Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide
Open accessAbstract
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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Small molecule inhibitors of NTCP can prevent HBV infection without interrupting BA uptake.
“However, small molecule inhibitors of NTCP can also prevent HBV infection without interrupting BA uptake.204”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [204]
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- Authors
- Kaneko, M., Futamura, Y., Tsukuda, S., Kondoh, Y., Sekine, T., Hirano, H., Fukano, K., Ohashi, H., Saso, W., Morishita, R., Matsunaga, S., Kawai, F., Ryo, A., Park, S.-Y., Suzuki, R., Aizaki, H., Ohtani, N., Sureau, C., Wakita, T., Osada, H., & Watashi, K.
- Affiliations
- Tokyo University of Science (JP)
- RIKEN Center for Sustainable Resource Science (JP)
- National Institute of Infectious Diseases (JP)
- Meiji Pharmaceutical University (JP)
- CellFree Sciences (Japan) (JP)
- Yokohama City University (JP)
- Inserm (FR)
- Corresponding author
- Osada, Hiroyuki
- Watashi, Koichi
- ORCID
- Venue
- Scientific Reports
- Published
- 2018-02-09
- Volume
- 8
- Issue
- 1
- Pages
- 2769-2769
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5807303
- OpenAlex
- W2804202464
- Cited by
- 26
- References
- 39
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 3
- FWCI
- 2.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Université de Lyon
- Japan Society for the Promotion of Science (15K09034, 16K19145, 16KT0111, 18H05503, 17H04085, 16H04699, 18K05366, 26460565)
- Topics
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Keywords
- hepatitis B virus, viral entry inhibitors, sodium taurocholate cotransporting polypeptide, normal tissue complication probability, high-throughput screening, coumarins, hepatitis D virus, bile acid absorption, hepatocyte infection
- MeSH terms
- Bile Acids and Salts, Coumarins, Hepatitis Delta Virus, Hepatitis B virus, Humans, Hepacivirus, Symporters, Organic Anion Transporters, Sodium-Dependent, Virus Attachment, Virus Internalization, Hep G2 Cells, Viral Fusion Protein Inhibitors
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