title: Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery.
abstract: 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 Ki 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.
authors: Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic; Department of Biochemistry, Faculty of Natural Science, Charles University, Albertov 6, Prague 2, Czech Republic.
authors: Jan
authors: J
authors: Tykvart
authors: Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic; Department of Biochemistry, Faculty of Natural Science, Charles University, Albertov 6, Prague 2, Czech Republic.
authors: Jiří
authors: J
authors: Schimer
authors: Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic.
authors: Jitka
authors: J
authors: Bařinková
authors: Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic; Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeňská 1083, Prague 4, Czech Republic.
authors: Petr
authors: P
authors: Pachl
authors: Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic.
authors: Lenka
authors: L
authors: Poštová-Slavětínská
authors: Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic.
authors: Pavel
authors: P
authors: Majer
authors: Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic; Department of Biochemistry, Faculty of Natural Science, Charles University, Albertov 6, Prague 2, Czech Republic.
authors: Jan
authors: J
authors: Konvalinka
authors: Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo n. 2, Prague 6, 166 10 Czech Republic; Department of Biochemistry, Faculty of Natural Science, Charles University, Albertov 6, Prague 2, Czech Republic. Electronic address: pavelsacha@gmail.com.
authors: Pavel
authors: P
authors: Šácha
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D015195:Drug Design; D005786:Gene Expression Regulation / Q000187:drug effects; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D053758:Nanoparticles / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity
chemical_list: D004337:Drug Carriers; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D014508:Urea; D043425:Glutamate Carboxypeptidase II
keywords: GCPII; PSMA; Specific drug targeting; Structure-aided drug design