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J Virol. 2015 Sep 16. pii: JVI.01855-15. [Epub ahead of print]
A novel tricyclic polyketide, vanitaracin A, specifically inhibits the entry of hepatitis B and D viruses through targeting NTCP.Kaneko M1, Watashi K2, Kamisuki S3, Matsunaga H3, Iwamoto M1, Kawai F4, Ohashi H1, Tsukuda S5, Shimura S6, Suzuki R7, Aizaki H7, Sugiyama M8, Park SY4, Ito T9, Ohtani N3, Sugawara F3, Tanaka Y10, Mizokami M8, Sureau C11, Wakita T7.
Author information
- 1Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
- 2Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Department of Applied Biological Science, Tokyo University of Science, Noda, Japan [email protected].
- 3Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
- 4Protein Design Laboratory, Yokohama City University, Yokohama, Japan.
- 5Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Micro-signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Wako, Japan.
- 6Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan SCYNEXIS, Inc., Durham, NC, USA.
- 7Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
- 8The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
- 9Digestive Diseases Center, Showa University Koto-Toyosu Hospital, Tokyo, Japan.
- 10Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya, Japan.
- 11Laboratoire de Virologie Moléculaire, Institut National de la Transfusion Sanguine (INTS), Paris, France.
AbstractAnti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. For a challenge of drug development, it is demanded to identify small molecules that suppress HBV infection from new chemical sources. Here, from a fungal-derived secondary metabolite library, we identify a structurally novel tricyclic polyketide, named vanitaracin A, which specifically inhibits HBV infection. Vanitaracin A inhibited the viral entry process with a submicromolar IC50 (IC50 = 0.61 ± 0.23 μM) without evident cytotoxicity (CC50 > 256 μM, selectivity index > 419) in primary human hepatocytes. Vanitaracin A did not affect HBV replication process. This compound was found to directly interact with the HBV entry receptor, sodium taurocholate cotransporting polypeptide (NTCP), and impaired its bile acid transport activity. Consistent with this NTCP targeting, antiviral activity of vanitaracin A was observed with hepatitis D virus (HDV), but not hepatitis C virus. Importantly, vanitaracin A inhibited infection of all the HBV genotypes tested (genotype A-D) and clinically-relevant NA-resistant HBV isolates. Thus, we identified a fungal metabolite, vanitaracin A, which was a potent, well-tolerated, and broadly active inhibitor of HBV and HDV entry. This compound, or its related analogs, could be part of an antiviral strategy for preventing reinfection with HBV, including clinically-relevant nucleos(t)ide analog-resistant virus.
IMPORTANCE: For achieving better treatment and prevention against hepatitis B virus (HBV), anti-HBV agents targeting a new molecule have been greatly demanded. Although sodium taurocholate cotransporting polypeptide (NTCP) has recently been reported as an essential host factor for HBV entry, there is limited number of report that identify new compounds targeting NTCP and inhibiting HBV entry. Here, from an uncharacterized chemical library, we isolated a structurally new compound, named vanitaracin A, which inhibited the entry process of HBV and hepatitis D virus (HDV). This compound was suggested to directly interact with NTCP and inhibit its transporter activity. Importantly, vanitaracin A inhibited the entry of all the HBV genotypes examined and that of a clinically-relevant nucleos(t)ide analog-resistant HBV isolate.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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