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Antiviral Agents

Identification of Retinoic Acid Receptor Agonists as Potent Hepatitis B Virus Inhibitors via a Drug Repurposing Screen

Baocun Li, Yang Wang, Fang Shen, Min Wu, Yaming Li, Zhong Fang, Jianyu Ye, Li Wang, Lu Gao, Zhenghong Yuan, Jieliang Chen
Baocun Li
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, ChinaRoche Innovation Center Shanghai, Shanghai, China
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Yang Wang
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
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Fang Shen
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, ChinaRoche Innovation Center Shanghai, Shanghai, China
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Min Wu
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
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Yaming Li
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
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Zhong Fang
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
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Jianyu Ye
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
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Li Wang
Roche Innovation Center Shanghai, Shanghai, China
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Lu Gao
Roche Innovation Center Shanghai, Shanghai, China
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Zhenghong Yuan
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
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Jieliang Chen
Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
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DOI: 10.1128/AAC.00465-18
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ABSTRACT

Currently available therapies for chronic hepatitis B virus (HBV) infection can efficiently reduce viremia but induce hepatitis B surface antigen (HBsAg) loss in very few patients; also, these therapies do not greatly affect the viral covalently closed circular DNA (cccDNA). To discover new agents with complementary anti-HBV effects, we performed a drug repurposing screen of 1,018 Food and Drug Administration (FDA)-approved compounds using HBV-infected primary human hepatocytes (PHH). Several compounds belonging to the family of retinoic acid receptor (RAR) agonists were identified that reduced HBsAg levels in a dose-dependent manner without significant cytotoxicity. Among them, tazarotene exhibited the most potent anti-HBV effect, with a half-maximal inhibitory concentration (IC50) for HBsAg of less than 30 nM in PHH. The inhibitory effect was also observed in HBV-infected differentiated HepaRG (dHepaRG) models, but not in HepG2.215 cells, and HBV genotypes A to D were similarly inhibited. Tazarotene was further demonstrated to repress HBV cccDNA transcription, as determined by the levels of HBV cccDNA and RNAs and the activation of HBV promoters. Moreover, RNA sequence analysis showed that tazarotene did not induce an interferon response but altered the expression of a number of genes associated with RAR and metabolic pathways. Inhibition of RARβ, but not RARα, by a specific antagonist significantly attenuated the anti-HBV activity of tazarotene, suggesting that tazarotene inhibits HBV in part through RARβ. Finally, a synergistic effect of tazarotene and entecavir on HBV DNA levels was observed. Therefore, RAR agonists as represented by tazarotene were identified as potential novel anti-HBV agents.

FOOTNOTES

    • Received 22 March 2018.
    • Returned for modification 5 April 2018.
    • Accepted 5 June 2018.
    • Accepted manuscript posted online 17 September 2018.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.00465-18.

  • Copyright © 2018 American Society for Microbiology.

All Rights Reserved.

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Identification of Retinoic Acid Receptor Agonists as Potent Hepatitis B Virus Inhibitors via a Drug Repurposing Screen
Baocun Li, Yang Wang, Fang Shen, Min Wu, Yaming Li, Zhong Fang, Jianyu Ye, Li Wang, Lu Gao, Zhenghong Yuan, Jieliang Chen
Antimicrobial Agents and Chemotherapy Nov 2018, 62 (12) e00465-18; DOI: 10.1128/AAC.00465-18

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Identification of Retinoic Acid Receptor Agonists as Potent Hepatitis B Virus Inhibitors via a Drug Repurposing Screen
Baocun Li, Yang Wang, Fang Shen, Min Wu, Yaming Li, Zhong Fang, Jianyu Ye, Li Wang, Lu Gao, Zhenghong Yuan, Jieliang Chen
Antimicrobial Agents and Chemotherapy Nov 2018, 62 (12) e00465-18; DOI: 10.1128/AAC.00465-18
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KEYWORDS

HBV
RAR agonist
tazarotene
antiviral agents
metabolic pathway

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