Papain family cysteine proteases are involved in an array of biological functions and pathologies. Although several of these enzymes are attractive drug targets, it difficult to design specific inhibitors due to the highly conserved active site cleft. To remedy this situation, we have synthesized highly specific inhibitors by mimicking a natural protein-protein interaction between the protease and a two turn alpha-helix. Inhibition was only possible through the stabilization of the two-turn alpha-helical peptides which was accomplished via stabilization of the peptide by reacting a simple rigid alkyl bromide linker with cysteines placed in a i,i+4 or i,i+7 configuration. Next, using a structure-based approach, we rationally varied individual side chains to optimize both potency and specificity. Resulting inhibitors were found to be potent, and highly selective competitive inhibitors for individual cysteine proteases using several members of the papain superfamily as examples including calpain, cathepsin L, cathepsin K and cathepsin S.

Building specific inhibitors of cysteine proteases by mimicking a natural protein alpha-helix interaction

244th National Meeting (2012)

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