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 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.
Perlman
Nurit
N
The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel.
Hazan
Maya
M
Shokhen
Michael
M
Albeck
Amnon
A
D020134:Catalytic Domain; D002401:Cathepsin B / Q000737:chemistry / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology*; D010206:Papain / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D004852:Epoxy Compounds; D010455:Peptides; D002401:Cathepsin B; D010206:Papain