Allosteric Regulation of Phosphatidylinositol 4-Kinase III Beta by an Antipicornavirus Compound MDL-860

Minetaro Arita; Georgi Dobrikov; Gerhard Pürstinger; Angel S Galabov

doi:10.1021/acsinfecdis.7b00053

Allosteric Regulation of Phosphatidylinositol 4-Kinase III Beta by an Antipicornavirus Compound MDL-860

ACS Infect Dis. 2017 Aug 11;3(8):585-594. doi: 10.1021/acsinfecdis.7b00053. Epub 2017 Jun 28.

Authors

Minetaro Arita¹, Georgi Dobrikov², Gerhard Pürstinger³, Angel S Galabov⁴

Affiliations

¹ Department of Virology II, National Institute of Infectious Diseases , 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan.
² Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences , Academician Georgi Bonchev Street, Bl. 9, 1113 Sofia, Bulgaria.
³ Institute of Pharmacy, University of Innsbruck , Innrain 80/82, A-6020 Innsbruck, Austria.
⁴ The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences , 26 Academician Georgi Bonchev Street, 1113 Sofia, Bulgaria.

PMID: 28605587
DOI: 10.1021/acsinfecdis.7b00053

Abstract

MDL-860 is a broad-spectrum antipicornavirus compound discovered in 1982 and one of the few promising candidates effective in in vivo virus infection. Despite the effectiveness, the target and the mechanism of action of MDL-860 remain unknown. Here, we have characterized antipoliovirus activity of MDL-860 and identified host phosphatidylinositol-4 kinase III beta (PI4KB) as the target. MDL-860 treatment caused covalent modification and irreversible inactivation of PI4KB. A cysteine residue at amino acid 646 of PI4KB, which locates at the bottom of a surface pocket apart from the active site, was identified as the target site of MDL-860. This work reveals the mechanism of action of this class of PI4KB inhibitors and offers insights into novel allosteric regulation of PI4KB activity.

Keywords: MDL-860; PI4KB; enterovirus; infection; picornavirus; virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Allosteric Site
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Cell Line, Tumor
Dose-Response Relationship, Drug
Gene Expression
HEK293 Cells
Host-Pathogen Interactions / drug effects*
Humans
Kinetics
Minor Histocompatibility Antigens / genetics
Minor Histocompatibility Antigens / metabolism
Models, Molecular
Muscle Cells / drug effects*
Muscle Cells / enzymology
Muscle Cells / virology
Nitriles / chemistry
Nitriles / pharmacology*
Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
Phosphotransferases (Alcohol Group Acceptor) / genetics
Phosphotransferases (Alcohol Group Acceptor) / metabolism
Picornaviridae / drug effects
Picornaviridae / physiology
Protein Binding
Virus Replication / drug effects

Substances

Antiviral Agents
Minor Histocompatibility Antigens
Nitriles
2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile
Phosphotransferases (Alcohol Group Acceptor)
phosphatidylinositol phosphate 4-kinase