Peptidyl epoxides extended in the P′ direction as cysteine protease inhibitors: Effect on affinity and mechanism of inhibition

Endo peptidyl epoxides, in which the central epoxidic moiety replaces the scissile amide bond of a P3–P3′ peptide, were designed as cysteine proteases inhibitors. The additional P′–S′ interactions, relative to those of an exo peptidyl epoxide of the same P3–P1 sequence, significantly improved affinity to the enzymes papain and cathepsin B, but also changed the mode of inhibition from active-site directed inactivation to reversible competitive inhibition. Computational models rationalize the binding affinity and the inhibition mechanism.

Extension of peptidyl epoxides in the C-terminal direction, to gain S′–P′ interactions with a target enzyme, increased affinity to cysteine proteases but changed the mechanism to reversible competitive inhibition.Figure optionsDownload as PowerPoint slide