Novel N-peptidyl-O-acyl hydroxamates: selective inhibitors of cysteine proteinases

A series of N-peptidyl-O-acyl hydroxamates with a lysine in P₁ was synthesized and tested as inactivators of lysosomal cysteine proteinases (cathepsins S, L, B and H) and trypsin-like serine proteinases (trypsin, thrombin, plasmin t-PA). N-peptidyl-O-acyl hydroxamates were shown to be selective inhibitors of cysteine proteinases. With the exception of cathepsin H, the lysosomal cysteine proteinases were inactivated 2-5 orders of magnitude more rapidly than serine proteinases with a comparable primary substrate specificity. The highest second-order rate constants of inactivation for the cysteine proteinases are in the range of 10⁵-10⁶ M^-1 s^-1. The order of inhibitor specificity for the cysteine proteinases is comparable to the enzyme's substrate specificity.