Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein
Jeroen R.P.M. Strating,
Lonneke van der Linden,
Lucian Albulescu,
Joëlle Bigay,
Minetaro Arita,
Leen Delang,
Pieter Leyssen,
Hilde M. van der Schaar,
Kjerstin H.W. Lanke,
Hendrik Jan Thibaut,
Rachel Ulferts,
Guillaume Drin,
Nina Schlinck,
Richard W. Wubbolts,
Navdar Sever,
Sarah A. Head,
Jun O. Liu,
Philip A. Beachy,
Maria A. De Matteis,
Matthew D. Shair,
Vesa M. Olkkonen,
Johan Neyts,
Frank J.M. van Kuppeveld
Affiliations
Jeroen R.P.M. Strating
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands
Lonneke van der Linden
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the Netherlands
Lucian Albulescu
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands
Joëlle Bigay
Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, UMR 7275, 06560 Valbonne, France
Minetaro Arita
Department of Virology II, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Leen Delang
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium
Pieter Leyssen
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium
Hilde M. van der Schaar
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands
Kjerstin H.W. Lanke
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the Netherlands
Hendrik Jan Thibaut
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands
Rachel Ulferts
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands
Guillaume Drin
Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, UMR 7275, 06560 Valbonne, France
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584CM Utrecht, the Netherlands
Navdar Sever
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
Sarah A. Head
Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Jun O. Liu
Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Philip A. Beachy
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
Maria A. De Matteis
Telethon Institute of Genetics and Medicine, Naples 80131, Italy
Matthew D. Shair
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
Vesa M. Olkkonen
Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland
Johan Neyts
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium
Frank J.M. van Kuppeveld
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands
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.
