Activation of peptide prodrugs by hK2

Abstract

The invention provides novel peptide prodrugs that contain cleavage sites specifically cleaved by human kallikrein 2 (hK2). These prodrugs are useful for substantially inhibiting the non-specific toxicity of a variety of therapeutic drugs. Upon cleavage of the prodrug by hK2, the therapeutic drugs are activated and exert their toxicity. Methods for treating cell proliferative disorders are also featured in the invention.

1 . A peptide comprising an amino acid sequence having a cleavage site specific for an enzyme having a proteolytic activity of human kallikrein 2 (hK2), wherein the peptide is 20 or fewer amino acids in length.  
     
     
         2 . The peptide of  claim 1 , wherein the sequence comprises: the amino acids 
 X 4 X 3 X 2 X 1 ,    wherein X 4  is from 0 to 20 amino acids; X 3  is lysine, serine, alanine, histadine or glutamine; X 2  is arginine, phenylalanine, lysine or histidine; and X 1  is arginine, histidine or lysine.    
     
     
         3 . The peptide of  claim 2 , further comprising X −1  linked to X 1 , wherein X −1  is from 1 to 10 amino acids.  
     
     
         4 . The peptide of  claim 2 , wherein X −1  is leucine, alanine or serine.  
     
     
         5 . The peptide of  claim 2 , further comprising amino acid X 5  linked to the amino terminus of X 4 , wherein X 5  is from 0 to 15 amino acids and wherein X 4  is glutamine, alanine, histidine or lysine.  
     
     
         6 . The peptide of  claim 5 , further comprising amino acid X 6  linked to the amino terminus of X 5 , wherein X 6  is from 0 to 14 amino acids and wherein X 5  is glycine, glutamic acid, or alanine.  
     
     
         7 . The peptide of  claim 3 , wherein X −1  comprises leucine.  
     
     
         8 . The peptide of  claim 6 , wherein the amino acid sequence is selected from the group consisting of Ala-Gln-Lys-Arg-Arg, Gly-Lys-Ser-Arg-Arg, Glu-Gln-Lys-Arg-Arg, Glu-Ala-Lys-Arg-Arg, Gly-Gln-Lys-Arg-Arg, Gly-Ala-Lys-Arg-Arg, Gly-Lys-Lys-Arg-Arg, Gly-His-Lys-Arg-Arg, Gly-Lys-Ala-Phe-Arg, Glu-Lys-Ala-Gln-Arg, and Glu-Lys-Ala-Arg-Arg.  
     
     
         9 . The peptide of  claim 1 , further comprising a capping group attached to the N-terminus of the peptide, the group inhibiting endopeptidase activity on the peptide.  
     
     
         10 . The peptide of  claim 9 , wherein the capping group is selected from the group consisting of acetyl, morpholinocarbonyl, benzyloxycarbonyl, glutaryl and succinyl substituents.  
     
     
         11 . A peptide of  claim 1 , further comprising an added substituent which renders the peptide water-soluble.  
     
     
         12 . A peptide of  claim 11 , wherein the added substituent is a polysaccharide.  
     
     
         13 . A peptide of  claim 12 , wherein the polysaccharide is selected from the group consisting of modified or unmodified dextran, cyclodextrin, and starch.  
     
     
         14 . A peptide of  claim 2 , further comprising an antibody attached to the 10 amino terminus of X 5 , or X 4  when X 5  is 0.  
     
     
         15 - 59 . (canceled)  
     
     
         60 . The peptide of  claim 1 , wherein X 1  and X 2  are arginine.  
     
     
         61 . The peptide of  claim 60 , wherein X 3  is lysine.  
     
     
         62 . The peptide of  claim 60 , wherein X 3  is serine.  
     
     
         63 . The peptide of  claim 1 , wherein the peptide comprises one or more D amino acid residues.  
     
     
         64 . The peptide of  claim 1 , wherein the peptide is a cyclic peptide.  
     
     
         65 . A peptide having a cleavage site specific for human kallikrein 2 (hK2) comprising the amino acid sequence Gly-Lys-Ala-Phe-Arg-Leu, wherein the peptide is 20 or fewer amino acids in length.