Design of potent and specific inhibitors of carboxypeptidases A and B

Abstract

The combination in 1 molecule of functional groups that can interact specifically with different substrate binding areas at the active site of carboxypeptidases A and B led to the development of potent and specific inhibitors of these enzymes. 2-Benzyl-3-mercaptopropanoic acid (SQ 14,603) has a Ki of 1.1 .times. 10-8 M vs. carboxypeptidase A and a Ki of 1.6 .times. 10-4 M vs. the B enzyme. 2-Mercaptomethyl5-guanidinopentanoic acid (SQ 24,798) has a Ki 4 .times. 10-10 M vs. carboxypeptidase B and a Ki of of 1.2 .times. 10-5 M vs. carboxypeptidase A. The SH groups of these inhibitors apparently bind to the catalytically important Zn ions of these enzymes and, in conjunction with the benzyl and guanidinopropyl side chains, they are responsible for their specificity.