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Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide
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 ap...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807303/ https://www.ncbi.nlm.nih.gov/pubmed/29426822 http://dx.doi.org/10.1038/s41598-018-20987-w |
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author | Kaneko, Manabu Futamura, Yushi Tsukuda, Senko Kondoh, Yasumitsu Sekine, Tomomi Hirano, Hiroyuki Fukano, Kento Ohashi, Hirofumi Saso, Wakana Morishita, Ryo Matsunaga, Satoko Kawai, Fumihiro Ryo, Akihide Park, Sam-Yong Suzuki, Ryosuke Aizaki, Hideki Ohtani, Naoko Sureau, Camille Wakita, Takaji Osada, Hiroyuki Watashi, Koichi |
author_facet | Kaneko, Manabu Futamura, Yushi Tsukuda, Senko Kondoh, Yasumitsu Sekine, Tomomi Hirano, Hiroyuki Fukano, Kento Ohashi, Hirofumi Saso, Wakana Morishita, Ryo Matsunaga, Satoko Kawai, Fumihiro Ryo, Akihide Park, Sam-Yong Suzuki, Ryosuke Aizaki, Hideki Ohtani, Naoko Sureau, Camille Wakita, Takaji Osada, Hiroyuki Watashi, Koichi |
author_sort | Kaneko, Manabu |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5807303 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58073032018-02-14 Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide Kaneko, Manabu Futamura, Yushi Tsukuda, Senko Kondoh, Yasumitsu Sekine, Tomomi Hirano, Hiroyuki Fukano, Kento Ohashi, Hirofumi Saso, Wakana Morishita, Ryo Matsunaga, Satoko Kawai, Fumihiro Ryo, Akihide Park, Sam-Yong Suzuki, Ryosuke Aizaki, Hideki Ohtani, Naoko Sureau, Camille Wakita, Takaji Osada, Hiroyuki Watashi, Koichi Sci Rep Article 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. Nature Publishing Group UK 2018-02-09 /pmc/articles/PMC5807303/ /pubmed/29426822 http://dx.doi.org/10.1038/s41598-018-20987-w Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Kaneko, Manabu Futamura, Yushi Tsukuda, Senko Kondoh, Yasumitsu Sekine, Tomomi Hirano, Hiroyuki Fukano, Kento Ohashi, Hirofumi Saso, Wakana Morishita, Ryo Matsunaga, Satoko Kawai, Fumihiro Ryo, Akihide Park, Sam-Yong Suzuki, Ryosuke Aizaki, Hideki Ohtani, Naoko Sureau, Camille Wakita, Takaji Osada, Hiroyuki Watashi, Koichi Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide |
title | Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide |
title_full | Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide |
title_fullStr | Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide |
title_full_unstemmed | Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide |
title_short | Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide |
title_sort | chemical array system, a platform to identify novel hepatitis b virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807303/ https://www.ncbi.nlm.nih.gov/pubmed/29426822 http://dx.doi.org/10.1038/s41598-018-20987-w |
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