Structure-based design of irreversible, tripeptidyl human rhinovirus 3C protease inhibitors containing N-methyl amino acids

Tripeptide-derived molecules incorporating N-methyl amino acid residues and C-terminal Michael acceptor moieties were evaluated as irreversible inhibitors of the cysteine-containing human rhinovirus 3C protease (3CP). Such compounds displayed good 3CP inhibition activity ( k obs [I] up to 610,000 M −1s −1) and potent in vitro antiviral properties (EC 50 approaching 0.03 μM) when tested against HRV serotype-14. Graphic