Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine

A potent hepatitis C virus protease protein inhibitor forms an irreversible covalent bond to a virally conserved noncatalytic cysteine in the protease substrate-binding pocket identified in a bioinformatic analysis. Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.