Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide
Year: 2018
Type: article
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.
Source: Scientific Reports
Authors: 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 Osada, Koichi Watashi
Institutions: Tokyo University of Science, National Institute of Infectious Diseases, RIKEN Center for Sustainable Resource Science, RIKEN, Meiji Pharmaceutical University, Institute of Medical Science, The University of Tokyo, The University of Tokyo, CellFree Sciences (Japan), Yokohama City University, Inserm, Institut National de la Transfusion Sanguine, Biologie intégrée du globule rouge et de l'Erythropoïèse, Japan Science and Technology Agency
Language: English
Topic: Hepatitis B Virus Studies
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,690
Awards: Analysis of the replication mechanism of hepatitis C virus in membrane vesicles containing replication complexes, Identification of host factors that regulate host susceptibility to hepatitis B virus infection and analysis of mechanisms., Systems Virology for understanding viral pathogenesis, G4744938201, Mechanistic analysis of hepatitis B virus entry and the host factors using new cell culture systems, The mechanism of obesity-associated liver cancer progression through cytokine cross-talk in tumor microenvironment., Development of ligand screening using chemical array and membrane protein-expressed cells, Analysis of regulation mechanisms of hepatitis B virus life cycle by kinases and post-translational modifications
OpenAlex ID: W2804202464