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 syn thesized and tested as inactivators of lysosomal cysteine proteinases (cathepsins S, L, B and H) and trypsin-like serine proteinases (trypsi n, thrombin, plasmin, t-PA). N-peptidyl-O-acyl hydroxamates were shown to be selective inhibitors of cysteine proteinases. With the exceptio n of cathepsin H, the lysosomal cysteine proteinases were inactivated 2-5 orders of magnitude more rapidly than serine proteinases with a co mparable primary substrate specificity. The highest second-order rate constants of inactivation for the cysteine proteinases are in the rang e of 10(5)-10(6) M-1 s-1. The order of inhibitor specificity for the c ysteine proteinases is comparable to the enzyme's substrate specificit y.