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Sci Rep. 2018 Feb 9;8(1):2769. doi: 10.1038/s41598-018-20987-w.

Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide.

Author information

1
Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan.
2
Department of Applied Biological Sciences, Tokyo University of Science, Noda, 278-8510, Japan.
3
Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), Wako, 351-0198, Japan.
4
Micro-signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies (CLST), Wako, 351-0198, Japan.
5
Bio-Active Compounds Discovery Research Unit, RIKEN CSRS, Wako, 351-0198, Japan.
6
Chemical Resource Development Research Unit, RIKEN CSRS, Wako, 351-0198, Japan.
7
Department of Analytical Biochemistry, Meiji Pharmaceutical University, Kiyose, 204-8588, Japan.
8
The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
9
CellFree Sciences Co., Ltd, Matsuyama, 790-8577, Japan.
10
Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0027, Japan.
11
Drug Design Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, Japan.
12
Laboratoire de Virologie Moléculaire, Institut National de la Transfusion Sanguine, INSERM U1134, Paris, 75015, France.
13
Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), Wako, 351-0198, Japan. hisyo@riken.jp.
14
Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan. kwatashi@nih.go.jp.
15
Department of Applied Biological Sciences, Tokyo University of Science, Noda, 278-8510, Japan. kwatashi@nih.go.jp.
16
CREST, JST, Saitama, 332-0012, Japan. kwatashi@nih.go.jp.

Abstract

Current anti-hepatitis B virus (HBV) agents including interferons and nucleos(t)ide analogs efficiently suppress HBV infection. However, as it is difficult to eliminate HBV from chronically infected liver, alternative anti-HBV agents targeting a new molecule are urgently needed. In this study, we applied a chemical array to high throughput screening of small molecules that interacted with sodium taurocholate cotransporting polypeptide (NTCP), an entry receptor for HBV. From approximately 30,000 compounds, we identified 74 candidates for NTCP interactants, and five out of these were shown to inhibit HBV infection in cell culture. One of such compound, NPD8716, a coumarin derivative, interacted with NTCP and inhibited HBV infection without causing cytotoxicity. Consistent with its NTCP interaction capacity, this compound was shown to block viral attachment to host hepatocytes. NPD8716 also prevented the infection with hepatitis D virus, but not hepatitis C virus, in agreement with NPD8716 specifically inhibiting NTCP-mediated infection. Analysis of derivative compounds showed that the anti-HBV activity of compounds was apparently correlated with the affinity to NTCP and the capacity to impair NTCP-mediated bile acid uptake. These results are the first to show that the chemical array technology represents a powerful platform to identify novel viral entry inhibitors.

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