Metallocarboxypeptidases: Emerging drug targets in biomedicine

Joan L. Arolas, Josep Vendrell, Francesc X. Aviles, Lloyd D. Fricker

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Metallocarboxypeptidases (MCPs) are commonly regarded as exopeptidases that actively participate in the digestion of proteins and peptides. In the recent years, however, novel MCPs comprising a wide range of physiological roles have been found in different mammalian extra-pancreatic tissues and fluids. Among them, CPU, also known as thrombin-activatable fibrinolysis inhibitor (TAFI), has been shown to cleave C-terminal Lys residues from partially degraded fibrin, acting as inhibitor of clot fibrinolysis and therefore constituting an important drug target for thrombolytic therapies. Other MCPs such as CPE, CPN, CPM, and CPD function as pro-hormone and neuropeptide processors and display several structural differences with the pancreatic-like enzymes. In addition, important advances have been made in the discovery and characterization of new endogenous and exogenous proteinaceous inhibitors; the structural determination of their complexes with several MCPs has revealed novel binding modes. Finally, the use of MCPs in antibody-directed enzyme pro-drug therapy (ADEPT) has proved to be an efficient approach for the delivery of lethal levels of chemotherapeutic drugs specifically at tumor tissues. Taken together, these recent developments may help to understand potential biomedical implications of MCPs. Future perspectives for the regulation of these enzymes through the use of more selective and potent inhibitors are also discussed in this review and combined with earlier observations in the field.

Original languageEnglish (US)
Pages (from-to)347-364
Number of pages18
JournalCurrent Pharmaceutical Design
Volume13
Issue number3
DOIs
StatePublished - Jan 2007

Fingerprint

Enzymes
Carboxypeptidase B2
Exopeptidases
Pharmaceutical Preparations
Thrombolytic Therapy
Prodrugs
Fibrinolysis
Neuropeptides
Fibrin
Proteolysis
Hormones
Drug Therapy
Peptides
Antibodies
Neoplasms

Keywords

  • ADEPT and GDEPT
  • Inhibitor-enzyme complex
  • Metallocarboxypeptidase
  • Metallocarboxypeptidase inhibitor
  • Neuropeptide processing
  • Pro-fibrinolytic drug
  • TAFI

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Metallocarboxypeptidases : Emerging drug targets in biomedicine. / Arolas, Joan L.; Vendrell, Josep; Aviles, Francesc X.; Fricker, Lloyd D.

In: Current Pharmaceutical Design, Vol. 13, No. 3, 01.2007, p. 347-364.

Research output: Contribution to journalArticle

Arolas, Joan L. ; Vendrell, Josep ; Aviles, Francesc X. ; Fricker, Lloyd D. / Metallocarboxypeptidases : Emerging drug targets in biomedicine. In: Current Pharmaceutical Design. 2007 ; Vol. 13, No. 3. pp. 347-364.
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