N-Haloacetyl-amino-acid amides as active-site-directed inhibitors of papain and cathepsin B

Abstract

A series of N-haloacetyl-amino-acid amides were synthesized and tested as models of cysteine-protease inhibitors. They irreversibly inactivated papain and cathepsin B via a reversible enzyme-inhibitor intermediate. Apparent second-order rate constants of inactivation ranging from 65 to 16 700 M −1 s −1 were observed. Reactivity against papain, as compared to glutathione, was increased 16 400-fold for N-bromoacetyl-leucine isopentylamide and 25 700-fold for the corresponding iodoacetyl derivative; these increases are probably due to proximity effects. No inhibition of trypsin, chymotrypsin and porcine pancreatic elastase was observed. Haloacetamides represent an interesting class of easily synthesized, efficient, irreversible inhibitors of cysteine proteases, which have low non-specific alkylating properties.