PEPTIDE GLYOXALS - A NOVEL CLASS OF INHIBITOR FOR SERINE AND CYSTEINEPROTEINASES

A series of novel synthetic dipeptides, containing a C-terminal glyoxa l grouping (-COCHO), have been tested as inhibitors against typical me mbers of the serine- and cysteine-proteinase families. For example, th e sequences benzyloxycarbonyl (Cbz)-Pro-Phe-CHO (I) and Cbz-Phe-Ala-CH O (II), which fulfil the known primary and secondary specificity requi rements of chymotrypsin and cathepsin B respectively, have been found to be potent reversible inhibitors of their respective target proteina se. Thus I was found to inhibit chymotrypsin with a K(i) of approximat ely 0.8 muM, whereas II exhibits a K(i) of approximately 80 nm against cathepsin B. These K(i) values are some 10-fold and 3-fold lower than those reported for the corresponding peptide-aldehyde inhibitors of c hymotrypsin and cathepsin B upon which the peptidyl-glyoxals were fash ioned. 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 muM.