Highly Selective Phosphatidylinositol 4‑Kinase IIIβ Inhibitors and Structural Insight into Their Mode of Action

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 thi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2015-05, Vol.58 (9), p.3767-3793
Main Authors: Mejdrová, Ivana, Chalupská, Dominika, Kögler, Martin, Šála, Michal, Plačková, Pavla, Baumlová, Adriana, Hřebabecký, Hubert, Procházková, Eliška, Dejmek, Milan, Guillon, Rémi, Strunin, Dmytro, Weber, Jan, Lee, Gary, Birkus, Gabriel, Mertlíková-Kaiserová, Helena, Boura, Evzen, Nencka, Radim
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - chemistry
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Binding Sites
Crystallography, X-Ray
Ethylenediamines - chemical synthesis
Ethylenediamines - chemistry
Ethylenediamines - pharmacology
HeLa Cells
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Isoenzymes - antagonists & inhibitors
Isoenzymes - chemistry
Molecular Docking Simulation
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) - chemistry
Protein Conformation
Pyrazoles - chemical synthesis
Pyrazoles - chemistry
Pyrazoles - pharmacology
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
RNA Viruses - drug effects
Structure-Activity Relationship
Triazines - chemical synthesis
Triazines - chemistry
Triazines - pharmacology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00499