Inhibition of metalloendopeptidases by 2‐mercaptoacetyl‐dipeptides

Abstract

A series of 2-mercaptoacetyl-dipeptides, a potential group of metalloendopeptidase inhibitors, was synthesized by coupling the N-hydroxysuccinimide ester of S-acetyl-2-mercaptoacetic acid with hydrophobic dipeptide methyl ester hydrochlorides, followed by hydrolysis with NaOH in aqueous methanol and acidification with HCl. The 2-mercaptoacetyl derivatives of L-phenylalanyl-L-leucine, L-leucyl-L-phenylalanine and L-leucyl-D-phenylalanine were prepared. The first 2 compounds inhibit effectively thermolysin from Bacillus thermoproteolyticus and a metalloendopeptidase isolated from Streptomyces griseus, with Ki values in the micromolar range or below. The third compound inhibits the 2 enzymes only poorly, showing the stereospecificity of the inhibition process. These inhibitors should provide a useful tool for the study of bacterial and mammalian metalloendopeptidases (or dipeptidyl carboxypeptidases) and for the assessment of their physiological role.