Oncotarget

Research Papers:

Development of a cell-based assay to identify hepatitis B virus entry inhibitors targeting the sodium taurocholate cotransporting polypeptide

Kei Miyakawa, Satoko Matsunaga, Yutaro Yamaoka, Mina Dairaku, Kento Fukano, Hirokazu Kimura, Tomoyuki Chimuro, Hironori Nishitsuji, Koichi Watashi, Kunitada Shimotohno, Takaji Wakita and Akihide Ryo _

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Oncotarget. 2018; 9:23681-23694. https://doi.org/10.18632/oncotarget.25348

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Abstract

Kei Miyakawa1, Satoko Matsunaga1, Yutaro Yamaoka1,2, Mina Dairaku1, Kento Fukano3, Hirokazu Kimura4, Tomoyuki Chimuro2, Hironori Nishitsuji5, Koichi Watashi3, Kunitada Shimotohno5, Takaji Wakita3 and Akihide Ryo1

1Department of Microbiology, Yokohama City University School of Medicine, Kanagawa 236-0004, Japan

2Isehara Research Laboratory, Technology and Development Division, Kanto Chemical Co., Inc., Kanagawa 259-1146, Japan

3Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan

4School of Medical Technology, Faculty of Health Sciences, Gunma Paz University, Gunma 370-0006, Japan

5Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan

Correspondence to:

Akihide Ryo, email: aryo@yokohama-cu.ac.jp

Keywords: HBV-permissive cell; anti-NTCP monoclonal antibody; glabridin; innate immune signaling; ISG

Received: January 06, 2018     Accepted: April 24, 2018     Published: May 04, 2018

ABSTRACT

Sodium taurocholate cotransporting polypeptide (NTCP) is a major entry receptor of hepatitis B virus (HBV) and one of the most attractive targets for anti-HBV drugs. We developed a cell-mediated drug screening method to monitor NTCP expression on the cell surface by generating a HepG2 cell line with tetracycline-inducible expression of NTCP and a monoclonal antibody that specifically detects cell-surface NTCP. Using this system, we screened a small molecule library for compounds that protected against HBV infection by targeting NTCP. We found that glabridin, a licorice-derived isoflavane, could suppress viral infection by inducing caveolar endocytosis of cell-surface NTCP with an IC50 of ~40 μM. We also found that glabridin could attenuate the inhibitory effect of taurocholate on type I interferon signaling by depleting the level of cell-surface NTCP. These results demonstrate that our screening system could be a powerful tool for discovering drugs targeting HBV entry.


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