title: Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: Synthesis and structural characterization.
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 1.79Å 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.
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: Sihyun
authors.initials: S
authors.lastname: Youn
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: Kyung Im
authors.initials: KI
authors.lastname: Kim
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídeňská 1083, 14220 Prague 4, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Ptacek
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: Kiwon
authors.initials: K
authors.lastname: Ok
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídeňská 1083, 14220 Prague 4, Czech Republic.
authors.forename: Zora
authors.initials: Z
authors.lastname: Novakova
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: YunHye
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Brain Science, Daegu Gyeongbuk Institute of Science & Technology, 50-1 Sang-Ri, Hyeonpung-Myeon, Dalseong-Gun, Daegu 711-873, South Korea.
authors.forename: JaeHyung
authors.initials: J
authors.lastname: Koo
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídeňská 1083, 14220 Prague 4, Czech Republic. Electronic address: cyril.barinka@ibt.cas.cz.
authors.forename: Cyril
authors.initials: C
authors.lastname: Barinka
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea; Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul, South Korea. Electronic address: yjbyun1@korea.ac.kr.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
mesh_terms: D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D006801:Humans; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001896:Boron Compounds; D004791:Enzyme Inhibitors; D014508:Urea; D043425:Glutamate Carboxypeptidase II
keywords: Carborane; Glutamate carboxypeptidase II; X-ray crystal structure