Matrix scaffold with antimicrobial activity

Abstract

The invention provides a scaffold of extracellular matrix polymers with recombinant chimeric peptides tethered thereto. The invention also provides recombinant chimeric peptides of antimicrobial peptides and extracellular matrix binding domains. The invention also provides methods for treating chronic wounds using the scaffold and/or recombinant chimeric peptides.

1 . A scaffold comprising one or more extracellular matrix polymers and one or more chimeric peptides comprising one or more antimicrobial peptides and one or more extracellular matrix binding domains, wherein said one or more antimicrobial peptides comprises LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES (SEQ ID NO: 3) and said extracellular matrix binding domain is linked to the C-terminal end of SEQ ID NO: 3. 
     
     
         2 . The scaffold according to  claim 1 , wherein said one or more chimeric peptides are added to previously produced extracellular matrix polymers. 
     
     
         3 . The scaffold according to  claim 1 , wherein said one or more extracellular matrix polymers are selected from the group consisting of naturally occurring, artificial and combinations thereof. 
     
     
         4 . The scaffold according to  claim 3 , wherein said one or more naturally occurring polymer is selected from the group consisting of: collagen, fibronectin, laminin, elastin, hyaluronan, fibrin, gelatin, alginate, glycosaminoglycans and combinations thereof. 
     
     
         5 . The scaffold according to  claim 3 , wherein said one or more artificial polymer is selected from the group consisting of poly-L-lactic acid, polyglycolic acid, polyurethane, polyethylene Terephthalate, polytetrafluoroethylene, polycaprolactone and combinations thereof. 
     
     
         6 . The scaffold according to  claim 1 , wherein said scaffold further comprises one or more antimicrobial peptides selected from the group consisting of cathelicidins, defensins, chrysophsin, cecropins, cationic alpha-helical small molecule peptides and combinations thereof. 
     
     
         7 . The scaffold according to  claim 1 , wherein said one or more extracellular matrix binding domains is selected from the group consisting of collagen binding domain, fibronectin binding domain, laminin binding domain, elastin binding domain, hyaluronan binding domain, fibrin binding domain, gelatin binding domain, alginate binding domain, glycosaminoglycan binding domain and combinations thereof. 
     
     
         8 . The scaffold according to  claim 1 , wherein said one or more extracellular matrix binding domains is selected from the group consisting of: TKKTLRT (SEQ ID NO: 5), CQDSETGTFY (SEQ ID NO: 6) and combinations thereof. 
     
     
         9 . The scaffold according to  claim 1 , wherein said one or more chimeric peptides further comprises an intervening peptide domain between said antimicrobial peptide and said extracellular matrix binding domain. 
     
     
         10 . The scaffold according to  claim 9 , wherein said intervening peptide domain comprises five aspartic acid residues, two lysine residues and a tyrosine residue. 
     
     
         11 . A method for treating wounds comprising contacting said wound with a scaffold comprising one or more extracellular matrix polymers and one or more chimeric peptides comprising one or more antimicrobial peptides and one or more extracellular matrix binding domains, wherein said one or more antimicrobial peptides comprises LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES (SEQ ID NO: 3) and said extracellular matrix binding domain is linked to the C-terminal end of SEQ ID NO: 3. 
     
     
         12 . The method according to  claim 11 , wherein said one or more peptides are added to previously produced extracellular matrix polymers. 
     
     
         13 . The method according to  claim 11 , wherein said one or more extracellular matrix polymers are selected from the group consisting of naturally occurring, artificial and combinations thereof. 
     
     
         14 . The method according to  claim 13 , wherein said one or more naturally occurring polymer is selected from the group consisting of collagen, fibronectin, laminin, elastin, hyaluronan, fibrin, gelatin, alginate, glycosaminoglycans and combinations thereof. 
     
     
         15 . The method according to  claim 13 , wherein said one or more artificial polymer is selected from the group consisting of poly-L-lactic acid, polyglycolic acid, polyurethane, polyethylene Terephthalate, polytetrafluoroethylene, polycaprolactone and combinations thereof. 
     
     
         16 . The method according to  claim 11 , wherein said scaffold further comprises one or more antimicrobial peptides selected from the group consisting of cathelicidins, defensins, chrysophsin, cecropins, cationic alpha-helical small molecule peptides and combinations thereof. 
     
     
         17 . The method according to  claim 11 , wherein said one or more extracellular matrix binding domains is selected from the group consisting of collagen binding domain, fibronectin binding domain, laminin binding domain, elastin binding domain, hyaluronan binding domain, fibrin binding domain, gelatin binding domain, alginate binding domain, glycosaminoglycan binding domain and combinations thereof. 
     
     
         18 . The method according to  claim 11 , wherein said one or more extracellular matrix binding domains is selected from the group consisting of TKKTLRT (SEQ ID NO: 5), CQDSETGTFY (SEQ ID NO: 6) and combinations thereof. 
     
     
         19 . The method according to  claim 11 , wherein said one or more chimeric peptides further comprises an intervening peptide domain between said antimicrobial peptide and said extracellular matrix binding domain. 
     
     
         20 . The method according to  claim 19 , wherein said intervening peptide domain comprises five aspartic acid residues, two lysine residues and a tyrosine residue. 
     
     
         21 . The method according to  claim 11 , wherein said wounds are chronic wounds. 
     
     
         22 . The method according to  claim 11 , wherein said wound is located in dermal or gastrointestinal tissue. 
     
     
         23 . A chimeric peptide comprising one or more antimicrobial peptides and one or more extracellular matrix binding domains, wherein said one or more antimicrobial peptides comprises LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES (SEQ ID NO: 3) and said extracellular matrix binding domain is linked to the C-terminal end of SEQ ID NO: 3. 
     
     
         24 . The chimeric peptide according to  claim 23 , wherein said one or more extracellular matrix binding domains is selected from the group consisting of collagen binding domain, fibronectin binding domain, laminin binding domain, elastin binding domain, hyaluronan binding domain, fibrin binding domain, gelatin binding domain, alginate binding domain, glycosaminoglycan binding domain and combinations thereof. 
     
     
         25 . The chimeric peptide according to  claim 23 , wherein said one or more extracellular matrix binding domains is selected from the group consisting of TKKTLRT (SEQ ID NO: 5), CQDSETGTFY (SEQ ID NO: 6) and combinations thereof. 
     
     
         26 . The chimeric peptide according to  claim 23 , wherein said one or more chimeric peptides further comprises an intervening peptide domain between said antimicrobial peptide and said extracellular matrix binding domain. 
     
     
         27 . The chimeric peptide according to  claim 26 , wherein said intervening peptide domain comprises five aspartic acid residues, two lysine residues and a tyrosine residue.