Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: Synthesis and structural characterization

Sihyun Youn, Kyung Im Kim, Jakub Ptacek, Kiwon Ok, Zora Novakova, YunHye Kim, JaeHyung Koo, Cyril Barinka, Youngjoo Byun

Research output: Contribution to journalArticle

Abstract

Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can decrease glutamate concentration and play a protective role against apoptosis or degradation of brain neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing inhibitor at 1.79 Å resolution. The X-ray analysis revealed that the bulky closo-carborane cluster is located in the spacious entrance funnel region of GCPII, indicating that the carborane cluster can be further structurally modified to identify promising lead structures of novel GCPII inhibitors.

Original languageEnglish (US)
Pages (from-to)5232-5236
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number22
DOIs
StatePublished - Nov 15 2015
Externally publishedYes

Keywords

  • Carborane
  • Glutamate carboxypeptidase II
  • X-ray crystal structure

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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