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.
|Original language||American English|
|Journal||Bioorganic & medicinal chemistry|
|State||Published - 2008|