Compositions and methods for the treatment of cast nephropathy and related conditions

Abstract

Provided are novel peptides of Formula SEQ ID No. 1: (SEQ ID No. 1) J 1 CysX 1 X 2 X 3 X 4 X 5 X 6 ProX 7 ThrCysJ 2 J 3 (J 4 ) s (J 5 ) t ; pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are which are effective inhibitors of light chains to uromodulin.

1 . A peptide of the Formula SEQ ID No. 1: 
       
         
           
                 
                 
               
                     
                   (SEQ ID No. 1) 
                 
                     
                   J 1 CysX 1 X 2 X 3 X 4 X 5 X 6 ProX 7 ThrCysJ 2 J 3 (J 4 ) s (J 5 ) t ; 
                 
             
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 J 1  is Aha or Arg; 
 X 1  to X 7  are each independently a natural or non-natural amino acid; 
 s, and t are each independently 0 or 1; 
 J 2  and J 3  are each independently Lys or Arg; 
 J 4 , if present is Lys or Arg; and 
 J 5 , if present is Lys or Arg. 
 
     
     
         2 . The peptide of  claim 1 , wherein X 1  is selected from Arg, Lys, His, Pro, Cys, Thr, Ser, Gln, Glu, Leu, Ile, Met, Ala, Val, Gly, n-Leu, Met, Asp, and Ile. 
     
     
         3 . The peptide of  claim 1 , wherein X 1  is selected from Arg, Gln, Glu, Leu, n-Leu, Met, Asp, and Ile. 
     
     
         4 . The peptide of  claim 1 , wherein X 1  is selected from Gln, Leu, and n-Leu. 
     
     
         5 . The peptide of  claim 1 , wherein X 2  is selected from a natural amino acid. 
     
     
         6 . The peptide of  claim 1 , wherein X 2  is selected from Ser, Thr, Cys, Met, Asn, Lys, Gln, His, Arg, Glu, and Asp. 
     
     
         7 . The peptide of  claim 1 , wherein X 2  is selected from Ser, Gln, His, Arg, Glu, and Asp. 
     
     
         8 . The peptide of  claim 1 , wherein X 2  is selected from Gln and His. 
     
     
         9 . The peptide of  claim 1 , wherein X 3  is selected from a natural amino acid. 
     
     
         10 . The peptide of  claim 1 , wherein X 3  is selected from Tyr, Trp, Phe, Ser, Thr, Cys, Met, Asn, Ala, Lys, His, Glu, Arg, and Asp. 
     
     
         11 . The peptide of  claim 1 , wherein X 3  is selected from Tyr, Ser, Ala, Glu, Arg, and Asp. 
     
     
         12 . The peptide of  claim 1 , wherein X 3  is selected from Tyr, Ser, Arg, and Asp. 
     
     
         13 . The peptide of  claim 1 , wherein X 4  is selected from a natural amino acid. 
     
     
         14 . The peptide of  claim 1 , wherein X 4  is selected from Gly, Ala, Val, Leu, Ile, Pro, Phe, Tyr, Trp, Asp, Glu, Lys, Arg, and His. 
     
     
         15 . The peptide of  claim 1 , wherein X 4  is selected from Leu, Asp, Gly, Tyr, Glu, and Arg. 
     
     
         16 . The peptide of  claim 1 , wherein X 4  is selected from Leu, Asp, Tyr, and Arg. 
     
     
         17 . The peptide of  claim 1 , wherein X 5  is selected from a natural amino acid. 
     
     
         18 . The peptide of  claim 1 , wherein X 5  is selected from Ser, Thr, Cys, Met, Asn, Gln, Asp, Glu, Lys, Arg, and His. 
     
     
         19 . The peptide of  claim 1 , wherein X 5  is selected from Tyr, Ser, Arg, Glu, and Asp. 
     
     
         20 . The peptide of  claim 1 , wherein X 6  is selected from Gly, Ala, Val, Leu, Ile, Pro, Phe, Tyr, Trp, Ser, Cys, Met, Gln, Lys, Arg, and His. 
     
     
         21 . The peptide of  claim 1 , wherein X 6  is selected from Ile, Leu, Pro, Val, Ala, Gly, His, Lys, and Arg. 
     
     
         22 . The peptide of  claim 1 , wherein X 6  is selected from Ile, Leu, and Arg. 
     
     
         23 . The peptide of  claim 1 , wherein X 6  is selected from Ile and Leu. 
     
     
         24 . The peptide of  claim 1 , wherein X 7  is selected from Gly, Ala, Val, Leu, Ile, Pro, Phe, Tyr, Trp, Ser, Thr, Cys, Met, Asn, Gln, Lys, Arg, and His. 
     
     
         25 . The peptide of  claim 1 , wherein X 7  is selected from Tyr, Phe, His, Lys, Arg, and Trp. 
     
     
         26 . The peptide of  claim 1 , wherein X 7  is selected from Tyr, Arg, and Trp. 
     
     
         27 . The peptide of  claim 1 , wherein X 7  is Tyr. 
     
     
         28 . The peptide of  claim 1 , wherein s and t are each 0. 
     
     
         29 . The peptide of  claim 1 , wherein s and t are each 1. 
     
     
         30 . The peptide of  claim 1 , where J 1  is Aha. 
     
     
         31 . The peptide of  claim 1 , wherein the peptide is selected from 
       
         
           
                 
                 
               
                     
                   AhaCQQSYSIPWTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYSIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQYDSLPLTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQYSYLPITCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQYSTAPWTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQYYSAPPTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQYKNYPWTCKK; 
                 
                     
                     
                 
                     
                   AhaCQHYDYLPITCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQSYSIPWTCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQSYSIPYTCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQ*SYSIPWTCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQS*YSIPWTCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQSY*SIPWTCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQ*SYSIPYTCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQS*YSIPYTCK*K*; 
                 
                     
                     
                 
                     
                   AhaCEQSYSIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQESYSIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQEYSIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSESIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYEIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYSEPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYSIEYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYSIPETCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYSIPYECKK; 
                 
                     
                     
                 
                     
                   AhaCRQSYSIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQRSYSIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQRYSIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSRSIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYRIPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYSRPYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYSIRYTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYSIPRTCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSYSIPYRCKK; 
                 
                     
                     
                 
                     
                   AhaCQQSY*SIPYTCK*K*K*K*; 
                 
                     
                     
                 
                     
                   AhaCQQYSYLPITCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQYSYLPITCR*R*; 
                 
                     
                     
                 
                     
                   AhaCQQSYLPITCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQYSLPITCK*K*; 
                 
                     
                     
                 
                     
                   AhaCQQYDLPITCK*K*; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   AhaCQQSYSIPYTCR*R*; 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         32 . A pharmaceutical composition comprising a peptide of  claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         33 . A method of treating cast neuropathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a peptide of  claim 1 , or a pharmaceutically acceptable salt thereof.