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

Manabu Kaneko, Yushi Futamura, Senko Tsukuda, Yasumitsu Kondoh, Tomomi Sekine, Hiroyuki Hirano, Kento Fukano, Hirofumi Ohashi, Wakana Saso, Ryo Morishita, Satoko Matsunaga, Fumihiro Kawai, Akihide Ryo, Sam Yong Park, Ryosuke Suzuki, Hideki Aizaki, Naoko Ohtani, Camille Sureau, Takaji Wakita, Hiroyuki OsadaKoichi Watashi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Article number2769
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018
Externally publishedYes

ASJC Scopus subject areas

  • General

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