PI4KIII inhibitor enviroxime impedes the replication of the hepatitis C virus by inhibiting PI3 kinases

The Journal of Antimicrobial Chemotherapy
Leen DelangJohan Neyts

Abstract

Many positive-stranded RNA viruses, including HCV, drastically remodel intracellular membranes to generate specialized environments for RNA replication. Phosphatidylinositol 4-kinase III (PI4KIII)α plays an essential role in the formation of HCV replication complexes and has therefore been explored as a potential drug target. Here, we characterized the anti-HCV activity of the PI4KIII inhibitors enviroxime and BF738735 and elucidated their mechanism of action. Antiviral assays were performed using HCV subgenomic replicons and infectious HCV. Enviroxime- and BF738735-resistant HCV replicons were generated by long-term culture with increasing compound concentrations. Intracellular localization of phosphatidylinositol 4-phosphate (PI4P) lipids was analysed by confocal microscopy. HCV subgenomic replicons resistant to either enviroxime or BF738735 proved cross-resistant and carried mutations in the NS3, NS4B and NS5A genes. Knockdown of PI4KIIIβ by small interfering RNA (siRNA) did not affect the replication of the HCV subgenomic replicon in this study. Furthermore, the compounds did not affect PI4P lipid levels at the replication complexes nor the phosphorylation status of NS5A, activities attributed to PI4KIIIα. Interestingly, th...Continue Reading

References

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Jul 4, 2013·Methods in Molecular Biology·Inge VliegenJohan Neyts
Jul 31, 2013·Antimicrobial Agents and Chemotherapy·Hilde M van der SchaarFrank J M van Kuppeveld
Apr 14, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Katharina Esser-NobisVolker Lohmann
Aug 16, 2015·Gut·Stefanie StöhrSandra Ciesek

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Citations

Sep 4, 2020·Metabolites·David BalgomaOlimpio Montero
Feb 5, 2021·Journal of Medicinal Chemistry·Rinky Raghuvanshi, Sandip B Bharate

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