title: A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide.
abstract: Anti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. A challenge of drug development is the identification of small molecules that suppress HBV infection from new chemical sources. Here, from a fungus-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 50% inhibitory concentration (IC50) (IC50 = 0.61 ± 0.23 μM), without evident cytotoxicity (50% cytotoxic concentration of >256 μM; selectivity index value of >419) in primary human hepatocytes. Vanitaracin A did not affect the 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 by all HBV genotypes tested (genotypes A to D) and clinically relevant NA-resistant HBV isolate. 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.
  
  
  OBJECTIVE
  For achieving better treatment and prevention of hepatitis B virus (HBV) infection, anti-HBV agents targeting a new molecule are in great demand. Although sodium taurocholate cotransporting polypeptide (NTCP) has recently been reported to be an essential host factor for HBV entry, there is a limited number of reports 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 process of entry 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 HBV genotypes examined and of a clinically relevant nucleos(t)ide analog-resistant HBV isolate.
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kaneko
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Department of Applied Biological Science, Tokyo University of Science, Noda, Japan kwatashi@nih.go.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Matsunaga
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: Protein Design Laboratory, Yokohama City University, Yokohama, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Kawai
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Micro-Signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Wako, Japan.
authors.forename: Senko
authors.initials: S
authors.lastname: Tsukuda
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan Scynexis, Inc., Durham, North Carolina, USA.
authors.forename: Satomi
authors.initials: S
authors.lastname: Shimura
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Aizaki
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Sugiyama
authors.affiliation: Protein Design Laboratory, Yokohama City University, Yokohama, Japan.
authors.forename: Sam-Yong
authors.initials: SY
authors.lastname: Park
authors.affiliation: Digestive Diseases Center, Showa University Koto-Toyosu Hospital, Tokyo, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ohtani
authors.affiliation: Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizokami
authors.affiliation: Laboratoire de Virologie Moléculaire, Institut National de la Transfusion Sanguine, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Sureau
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
mesh_terms: D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D055808:Drug Discovery / Q000379:methods; D019084:Fluorescent Antibody Technique, Indirect; D006509:Hepatitis B / Q000188:drug therapy*; D006515:Hepatitis B virus / Q000502:physiology*; D003698:Hepatitis Delta Virus / Q000502:physiology*; D006801:Humans; D008163:Luminescent Measurements; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D061065:Polyketides / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries; D020349:Surface Plasmon Resonance; D027981:Symporters / Q000378:metabolism*; D032901:Talaromyces / Q000737:chemistry*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D017931:DNA Primers; D029363:Organic Anion Transporters, Sodium-Dependent; D061065:Polyketides; D054852:Small Molecule Libraries; D027981:Symporters; C000605351:vanitaracin A; C071908:sodium-bile acid cotransporter