TY - JOUR
T1 - Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein
AU - Strating, Jeroen R.P.M.
AU - van der Linden, Lonneke
AU - Albulescu, Lucian
AU - Bigay, Joëlle
AU - Arita, Minetaro
AU - Delang, Leen
AU - Leyssen, Pieter
AU - van der Schaar, Hilde M.
AU - Lanke, Kjerstin H.W.
AU - Thibaut, Hendrik Jan
AU - Ulferts, Rachel
AU - Drin, Guillaume
AU - Schlinck, Nina
AU - Wubbolts, Richard W.
AU - Sever, Navdar
AU - Head, Sarah A.
AU - Liu, Jun O.
AU - Beachy, Philip A.
AU - DeMatteis, Maria A.
AU - Shair, Matthew D.
AU - Olkkonen, Vesa M.
AU - Neyts, Johan
AU - van Kuppeveld, Frank J.M.
N1 - Funding Information:
We thank Stijn Delmotte, Katrien Geerts, Caroline Collard, Gerrit Koen, and Katja Wolthers for assistance in acquisition of part of the antiviral data; Patrick Celie and Alex Fisch (Netherlands Cancer Institute, Amsterdam) for help with the MST measurements; and the Center for Cell Imaging (Faculty of Veterinary Medicine, Utrecht University) for support with microscopy experiments. This work was supported by grants from the “Convenant K.U. Leuven-Radboud University Nijmegen” framework (L.v.d.L., J.N., and F.J.M.v.K.), the European Union FP7 Marie Curie Initial Training Network “EUVIRNA” (grant agreement number 264286) (F.J.M.v.K.) and FP7 Large Scale Collaborative Project “SILVER” (grant agreement number 260644) (F.J.M.v.K.), the KU Leuven geconcerteerde onderzoeksactie (GOA/10/014) (J.N.), the Belgian Science Policy Office (BELSPO, Belvir consortium, IAP, phase VII) (J.N.), the Fund for Scientific Research of Flanders (FWO) (L.D.), CNRS and ANR (2010-1503-01) (J.B. and G.D.), the Sigrid Juselius Foundation (V.M.O.), the Finnish Foundation for Cardiovascular Research (V.M.O.), the Magnus Ehrnrooth Foundation (V.M.O.), and the Netherlands Organisation for Scientific Research (N.W.O.): ECHO-700.57.001, ALW-820.02.018 and VICI-91812628 (F.J.M.v.K.), VENI-722.012.066 (J.R.P.M.S.), and VENI-863.12.005 (H.M.v.d.S.). M.A. was supported in part by Grants-in-Aid for the Promotion of Polio Eradication and Research on Emerging and Re-emerging Infectious Diseases from the Ministry of Health, Labor and Welfare, Japan; a grant from the World Health Organization for a collaborative research project of the Global Polio Eradication Initiative; and by JSPS KAKENHI grant 25460579. N. Sever and P.A.B. are supported by the NIH. P.A.B. is an investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. N. Schlinck is an employee of NanoTemper Technologies GmbH.
Publisher Copyright:
© 2015 The Authors.
PY - 2015/2/3
Y1 - 2015/2/3
N2 - Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, weidentify 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.
AB - Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, weidentify 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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U2 - 10.1016/j.celrep.2014.12.054
DO - 10.1016/j.celrep.2014.12.054
M3 - Article
C2 - 25640182
AN - SCOPUS:84922769738
VL - 10
SP - 600
EP - 615
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
ER -