title: Highly Selective Phosphatidylinositol 4-Kinase IIIβ Inhibitors and Structural Insight into Their Mode of Action.
abstract: Phosphatidylinositol 4-kinase IIIβ is a cellular lipid kinase pivotal to pathogenesis of various RNA viruses. These viruses hijack the enzyme in order to modify the structure of intracellular membranes and use them for the construction of functional replication machinery. Selective inhibitors of this enzyme are potential broad-spectrum antiviral agents, as inhibition of this enzyme results in the arrest of replication of PI4K IIIβ-dependent viruses. Herein, we report a detailed study of novel selective inhibitors of PI4K IIIβ, which exert antiviral activity against a panel of single-stranded positive-sense RNA viruses. Our crystallographic data show that the inhibitors occupy the binding site for the adenine ring of the ATP molecule and therefore prevent the phosphorylation reaction.
authors.forename: Ivana
authors.initials: I
authors.lastname: Mejdrová
authors.forename: Dominika
authors.initials: D
authors.lastname: Chalupská
authors.forename: Martin
authors.initials: M
authors.lastname: Kögler
authors.forename: Michal
authors.initials: M
authors.lastname: Šála
authors.forename: Pavla
authors.initials: P
authors.lastname: Plačková
authors.forename: Adriana
authors.initials: A
authors.lastname: Baumlová
authors.forename: Hubert
authors.initials: H
authors.lastname: Hřebabecký
authors.forename: Eliška
authors.initials: E
authors.lastname: Procházková
authors.forename: Milan
authors.initials: M
authors.lastname: Dejmek
authors.forename: Rémi
authors.initials: R
authors.lastname: Guillon
authors.forename: Dmytro
authors.initials: D
authors.lastname: Strunin
authors.forename: Jan
authors.initials: J
authors.lastname: Weber
authors.affiliation: ‡Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.affiliation: ‡Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkus
authors.forename: Helena
authors.initials: H
authors.lastname: Mertlíková-Kaiserová
authors.forename: Evzen
authors.initials: E
authors.lastname: Boura
authors.forename: Radim
authors.initials: R
authors.lastname: Nencka
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005029:Ethylenediamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D062105:Molecular Docking Simulation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012328:RNA Viruses / Q000187:drug effects; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000255:Adenosine Triphosphate; D000998:Antiviral Agents; D005029:Ethylenediamines; D007093:Imidazoles; D007527:Isoenzymes; D017853:Phosphotransferases (Alcohol Group Acceptor); D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D014227:Triazines; C581087:PI4KB protein, human