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Abstract
In what corresponds to a life span, metallocarboxypeptidases (MCPs) have jumped from
being mere contaminants in animal pancreas powders (in depression year 1929) to be
key players in cellular and molecular processes (in yet-another-depression years 2009-2010).
MCPs are unique zinc-dependent enzymes that catalyze the breakdown of the amide bond
at the C-terminus of peptide and protein substrates and participate in the recovery
of dietary amino acids, tissue organogenesis, neurohormone and cytokine maturation
and other important physiological processes. More than 26 genes code for MCPs in the
human genome, many of them still waiting to be fully understood in terms of physiological
function. A variety of MCPs have been linked to diseases in man: acute pancreatitis
and pancreas cancer, type 2 diabetes, Alzheimer's Disease, various types of cancer,
and fibrinolysis and inflammation. Many of these discoveries have been made possible
thanks to recent advances, as exemplified by plasma carboxypeptidases N and B, known
for fifty and twenty years, respectively, which have had their structures released
only very recently. Plasma carboxypeptidase B is a biological target for therapy because
of its involvement in the coagulation/fibrinolysis processes. Besides, the widespread
use of carboxypeptidase A as a benchmark metalloprotease since the early days of Biochemistry
has allowed the identification and design of an increasingly vast repertory of small
molecular weight inhibitors. With these two examples we wish to emphasize that MCPs
have become part of the drug discovery portfolio of pharmaceutical companies and academic
research laboratories. This paper will review key developments in the discovery and
design of MCP small molecular weight inhibitors, with an emphasis on the discovery
of chemically diverse entities. Although encouraging advances have been achieved in
the last few years, the specificity and oral bioavailability of the new chemotherapeutic
agents seem to pose a challenge to medicinal chemists.