a peptide sequence comprising a sequence with at least about 80% sequence identity to SEQ ID NO: 81. 
     
     
         16 . The method of  claim 1 , wherein the hyaluronic acid binding peptide comprises an amino acid sequence selected from the group consisting of:
 i) GAHWQFNALTVRGG (SEQ ID NO: 2), GDRRRRRMWHRQ (SEQ ID NO: 3), GKHLGGKHRRSR (SEQ ID NO: 4), RGTHHAQKRRS (SEQ ID NO: 5), RRHKSGHIQGSK (SEQ ID NO: 6), SRMHGRVRGRHE (SEQ ID NO: 7), RRRAGLTAGRPR (SEQ ID NO: 8), RYGGHRTSRKWV (SEQ ID NO: 9), RSARYGHRRGVG (SEQ ID NO: 10), GLRGNRRVFARP (SEQ ID NO: 11), SRGQRGRLGKTR (SEQ ID NO: 12), DRRGRSSLPKLAGPVEFPDRKIKGRR (SEQ ID NO: 13), RMRRKGRVKHWG (SEQ ID NO: 14), RGGARGRHKTGR (SEQ ID NO: 15), TGARQRGLQGGWGPRHLRGKDQPPGR (SEQ ID NO: 16), RQRRRDLTRVEG (SEQ ID NO: 17), STKDHNRGRRNVGPVSRSTLRDPIRR (SEQ ID NO: 18), RRIGHQVGGRRN (SEQ ID NO: 19), RLESRAAGQRRA (SEQ ID NO: 20), GGPRRHLGRRGH (SEQ ID NO: 21), VSKRGHRRTAHE (SEQ ID NO: 22), RGTRSGSTR (SEQ ID NO: 23), RRRKKIQGRSKR (SEQ ID NO: 24), RKSYGKYQGR (SEQ ID NO: 25), KNGRYSISR (SEQ ID NO: 26), RRRCGQKKK (SEQ ID NO: 27), KQKIKHVVKLK (SEQ ID NO: 28), KLKSQLVKRK (SEQ ID NO: 29), RYPISRPRKR (SEQ ID NO: 30), KVGKSPPVR (SEQ ID NO: 31), KTFGKMKPR (SEQ ID NO: 32), RIKWSRVSK (SEQ ID NO: 33) and KRTMRPTRR (SEQ ID NO: 34); or   ii) any peptide sequence comprising a sequence with at least about 80% sequence identity to the amino acid sequence of i).   
     
     
         17 . The method of  claim 1 , wherein the hyaluronic acid binding peptide is GAHWQFNALTVRGG (SEQ ID NO: 2), GDRRRRRMWHRQ (SEQ ID NO: 3), GKHLGGKHRRSR (SEQ ID NO: 4), RGTHHAQKRRS (SEQ ID NO: 5), RRHKSGHIQGSK (SEQ ID NO: 6), SRMHGRVRGRHE (SEQ ID NO: 7), RRRAGLTAGRPR (SEQ ID NO: 8), RYGGHRTSRKWV (SEQ ID NO: 9), RSARYGHRRGVG (SEQ ID NO: 10), GLRGNRRVFARP (SEQ ID NO: 11), SRGQRGRLGKTR (SEQ ID NO: 12), DRRGRSSLPKLAGPVEFPDRKIKGRR (SEQ ID NO: 13), RMRRKGRVKHWG (SEQ ID NO: 14), RGGARGRHKTGR (SEQ ID NO: 15), TGARQRGLQGGWGPRHLRGKDQPPGR (SEQ ID NO: 16), RQRRRDLTRVEG (SEQ ID NO: 17), STKDHNRGRRNVGPVSRSTLRDPIRR (SEQ ID NO: 18), RRIGHQVGGRRN (SEQ ID NO: 19), RLESRAAGQRRA (SEQ ID NO: 20), GGPRRHLGRRGH (SEQ ID NO: 21), VSKRGHRRTAHE (SEQ ID NO: 22), RGTRSGSTR (SEQ ID NO: 23), RRRKKIQGRSKR (SEQ ID NO: 24), RKSYGKYQGR (SEQ ID NO: 25), KNGRYSISR (SEQ ID NO: 26), RRRCGQKKK (SEQ ID NO: 27), KQKIKHVVKLK (SEQ ID NO: 28), KLKSQLVKRK (SEQ ID NO: 29), RYPISRPRKR (SEQ ID NO: 30), KVGKSPPVR (SEQ ID NO: 31), KTFGKMKPR (SEQ ID NO: 32), RIKWSRVSK (SEQ ID NO: 33) or KRTMRPTRR (SEQ ID NO: 34). 
     
     
         18 . The method of  claim 1 , wherein the hyaluronic acid binding peptide is GAHWQFNALTVRGG (SEQ ID NO: 2), or a peptide sequence comprising a sequence with at least about 80% sequence identity to SEQ ID NO: 2. 
     
     
         19 . A method of treating and/or preventing osteoarthritis in a joint of a patient, comprising injecting to the joint an extracellular matrix-binding synthetic peptidoglycan comprising:
 a) chondroitin sulfate;   b) from about 1 to about 80 collagen binding peptide(s); and   c) from about 1 to about 80 hyaluronic acid binding peptide(s);   wherein the peptides of b) and c) are covalently bonded to the glycan; and further wherein the collagen binding peptide(s) is WYRGRLGC (SEQ ID NO: 81), or a peptide sequence comprising a sequence with at least about 80% sequence identity to SEQ ID NO: 81, and the hyaluronic acid binding peptide(s) is GAHWQFNALTVRGG (SEQ ID NO: 2), or a peptide sequence comprising a sequence with at least about 80% sequence identity to SEQ ID NO: 2.   
     
     
         20 . The method of  claim 19 , wherein the peptides are covalently bonded to the glycan via a linker. 
     
     
         21 . The method of  claim 20 , wherein the linker is N-[β-maleimidopropionic acid]hydrazide (BMPH). 
     
     
         22 . A method of treating and/or preventing cartilage degeneration in a joint of a patient, comprising injecting to the joint an extracellular matrix-binding synthetic peptidoglycan comprising:
 a) chondroitin sulfate;   b) from about 5 to about 20 collagen binding peptide(s); and   c) from about 5 to about 20 hyaluronic acid binding peptide(s);   wherein the peptides of b) and c) are covalently bonded to the glycan via N-[β-maleimidopropionic acid]hydrazide (BMPH); and further wherein the collagen binding peptide(s) are WYRGRLGC (SEQ ID NO: 81), or a peptide sequence comprising a sequence with at least about 80% sequence identity to SEQ ID NO: 81, and the hyaluronic acid binding peptide(s) are GAHWQFNALTVRGG (SEQ ID NO: 2), or a peptide sequence comprising a sequence with at least about 80% sequence identity to SEQ ID NO: 2.   
     
     
         23 . A method of treating and/or preventing cartilage degeneration in a joint of a patient, comprising injecting to the joint an extracellular matrix-binding synthetic peptidoglycan comprising:
 a) a glycan;   b) from about 1 to about 80 collagen binding peptide(s); and   c) from about 1 to about 80 hyaluronic acid binding peptide(s);   wherein the peptides of b) and c) are covalently bonded to the glycan.