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 10(5)-10(6) M-1 s-1. The order of inhibitor specificity for the cysteine proteinases is comparable to the enzyme's substrate specificity.
Institute of Biochemistry, Medical Faculty, Martin-Luther-University, Halle, Germany.
D
D
Brömme
U
U
Neumann
H
H
Kirschke
H U
HU
Demuth
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002403:Cathepsins / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis*; D004789:Enzyme Activation / Q000187:drug effects; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis*; D012697:Serine Endopeptidases / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D006877:Hydroxamic Acids; D010455:Peptides; D002403:Cathepsins; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases