N-Peptidyl-O-carbamoyl amino acid hydroxamates: Irreversible inhibitors for the study of the S2′ specificity of cysteine proteinases

AbstractA series of new inhibitors for cysteine proteinases with the general structure Z-Phe-Gly-NHO-CO-Aa (Aa = amino acids) was synthesized and tested as inhibitors of papain-like enzymes (cathepsins S, L, B and papain). Like N-peptidyl-O-acyl hydroxamates the inhibitors inactivate cysteine proteinases by a sulfenamidation of the active site cysteine residue. The most effective inhibitors display second order-rate constants of inactivation in the range of 103–104 M−1·s−1. Since the structure of the N-peptidyl-O-carbamoyl amino acid hydroxamates allows the variation of the leaving group this class of inhibitors was used as a new tool for the evaluation of the S2′ specificity of cysteine proteinases