Počet záznamů: 1  

Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery

  1. 1. 0431499 - UOCHB-X 2015 RIV GB eng J - Článek v odborném periodiku
    Tykvart, Jan - Schimer, Jiří - Bařinková, Jitka - Pachl, Petr - Poštová Slavětínská, Lenka - Majer, Pavel - Konvalinka, Jan - Šácha, Pavel
    Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery.
    Bioorganic & Medicinal Chemistry. Roč. 22, č. 15 (2014), s. 4099-4108 ISSN 0968-0896
    Grant CEP: GA ČR GBP208/12/G016
    Grant ostatní:OPPK(CZ) CZ.2.16/3.1.00/24016
    Institucionální podpora: RVO:61388963
    Klíčová slova: GCPII * PSMA * structure-aided drug design * specific drug targeting
    Kód oboru RIV: CE - Biochemie
    Impakt faktor: 2.793, rok: 2014

    Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA), is an established prostate cancer marker and is considered a promising target for specific anticancer drug delivery. Low-molecular-weight inhibitors of GCPII are advantageous specific ligands for this purpose. However, they must be modified with a linker to enable connection of the ligand with an imaging molecule, anticancer drug, and/or nanocarrier. Here, we describe a structure-activity relationship (SAR) study of GCPII inhibitors with linkers suitable for imaging and drug delivery. Structure-assisted inhibitor design and targeting of a specific GCPII exosite resulted in a 7-fold improvement in K-i value compared to the parent structure. X-ray structural analysis of the inhibitor series led to the identification of several inhibitor binding modes. We also optimized the length of the inhibitor linker for effective attachment to a biotin-binding molecule and showed that the optimized inhibitor could be used to target nanoparticles to cells expressing GCPII.
    Trvalý link: http://hdl.handle.net/11104/0236131