期刊
CELL REPORTS
卷 10, 期 4, 页码 600-615出版社
CELL PRESS
DOI: 10.1016/j.celrep.2014.12.054
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资金
- Convenant K.U. Leuven-Radboud University Nijmegen
- European Union FP7 Marie Curie Initial Training Network EUVIRNA [264286]
- FP7 Large Scale Collaborative Project SILVER'' [260644]
- KU Leuven geconcerteerde onderzoeksactie [GOA/10/014]
- Belgian Science Policy Office (BELSPO, Belvir consortium, IAP, phase VII)
- Fund for Scientific Research of Flanders (FWO)
- CNRS
- ANR [2010-1503-01]
- Sigrid Juselius Foundation
- Finnish Foundation for Cardiovascular Research
- Magnus Ehrnrooth Foundation
- Netherlands Organisation for Scientific Research (N.W.O.) [ECHO-700.57.001, ALW-820.02.018, VICI-91812628, VENI-722.012.066, VENI-863.12.005]
- Ministry of Health, Labor and Welfare, Japan
- World Health Organization for a collaborative research project of the Global Polio Eradication Initiative
- JSPS KAKENHI [25460579]
- NIH
- Grants-in-Aid for Scientific Research [25460579] Funding Source: KAKEN
- Novo Nordisk Fonden [NNF11OC1014724] Funding Source: researchfish
- Fondazione Telethon Funding Source: Custom
Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, we identify ITZ as a broad-spectrum inhibitor of enteroviruses (e.g., poliovirus, coxsackievirus, enterovirus-71, rhinovirus). We demonstrate that ITZ inhibits viral RNA replication by targeting oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4). Consistently, OSW-1, a specific OSBP/ORP4 antagonist, also inhibits enterovirus replication. Knockdown of OSBP inhibits virus replication, whereas overexpression of OSBP or ORP4 counteracts the antiviral effects of ITZ and OSW-1. ITZ binds OSBP and inhibits its function, i.e., shuttling of cholesterol and phosphatidylinositol-4-phosphate between membranes, thereby likely perturbing the virus-induced membrane alterations essential for viral replication organelle formation. ITZ also inhibits hepatitis C virus replication, which also relies on OSBP. Together, these data implicate OSBP/ORP4 as molecular targets of ITZ and point to an essential role of OSBP/ORP4-mediated lipid exchange in virus replication that can be targeted by antiviral drugs.
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