48] N,O-Diacyl hydroxamates as selective and irreversible inhibitors of cysteine proteinases

Abstract

Publisher Summary This chapter examines N, O -diacyl hydroxamates as selective and irreversible inhibitors of cysteine proteinases. Cysteine proteases represent attractive targets for the design of inhibitors as the proteinases play a role in degenerative diseases and in malignant tumor and parasite development. Inhibitors of cysteine proteases consist of a peptide part binding to the S specificity subsites of the target proteinase and a reactive group interacting with a catalytic active site residue. N, O -diacyl hydroxamates is a novel class of peptide-derived inhibitors, which permits variations of the N -acyl and O -acyl residues and, thus, a selective control of their affinity and reactivity toward the enzymes. N, O -diacyl hydroxamates are easily accessible synthetically. N, O -diacyl hydroxamates are stable under acidic conditions however less stable toward strong alkali. N, O -Diacyl hydroxamates react irreversibly with their target cysteine proteinase. No recovery of activity of the enzyme is achieved after the removal of the excess inhibitor. The irreversibility of inactivation can be confirmed by gel-filtration or dilution experiments.