Structure-activity relationships of glutamate carboxypeptidase II (GCPII) inhibitors

D. V. Ferraris, K. Shukla, Takashi Tsukamoto

Research output: Contribution to journalArticle

Abstract

Glutamate carboxypeptidase II (GCPII, EC 3.4.17.21) is a zinc metallopeptidase that hydrolyzes N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate in the nervous system. Inhibition of GCPII has the potential to reduce extracellular glutamate and represents an opportune target for treating neurological disorders in which excess glutamate is considered pathogenic. Furthermore, GCPII was found to be identical to a tumor marker, prostate-specific membrane antigen (PSMA), and has drawn significant interest as a diagnostic and/or therapeutic target in oncology. Over the past 15 years, tremendous efforts have been made in the discovery of potent GCPII inhibitors, particularly those with phosphorus-, urea- and thiol-based zinc binding groups. In addition, significant progress has been made in understanding the three-dimensional structural characteristics of GCPII in complex with various ligands. The purpose of this review article is to analyze the structure-activity relationships (SAR) of GCPII inhibitors reported to date, which are classified on the basis of their zinc-binding group. SAR and crystallographic data are evaluated in detail for each of these series to highlight the future challenges and opportunities to identify clinically viable GCPII inhibitors.

Original languageEnglish (US)
Pages (from-to)1282-1294
Number of pages13
JournalCurrent Medicinal Chemistry
Volume19
Issue number9
DOIs
StatePublished - Mar 2012

Fingerprint

Glutamate Carboxypeptidase II
Structure-Activity Relationship
Zinc
Glutamic Acid
Oncology
Neurology
Metalloproteases
Tumor Biomarkers
Nervous System Diseases
Sulfhydryl Compounds
Phosphorus
Nervous System
Urea
Ligands

Keywords

  • glutamate
  • Glutamate carboxypeptidase II (GCPII)
  • metallopeptidase inhibitors
  • N-acetylaspartylglutamate (NAAG)
  • prostate-specific membrane antigen (PSMA)

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Structure-activity relationships of glutamate carboxypeptidase II (GCPII) inhibitors. / Ferraris, D. V.; Shukla, K.; Tsukamoto, Takashi.

In: Current Medicinal Chemistry, Vol. 19, No. 9, 03.2012, p. 1282-1294.

Research output: Contribution to journalArticle

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