Aziridinyl peptides as inhibitors of cysteine proteases: Effect of a free carboxylic acid function on inhibition

Peptides containing aziridine-2,3-dicarboxylate (Azi) as electrophilic buil ding block are evaluated as inhibitors of the cysteine proteases papain, ca thepsin B, cathepsin L and clostripain. The influence of a free carboxylic acid as functional group at different positions of the inhibitor molecule o n inhibition is analyzed. Structure-activity relationships and binding mode hypotheses are discussed. In contrast to the bacterial enzyme clostripain, the papain like mammalian proteases (cathepsins) are irreversibly inactiva ted by aziridinyl peptides. N-Unsubstituted aziridines are much more potent inhibitors of papain and cathepsins if they contain the free carboxylic ac id attached to the aziridine ring (HOAzi-Leu-ProOBzl). Two free carboxylic acid functions at the aziridine ring are necessary for good inhibition of t hese enzymes by N'-acylated aziridinyl peptides (BOC-Phe-Azi(OH)(2)). Chime ric bispeptidyl derivatives are selective CB inhibitors if the free acid is located at the C-terminus of the peptide (BOC-Phe-(EtO)Azi-Leu-ProOH). Clo stripain is only inhibited by aziridinyl peptide esters. (C) 2000 Elsevier Science Ltd. All rights reserved.