Peptidyl epoxides extended in the P' direction as cysteine protease inhibitors: effect on affinity and mechanism of inhibition |
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Authors: | Perlman Nurit Hazan Maya Shokhen Michael Albeck Amnon |
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Institution: | The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel. |
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Abstract: | Endo peptidyl epoxides, in which the central epoxidic moiety replaces the scissile amide bond of a P(3)-P(3)' peptide, were designed as cysteine proteases inhibitors. The additional P'-S' interactions, relative to those of an exo peptidyl epoxide of the same P(3)-P(1) 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. |
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