Use of angiotensin II fragments and analogs thereof in tissue repair

Abstract

Peptides consisting essentially of Angiotensin II fragments and analogs thereof are useful in accelerating wound healing. These compounds form the basis of compositions useful for accelerating wound healing, in which the active agent is present in an amount effective to accelerate wound healing. Preferably, the compositions are in the form of matrical of micellar solutions. The peptides may include amino-terminal and/or carboxy-terminal domains, and/or may be PEGylated to resist peptidase attack yet retain their usefulness for accelerating wound healing.

1 . A method of accelerating wound healing, comprising applying to a wound an effective amount to accelerate wound healing of at least one peptide other than Angiotensin II, said peptide consisting essentially of at least three contiguous amino acids and having a sequence corresponding to a subsequence of groups R 1 —R 8  in general formula I:  
         R 1 —R 2 —R 3 —R 4 —R 5 —R 6 —R 7 —R 8  (SEQ ID NO:15), wherein  R 1  is selected from the group consisting of Asp, Glu, Asn, Acpc, Ala, Me 2 Gly, Pro, Bet, Glu(NH 2 ), Gly, Asp(NH 2 ) and Suc;    R 2  is selected from the group consisting of Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;    R 3  is selected from the group consisting of Val, Ala, Leu, Ile, Gly, Pro, Aib, Acpc and Tyr;    R 4  is selected from the group consisting of Tyr, Thr, Ser and azaTyr;    R 5  is selected from the group consisting of Ile, Ala, Leu, Val and Gly;    R 6  is His or Arg;    R 7  is Pro or Ala; and    R 8  is selected from the group consisting of Phe, Phe(Br), Ile and Tyr, excluding sequences wherein R 4  is an amino terminal Tyr group of the peptide.    
     
     
         2 . A method according to  claim 1 , wherein the peptide is administered in matrical or micellar solution.  
     
     
         3 . A method according to  claim 1 , wherein the peptide is administered in an amount of at least 0.1 ng per kg body weight in a suitable carrier or diluent.  
     
     
         4 . A method according to  claim 3 , wherein the carrier or diluent is selected from the group consisting of carboxymethyl cellulose preparations, crystalloid preparations, viscoelastics, polyethylene glycols and polypropylene glycols.  
     
     
         5 . A method according to  claim 1 , wherein the peptide is administered in conjunction with a wound dressing.  
     
     
         6 . A method according to  claim 1 , wherein the peptide has a sequence consisting essentially of R 1 —R 2 —R 3  in general formula I.  
     
     
         7 . A method according to  claim 6 , wherein the peptide has a sequence consistently essentially  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Asp-Arg-Val. 
                   (SEQ ID NO: 11) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         8 . A method according to  claim 1 , wherein the peptide has a sequence consisting essentially of R 1 —R 2 —R 3 —R 4  in general formula I.  
     
     
         9 . A method according to  claim 8 , wherein the peptide has a sequence consistently essentially of  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Asp-Arg-Val-Tyr. 
                   (SEQ ID NO: 10) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         10 . A method according to  claim 1 , wherein the peptide has a sequence consisting essentially of R 1 —R 2 —R 3 —R 4 —R 5  in general formula I.  
     
     
         11 . A method according to  claim 10 , wherein the peptide has a sequence consistently essentially of  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Asp-Arg-Val-Tyr-Ile. 
                   (SEQ ID NO: 9) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         12 . A method according to  claim 1 , wherein the peptide has a sequence consisting essentially of R 1 —R 2 —R 3 —R 4 —R 5 —R 6  in general formula I.  
     
     
         13 . A method according to  claim 12 , wherein the peptide has a sequence consistently essentially of  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Asp-Arg-Val-Tyr-Ile-His. 
                   (SEQ ID NO: 8) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         14 . A method according to  claim 1 , wherein the peptide has a sequence consisting essentially of R 3 —R 4 —R 5 —R 6 —R 7  in general formula I.  
     
     
         15 . A method according to  claim 14 , wherein the peptide has a sequence consistently essentially of  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Val-Tyr-Ile-His-Pro. 
                   (SEQ ID NO: 6) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         16 . A method according to  claim 1 , wherein the peptide has a sequence consisting essentially of R 2 —R 3 —R 4 —R 5 —R 6 —R 7  in general formula I.  
     
     
         17 . A method according to  claim 16 , wherein the peptide has a sequence consistently essentially of  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Arg-Val-Tyr-Ile-His-Pro. 
                   (SEQ ID NO: 5) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         18 . A method according to  claim 1 , wherein the peptide has a sequence consisting essentially of R 3 —R 4 —R 5 —R 6 —R 7 —R 8  in general formula I.  
     
     
         19 . A method according to  claim 18 , wherein the peptide has a sequence consistently essentially of  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Val-Tyr-Ile-His-Pro-Phe. 
                   (SEQ ID NO: 3) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         20 . A method according to  claim 1 , wherein the peptide has a sequence consisting essentially of R 5 —R 6 —R 7 —R 8  in general formula I.  
     
     
         21 . A method according to  claim 20 , wherein the peptide has a sequence consistently essentially of  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Ile-His-Pro-Phe. 
                   (SEQ ID NO: 7) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         22 . A method according to  claim 1 , wherein the peptide comprises poly-Gly.  
     
     
         23 . A method according to  claim 22 , wherein the peptide has a sequence selected from  
       
         
           
                 
                 
                 
               
                     
                 
                   Asp-Arg-Val-Gly-Gly-Gly-Gly and 
                   (SEQ ID NO: 16) 
                     
                 
                     
                 
                   Gly-Gly-Gly-Asp-Arg-Val. 
                   (SEQ ID NO: 17) 
                 
                     
                 
             
                
                
                
                
                
               
            
           
         
       
     
     
         24 . A method according to  claim 1 , wherein the peptide comprises poly-Lys.  
     
     
         25 . A method according to  claim 24 , wherein the peptide has a sequence selected from  
       
         
           
                 
                 
                 
               
                     
                 
                   Arg-Val-Tyr-Ile-His-Pro-Lys-Lys- 
                   (SEQ ID NO: 18) 
                     
                 
                     
                 
                   Lys and 
                 
                     
                 
                   Lys-Lys-Lys-Lys-Lys-Arg-Val-Tyr- 
                   (SEQ ID NO: 19) 
                 
                     
                 
                   Ile-His-Pro 
                 
                     
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         26 . A method according to  claim 1 , wherein the peptide comprises a D-amino acid.  
     
     
         27 . A method according to  claim 26 , wherein the peptide has a sequence selected from  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   D-Ala-Ile-His-Pro-Phe; and 
                   (SEQ ID NO: 20) 
                     
                 
                     
                     
                 
                     
                   Ile-His-Pro-Phe-D-Ala 
                   (SEQ ID NO: 21) 
                 
                     
                     
                 
             
                
                
                
                
                
               
            
           
         
       
     
     
         28 . A method according to  claim 1 , wherein the peptide is PEGylated.  
     
     
         29 . A method according to  claim 28 , wherein the PEGylated peptide is selected from the peptides of SEQ ID NOS. 3, 5, 6, 7, 8, 9, 10, and 11.