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

Article abstract of DOI:10.1016/j.bmc.2008.08.031

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.