Structure-based design of ketone-containing, tripeptidyl human rhinovirus 3C protease inhibitors

Tripeptide-derived molecules incorporating C-terminal ketone electrophiles were evaluated as reversible inhibitors of the cysteine-containing human rhinovirus 3C protease (3CP). An optimized example of such compounds displayed potent 3CP inhibition activity (Ki=0.0045 μM) and in vitro antiviral properties (EC50=0.34 μM) when tested against HRV serotype-14.