Peptide glyoxals: a novel class of inhibitor for serine and cysteine proteinases.
A series of novel synthetic dipeptides, containing a C-terminal glyoxal grouping (-COCHO), have been tested as inhibitors against typical members of the serine- and cysteine-proteinase families. For example, the sequences benzyloxycarbonyl (Cbz)-Pro-Phe-CHO (I) and Cbz-Phe-Ala-CHO (II), which fulfil the known primary and secondary specificity requirements of chymotrypsin and cathepsin B respectively, have been found to be potent reversible inhibitors of their respective target proteinase. Thus I was found to inhibit chymotrypsin with a Ki of approximately 0.8 microM, whereas II exhibits a Ki of approximately 80 nm against cathepsin B. These Ki values are some 10-fold and 3-fold lower than those reported for the corresponding peptide-aldehyde inhibitors of chymotrypsin and cathepsin B upon which the peptidyl-glyoxals were fashioned. Unexpectedly, the sequence Cbz-Pro-Ala-CHO, which was designed to inhibit elastase-like proteinases, exhibited no inhibitory activity towards porcine pancreatic elastase, even when used at concentrations as high as 200 microM.
Walker
B
B
Division of Biochemistry, School of Biology and Biochemistry, Queen's University of Belfast, U.K.
McCarthy
N
N
Healy
A
A
Ye
T
T
McKervey
M A
MA
D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002417:Cattle; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D006037:Glyoxal / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013552:Swine
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D015842:Serine Proteinase Inhibitors; D006037:Glyoxal; D002918:Chymotrypsin; D010196:Pancreatic Elastase; D002401:Cathepsin B