Metallocarboxypeptidases and their Inhibitors: Recent Developments in Biomedically Relevant Protein and Organic Ligands

Metallocarboxypeptidases (MCPs) are zinc-dependent exoproteases that have been for long considered benchmark enzymes, perform a wide range of physiological roles and have been regarded as interesting drug targets. Several crystal structures of MCPs in complex with protein and small molecular weight inhibitors have recently been obtained providing a framework for understanding the binding properties of these ligands. Much of the latest research focused on carboxypeptidase U or thrombin-activable fibrinolysis inhibitor (CPU/TAFI) which has fueled new designs in the field of cardiovascular drugs. Further, new details on the catalytic mechanism of MCPs have emerged from recent crystal structures of covalently modified forms and the pace of investigations on inhibitors has been steadily fastening in the last years. This paper will focus on the latest research carried on metallocarboxypeptidase small molecular weight inhibitors as drug candidates and will give an update of protein inhibitors to emphasize the growing interest for products isolated from natural sources.