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Vaccines and Antiviral Agents

Screening of FDA-Approved Drugs for Inhibitors of Japanese Encephalitis Virus Infection

Shaobo Wang, Yang Liu, Jiao Guo, Peilin Wang, Leike Zhang, Gengfu Xiao, Wei Wang
Michael S. Diamond, Editor
Shaobo Wang
aState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
bUniversity of the Chinese Academy of Sciences, Beijing, China
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Yang Liu
aState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
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Jiao Guo
aState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
bUniversity of the Chinese Academy of Sciences, Beijing, China
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Peilin Wang
aState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
bUniversity of the Chinese Academy of Sciences, Beijing, China
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Leike Zhang
aState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
bUniversity of the Chinese Academy of Sciences, Beijing, China
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Gengfu Xiao
aState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
bUniversity of the Chinese Academy of Sciences, Beijing, China
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Wei Wang
aState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
bUniversity of the Chinese Academy of Sciences, Beijing, China
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Michael S. Diamond
Washington University School of Medicine
Roles: Editor
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DOI: 10.1128/JVI.01055-17
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ABSTRACT

Japanese encephalitis virus (JEV), an arthropod-borne flavivirus, is a major cause of acute viral encephalitis in humans. No approved drug is available for the specific treatment of JEV infections, and the available vaccines are not effective against all clinical JEV isolates. In the study described here, a high-throughput screening of an FDA-approved drug library for inhibitors of JEV was performed. Five hit drugs that inhibited JEV infection with a selective index of >10 were identified. The antiviral activities of these five hit drugs against other flavivirus, including Zika virus, were also validated. As three of the five hit drugs were calcium inhibitors, additional types of calcium inhibitors that confirmed that calcium is essential for JEV infection, most likely during viral replication, were utilized. Adaptive mutant analysis uncovered that replacement of Q130, located in transmembrane domain 3 of the nonstructural NS4B protein, which is relatively conserved in flaviviruses, with R or K conferred JEV resistance to manidipine, a voltage-gated Ca2+ channel (VGCC) inhibitor, without an apparent loss of the viral growth profile. Furthermore, manidipine was indicated to protect mice against JEV-induced lethality by decreasing the viral load in the brain, while it abrogated the histopathological changes associated with JEV infection. This study provides five antiflavivirus candidates and identifies cytoplasmic calcium to be a novel antiviral target for the treatment of JEV infection. The findings reported here provide therapeutic possibilities for combating infections caused by flaviviruses.

IMPORTANCE No approved therapy for the treatment of Japanese encephalitis virus infection is currently available. Repurposing of approved drugs would accelerate the development of a therapeutic stratagem. In this study, we screened a library of FDA-approved drugs and identified five hit drugs, especially calcium inhibitors, exerting antiflavivirus activity that blocked viral replication. The in vivo efficacy and toxicity of manidipine were investigated with a mouse model of JEV infection, and the viral target was identified by generating an adaptive mutant.

  • Copyright © 2017 Wang et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license .

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Screening of FDA-Approved Drugs for Inhibitors of Japanese Encephalitis Virus Infection
Shaobo Wang, Yang Liu, Jiao Guo, Peilin Wang, Leike Zhang, Gengfu Xiao, Wei Wang
Journal of Virology Oct 2017, 91 (21) e01055-17; DOI: 10.1128/JVI.01055-17

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Screening of FDA-Approved Drugs for Inhibitors of Japanese Encephalitis Virus Infection
Shaobo Wang, Yang Liu, Jiao Guo, Peilin Wang, Leike Zhang, Gengfu Xiao, Wei Wang
Journal of Virology Oct 2017, 91 (21) e01055-17; DOI: 10.1128/JVI.01055-17
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KEYWORDS

antiviral agents
Encephalitis Virus, Japanese
Encephalitis, Japanese
High-Throughput Screening Assays
virus replication
FDA-approved drugs
Japanese encephalitis virus
NS4B
Flavivirus
high-throughput screening
manidipine

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