title: Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein.
abstract: 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.
authors: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands; Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the Netherlands.
authors: Jeroen R P M
authors: JR
authors: Strating
authors: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the Netherlands; Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium.
authors: Lonneke
authors: L
authors: van der Linden
authors: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands; Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the Netherlands.
authors: Lucian
authors: L
authors: Albulescu
authors: Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, UMR 7275, 06560 Valbonne, France.
authors: Joëlle
authors: J
authors: Bigay
authors: Department of Virology II, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
authors: Minetaro
authors: M
authors: Arita
authors: Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium.
authors: Leen
authors: L
authors: Delang
authors: Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium.
authors: Pieter
authors: P
authors: Leyssen
authors: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands; Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the Netherlands.
authors: Hilde M
authors: HM
authors: van der Schaar
authors: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the Netherlands.
authors: Kjerstin H W
authors: KH
authors: Lanke
authors: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands.
authors: Hendrik Jan
authors: HJ
authors: Thibaut
authors: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands; Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the Netherlands.
authors: Rachel
authors: R
authors: Ulferts
authors: Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, UMR 7275, 06560 Valbonne, France.
authors: Guillaume
authors: G
authors: Drin
authors: NanoTemper Technologies GmbH, 81369 München, Germany.
authors: Nina
authors: N
authors: Schlinck
authors: Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584CM Utrecht, the Netherlands.
authors: Richard W
authors: RW
authors: Wubbolts
authors: Department of Biochemistry and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Navdar
authors: N
authors: Sever
authors: Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors: Sarah A
authors: SA
authors: Head
authors: Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors: Jun O
authors: JO
authors: Liu
authors: Department of Biochemistry and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Philip A
authors: PA
authors: Beachy
authors: Telethon Institute of Genetics and Medicine, Naples 80131, Italy.
authors: Maria A
authors: MA
authors: De Matteis
authors: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors: Matthew D
authors: MD
authors: Shair
authors: Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland.
authors: Vesa M
authors: VM
authors: Olkkonen
authors: Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium.
authors: Johan
authors: J
authors: Neyts
authors: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands; Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the Netherlands. Electronic address: f.j.m.vankuppeveld@uu.nl.
authors: Frank J M
authors: FJ
authors: van Kuppeveld
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004770:Enterovirus / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D011987:Receptors, Steroid / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*; D000098825:Oxysterol Binding Proteins
chemical_list: D000998:Antiviral Agents; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; D017964:Itraconazole
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