E-64 ANALOGS AS INHIBITORS OF CATHEPSIN-B - ON THE ROLE OF THE ABSOLUTE-CONFIGURATION OF THE EPOXYSUCCINYL GROUP

A series of trans-epoxysuccinyl-peptide derivatives based on the natur al inhibitor E-64 were synthesized in the (2R,3R) and (2S,3S) configur ation in order to analyze the role of the stereochemistry of this resi due in dictating inhibitory potency and selectivity for cysteine prote ases. We confirmed that binding of E-64 like trans-epoxysuccinyl compo unds is remarkably favored by the (2S,3S) con figuration, but we also found that CA030-type compounds are stronger inhibitors in the (2R,3R) configuration than the related diastereomers. Consequently, the struc tural requirements for exploiting both the S and S' subsites are not a dditive and a structure-based design of bis-peptidyl derivatives of tr ans-epoxysuccinic acid to increase selective inhibition becomes even m ore difficult. Additional contrasting effects were observed for the pH optima required in the electrostatic interactions at the S and S' sub sites. (C) 1997 Elsevier Science Ltd.