Vemurafenib Inhibits Acute and Chronic Enterovirus Infection by Affecting Cellular Kinase Phosphatidylinositol 4-Kinase Type IIIβ
Laajala, M., Zwaagstra, M., Martikainen, M., Nekoua, M. P., Benkahla, M., Sane, F., Gervais, E., Campagnola, G., Honkimaa, A., Sioofy-Khojine, A.-B., Hyöty, H., Ojha, R., Bailliot, M., Balistreri, G., Peersen, O., Hober, D., Van Kuppeveld, F., & Marjomäki, V. (2023). Vemurafenib Inhibits Acute and Chronic Enterovirus Infection by Affecting Cellular Kinase Phosphatidylinositol 4-Kinase Type IIIβ. Microbiology Spectrum, 11(4), Article e00552-23. https://doi.org/10.1128/spectrum.00552-23
Published inMicrobiology Spectrum
© 2023 Laajala et al.
Enteroviruses are one of the most abundant viruses causing mild to serious acute infections in humans and also contributing to chronic diseases like type 1 diabetes. Presently, there are no approved antiviral drugs against enteroviruses. Here, we studied the potency of vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAFV600E mutant-related melanoma, as an antiviral against enteroviruses. We showed that vemurafenib prevented enterovirus translation and replication at low micromolar dosage in an RAF/MEK/ERK-independent manner. Vemurafenib was effective against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect was related to a cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevented infection efficiently in acute cell models, eradicated infection in a chronic cell model, and lowered virus amounts in pancreas and heart in an acute mouse model. Altogether, instead of acting through the RAF/MEK/ERK pathway, vemurafenib affects the cellular PI4KB and, hence, enterovirus replication, opening new possibilities to evaluate further the potential of vemurafenib as a repurposed drug in clinical care. ...
PublisherAmerican Society for Microbiology
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Additional information about fundingThis work was supported by FiDiPro and the Jane & Aatos and Erkko Foundation (M.L.and V.M.). Parts of this project were supported by the University of Helsinki Doctoral Program in Microbiology and Biotechnology (R.O.) and the Academy of Finland Research Grant 318434 (G.B. and R.O.) and NIH grant R01 AI059130 (O.P.). High-throughput imaging was performed at the Light Microscopy Unit of the University of Helsinki. ...
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