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Article

The Antimalarial Compound Atovaquone Inhibits Zika and Dengue Virus Infection by Blocking E Protein-Mediated Membrane Fusion

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Research Center for Asian Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 113-0033, Japan
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Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 113-0033, Japan
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Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 113-0033, Japan
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Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100864, China
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China-Japan Joint Laboratory of Molecular Immunology & Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100864, China
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Division of Molecular Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 113-0033, Japan
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Department of Microbiology and Infection, Kochi Medical School, Kochi University, Kochi 780-8072, Japan
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Senior Professor Office, The University of Tokyo, Tokyo 113-0033, Japan
*
Authors to whom correspondence should be addressed.
Academic Editor: Deborah H. Fuller
Viruses 2020, 12(12), 1475; https://doi.org/10.3390/v12121475
Received: 7 December 2020 / Revised: 16 December 2020 / Accepted: 19 December 2020 / Published: 21 December 2020
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
Flaviviruses bear class II fusion proteins as their envelope (E) proteins. Here, we describe the development of an in vitro quantitative mosquito-cell-based membrane-fusion assay for the E protein using dual split proteins (DSPs). The assay does not involve the use of live viruses and allows the analysis of a membrane-fusion step independent of other events in the viral lifecycle, such as endocytosis. The progress of membrane fusion can be monitored continuously by measuring the activities of Renilla luciferase derived from the reassociation of DSPs during cell fusion. We optimized the assay to screen an FDA-approved drug library for a potential membrane fusion inhibitor using the E protein of Zika virus. Screening results identified atovaquone, which was previously described as an antimalarial agent. Atovaquone potently blocked the in vitro Zika virus infection of mammalian cells with an IC90 of 2.1 µM. Furthermore, four distinct serotypes of dengue virus were also inhibited by atovaquone with IC90 values of 1.6–2.5 µM, which is a range below the average blood concentration of atovaquone after its oral administration in humans. These findings make atovaquone a likely candidate drug to treat illnesses caused by Zika as well as dengue viruses. Additionally, the DSP assay is useful to study the mechanism of membrane fusion in Flaviviruses. View Full-Text
Keywords: Zika virus; Dengue virus; antiviral drugs; high-throughput screening; cell-based membrane fusion assay Zika virus; Dengue virus; antiviral drugs; high-throughput screening; cell-based membrane fusion assay
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MDPI and ACS Style

Yamamoto, M.; Ichinohe, T.; Watanabe, A.; Kobayashi, A.; Zhang, R.; Song, J.; Kawaguchi, Y.; Matsuda, Z.; Inoue, J.-i. The Antimalarial Compound Atovaquone Inhibits Zika and Dengue Virus Infection by Blocking E Protein-Mediated Membrane Fusion. Viruses 2020, 12, 1475. https://doi.org/10.3390/v12121475

AMA Style

Yamamoto M, Ichinohe T, Watanabe A, Kobayashi A, Zhang R, Song J, Kawaguchi Y, Matsuda Z, Inoue J-i. The Antimalarial Compound Atovaquone Inhibits Zika and Dengue Virus Infection by Blocking E Protein-Mediated Membrane Fusion. Viruses. 2020; 12(12):1475. https://doi.org/10.3390/v12121475

Chicago/Turabian Style

Yamamoto, Mizuki; Ichinohe, Takeshi; Watanabe, Aya; Kobayashi, Ayako; Zhang, Rui; Song, Jiping; Kawaguchi, Yasushi; Matsuda, Zene; Inoue, Jun-ichiro. 2020. "The Antimalarial Compound Atovaquone Inhibits Zika and Dengue Virus Infection by Blocking E Protein-Mediated Membrane Fusion" Viruses 12, no. 12: 1475. https://doi.org/10.3390/v12121475

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