Design of potent and specific inhibitors of carboxypeptidases A and B

The combination in one molecule of functional groups that can interact specifically with different substrate binding areas at the active site of carboxypeptidases A and B has led to the development of potent and specific inhibitors of these enzymes. 2-Benzyl-3-mercaptopropanoic acid (SQ 14,603) has...

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Bibliographic Details
Published in:Biochemistry (Easton) 1979-04, Vol.18 (8), p.1427-1430
Main Authors: Ondetti, Miguel A, Condon, Michael E, Reid, Joyce, Sabo, Emily F, Cheung, Hong S, Cushman, David W
Format: Article
Language:English
Subjects:
3-Mercaptopropionic Acid - analogs & derivatives
3-Mercaptopropionic Acid - pharmacology
Binding Sites
Carboxypeptidases - antagonists & inhibitors
Guanidines - pharmacology
Kinetics
Methods
Protease Inhibitors - chemical synthesis
Structure-Activity Relationship
Sulfhydryl Compounds
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Summary:The combination in one molecule of functional groups that can interact specifically with different substrate binding areas at the active site of carboxypeptidases A and B has 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 x 10(-8) M vs. carboxypeptidase A and a Ki of 1.6 x 10(-4) M vs. the B enzyme. 2-Mercaptomethyl-5-guanidinopentanoic acid (SQ 24,798) has a Ki of 4 x 10(-10) M vs. carboxypeptidase B and a Ki of 1.2 x 10(-5) M vs. carboxypeptidase A. It is proposed that the sulfhydryl groups of these inhibitors bind to the catalytically important zinc ions of these enzymes, and that, in conjunction with the benzyl and guanidinopropyl side chains, they are responsible for their specificity.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi00575a006