Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein
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 oxy...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2015-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714011218 |
| _version_ | 1818062234620788736 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jeroen R.P.M. Strating |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T14:00:58Z |
| format | Article |
| id | doaj.art-bf5c36a32e6b4b4f8255f844489c246c |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T14:00:58Z |
| publishDate | 2015-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-bf5c36a32e6b4b4f8255f844489c246c2022-12-22T01:45:49ZengElsevierCell Reports2211-12472015-02-0110460061510.1016/j.celrep.2014.12.054Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding ProteinJeroen R.P.M. Strating0Lonneke van der Linden1Lucian Albulescu2Joëlle Bigay3Minetaro Arita4Leen Delang5Pieter Leyssen6Hilde M. van der Schaar7Kjerstin H.W. Lanke8Hendrik Jan Thibaut9Rachel Ulferts10Guillaume Drin11Nina Schlinck12Richard W. Wubbolts13Navdar Sever14Sarah A. Head15Jun O. Liu16Philip A. Beachy17Maria A. De Matteis18Matthew D. Shair19Vesa M. Olkkonen20Johan Neyts21Frank J.M. van Kuppeveld22Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the NetherlandsDepartment of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the NetherlandsVirology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the NetherlandsInstitut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, UMR 7275, 06560 Valbonne, FranceDepartment of Virology II, National Institute of Infectious Diseases, Tokyo 208-0011, JapanLaboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, BelgiumLaboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, BelgiumVirology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the NetherlandsDepartment of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the NetherlandsVirology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the NetherlandsVirology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the NetherlandsInstitut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, UMR 7275, 06560 Valbonne, FranceNanoTemper Technologies GmbH, 81369 München, GermanyDepartment of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584CM Utrecht, the NetherlandsDepartment 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, USADepartment of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USADepartment of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USADepartment 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, USATelethon Institute of Genetics and Medicine, Naples 80131, ItalyDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USAMinerva Foundation Institute for Medical Research, 00290 Helsinki, FinlandLaboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, BelgiumVirology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the NetherlandsItraconazole (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.http://www.sciencedirect.com/science/article/pii/S2211124714011218 |
| spellingShingle | 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 Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein Cell Reports |
| title | Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein |
| title_full | Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein |
| title_fullStr | Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein |
| title_full_unstemmed | Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein |
| title_short | Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein |
| title_sort | itraconazole inhibits enterovirus replication by targeting the oxysterol binding protein |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714011218 |
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