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

SYSNO ASEP	0431499
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery
Author(s)	Tykvart, Jan (UOCHB-X)_{RID, ORCID} Schimer, Jiří (UOCHB-X)_{RID, ORCID} Bařinková, Jitka (UOCHB-X) Pachl, Petr (UOCHB-X)_{RID, ORCID} Poštová Slavětínská, Lenka (UOCHB-X)_RID Majer, Pavel (UOCHB-X) Konvalinka, Jan (UOCHB-X)_{RID, ORCID} Šácha, Pavel (UOCHB-X)_{RID, ORCID}
Number of authors	8
Source Title	Bioorganic & Medicinal Chemistry. - : Elsevier - ISSN 0968-0896 Roč. 22, č. 15 (2014), s. 4099-4108
Number of pages	10 s.
Language	eng - English
Country	GB - United Kingdom
Keywords	GCPII ; PSMA ; structure-aided drug design ; specific drug targeting
Subject RIV	CE - Biochemistry
R&D Projects	GBP208/12/G016 GA ČR - Czech Science Foundation (CSF)
Institutional support	UOCHB-X - RVO:61388963
UT WOS	000339859700034
EID SCOPUS	84905081813
DOI	10.1016/j.bmc.2014.05.061
Annotation	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.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Year of Publishing	2015

Number of the records: 1