Design of highly potent urea-based, exosite-binding inhibitors selective for glutamate carboxypeptidase II.
We present here a structure-aided design of inhibitors targeting the active site as well as exosites of glutamate carboxypeptidase II (GCPII), a prostate cancer marker, preparing potent and selective inhibitors that are more than 1000-fold more active toward GCPII than its closest human homologue, glutamate carboxypeptidase III (GCPIII). Additionally, we demonstrate that the prepared inhibitor conjugate can be used for sensitive and selective imaging of GCPII in mammalian cells.
†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 Science, Charles University, Albertov 6, Prague 2, 128 43, Czech Republic.
Jan
J
Tykvart
†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 Science, Charles University, Albertov 6, Prague 2, 128 43, Czech Republic.
Jiří
J
Schimer
†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.
Andrej
A
Jančařík
†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.
Jitka
J
Bařinková
†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 Science, Charles University, Albertov 6, Prague 2, 128 43, Czech Republic.
Václav
V
Navrátil
†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.
Jana
J
Starková
†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.
Karolína
K
Šrámková
†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 Science, Charles University, Albertov 6, Prague 2, 128 43, Czech Republic.
Jan
J
Konvalinka
†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.
Pavel
P
Majer
†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 Science, Charles University, Albertov 6, Prague 2, 128 43, Czech Republic.
Pavel
P
Šácha
D001665:Binding Sites; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry*
D004791:Enzyme Inhibitors; D014508:Urea; D043425:Glutamate Carboxypeptidase II