학술논문
Posaconazole inhibits dengue virus replication by targeting oxysterol-binding protein.
Document Type
Academic Journal
Author
Meutiawati F; Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.; Bezemer B; Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.; Strating JRPM; Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.; Overheul GJ; Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.; Žusinaite E; Institute of Technology, University of Tartu, Tartu, Estonia.; van Kuppeveld FJM; Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.; van Cleef KWR; Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.; van Rij RP; Department of Medical Microbiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: ronald.vanrij@radboudumc.nl.
Source
Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8109699 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-9096 (Electronic) Linking ISSN: 01663542 NLM ISO Abbreviation: Antiviral Res Subsets: MEDLINE
Subject
Language
English
Abstract
Dengue virus (DENV) is associated with an estimated 390 million infections per year, occurring across approximately 100 countries in tropical and sub-tropical regions. To date, there are no antiviral drugs or specific therapies to treat DENV infection. Posaconazole and itraconazole are potent antifungal drugs that inhibit ergosterol biosynthesis in fungal cells, but also target a number of human proteins. Here, we show that itraconazole and posaconazole have antiviral activity against DENV. Posaconazole inhibited replication of multiple serotypes of DENV and the related flavivirus Zika virus, and reduced viral RNA replication, but not translation of the viral genome. We used a combination of knockdown and drug sensitization assays to define the molecular target of posaconazole that mediates its antiviral activity. We found that knockdown of oxysterol-binding protein (OSBP) inhibited DENV replication. Moreover, knockdown of OSBP, but not other known targets of posaconazole, enhanced the inhibitory effect of posaconazole. Our findings imply OSBP as a potential target for the development of antiviral compounds against DENV.
(Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
(Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)