title: Rational Design of Novel Highly Potent and Selective Phosphatidylinositol 4-Kinase IIIβ (PI4KB) Inhibitors as Broad-Spectrum Antiviral Agents and Tools for Chemical Biology.
abstract: Phosphatidylinositol 4-kinase IIIβ (PI4KB) is indispensable for the replication of various positive-sense single stranded RNA viruses, which hijack this cellular enzyme to remodel intracellular membranes of infected cells to set up the functional replication machinery. Therefore, the inhibition of this PI4K isoform leads to the arrest of viral replication. Here, we report on the synthesis of novel PI4KB inhibitors, which were rationally designed based on two distinct structural types of inhibitors that bind in the ATP binding side of PI4KB. These "hybrids" not only excel in outstanding inhibitory activity but also show high selectivity to PI4KB compared to other kinases. Thus, these compounds exert selective nanomolar or even subnanomolar activity against PI4KB as well as profound antiviral effect against hepatitis C virus, human rhinovirus, and coxsackievirus B3. Our crystallographic analysis unveiled the exact position of the side chains and explains their extensive contribution to the inhibitory activity.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.|Department of Chemistry of Natural Compounds, Institute of Chemical Technology Prague , Technická 5, Prague 166 28, Czech Republic.
authors.forename: Ivana
authors.initials: I
authors.lastname: Mejdrová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Dominika
authors.initials: D
authors.lastname: Chalupská
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Plačková
authors.affiliation: Institute of Medical Virology, Justus Liebig University Giessen , Schubertstrasse 81, D-35392 Giessen, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Müller
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Šála
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Klíma
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Adriana
authors.initials: A
authors.lastname: Baumlová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hřebabecký
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Eliška
authors.initials: E
authors.lastname: Procházková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Dejmek
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Strunin
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Weber
authors.affiliation: Department of Chemistry of Natural Compounds, Institute of Chemical Technology Prague , Technická 5, Prague 166 28, Czech Republic.
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Marika
authors.initials: M
authors.lastname: Matoušová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Helena
authors.initials: H
authors.lastname: Mertlíková-Kaiserová
authors.affiliation: Institute of Medical Virology, Justus Liebig University Giessen , Schubertstrasse 81, D-35392 Giessen, Germany.
authors.forename: John
authors.initials: J
authors.lastname: Ziebuhr
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkus
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Evzen
authors.identifier: 0000-0002-9652-4065
authors.initials: E
authors.lastname: Boura
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre , Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Radim
authors.identifier: 0000-0001-6167-0380
authors.initials: R
authors.lastname: Nencka
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors*; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D019870:1-Phosphatidylinositol 4-Kinase