Peptide-polymer conjugates

Abstract

This invention relates to a conjugate of a polymer moiety and an erythropoietin moiety.

1 . A peptide-polymer conjugate of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein
 each of R 1 , R 2 , R 3 , R 4 , and R 5 , independently, is H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteraryl, C 3-8  cycloalkyl, or C 3-8  heterocycloalkyl; 
 each of A 1  and A 2 , independently, is a polymer moiety; 
 each of G 1 , G 2 , and G 3 , independently, is a bond or a linking functional group; 
 P is an erythropoietin moiety, the nitrogen atom of the N-terminus of P being bonded to G 3 ; 
 m is 0 or an integer of 1-10; and 
 n is an integer of 1-10. 
 
     
     
         2 . The conjugate of  claim 1 , wherein P is an erythropoietin moiety in which 1-4 additional amino acid residues are attached to the N-terminus of a native erythropoietin. 
     
     
         3 . The conjugate of  claim 1 , wherein each of A 1  and A 2  is a polyethylene glycol moiety having a molecular weight of 2-100 kD. 
     
     
         4 . The conjugate of  claim 3 , wherein each of A 1  and A 2  is a polyethylene glycol moiety having a molecular weight of 10-30 kD. 
     
     
         5 . The conjugate of  claim 4 , wherein each of G 1  and G 2  is 
       
         
           
           
               
               
           
         
       
       in which the O is bonded to A 1  or A 2 , and the N atom is bonded to a carbon atom; and G 3  is a bond. 
     
     
         6 . The conjugate of  claim 5 , wherein m is 4, n is 2, and each of R 1 , R 2 , R 3 , R 4 , and R 5  is H. 
     
     
         7 . The conjugate of  claim 1 , wherein the conjugate is 
       
         
           
           
               
               
           
         
       
       in which mPEG is a methoxy-capped polyethylene glycol moiety having a molecular weight of 20 kD. 
     
     
         8 . A peptide-polymer conjugate of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein
 each of R 1 , R 2 , R 3 , and R 4 , independently, is H, C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, aryl, heteraryl, C 3-8  cycloalkyl, or C 3-8  heterocycloalkyl; 
 n is an integer of 2-10; 
 A is a polymer moiety; 
 G is a linking functional group; and 
 P is an erythropoietin moiety, the nitrogen atom of the N-terminus of the peptide moiety being bonded to the carbon atom in the 
 
       
         
           
           
               
               
           
         
       
       moiety shown in the formula above. 
     
     
         9 . The conjugate of  claim 8 , wherein G is 
       
         
           
           
               
               
           
         
       
       in which the O atom is bonded to A and the N atom is bonded to a carbon atom. 
     
     
         10 . The conjugate of  claim 9 , wherein A is a polyethylene glycol moiety having a molecular weight of 10-40 kD. 
     
     
         11 . The conjugate of  claim 10 , wherein A is a polyethylene glycol moiety having a molecular weight of 20-30 kD. 
     
     
         12 . The conjugate of  claim 8 , wherein n is 1.