title: A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins.
abstract: Introduction of direct-acting antivirals against hepatitis C virus (HCV) has provided a revolutionary improvement in the treatment outcome. In contrast to HCV, however, the strategy for developing new antiviral agents against hepatitis B virus (HBV), especially viral-targeting compounds, is limited because HBV requires only four viral genes for its efficient replication/infection. Here, we identify an oligomeric flavonoid, proanthocyanidin (PAC) and its analogs, which inhibit HBV entry into host cells by targeting the HBV large surface protein (LHBs). Through cell-based chemical screening, PAC was identified to inhibit HBV infection with little cytotoxic effect. PAC prevented the attachment of the preS1 region in the LHBs to its cellular receptor, sodium taurocholate cotransporting polypeptide (NTCP). PAC was shown to target HBV particles and impair their infectivity, whereas it did not affect the NTCP-mediated bile acid transport activity. Chemical biological techniques demonstrated that PAC directly interacted with the region essential for receptor binding in the preS1 region in the LHBs protein. Importantly, PAC had a pan-genotypic anti-HBV activity and was also effective against a clinically relevant nucleoside analog-resistant HBV isolate. We further showed that PAC augmented the ability of a nucleoside analog, tenofovir, to interrupt HBV spread over time in primary human hepatocytes by cotreatment. Moreover, derivative analysis could identify small molecules that demonstrated more-potent anti-HBV activity over PAC.
  
  
  
  PAC and its analogs represent a new class of anti-HBV agents that directly target the preS1 region of the HBV large surface protein. These agents could contribute to the development of a potent, well-tolerated, and broadly active inhibitor of HBV infection. (Hepatology 2017;65:1104-1116).
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.|Micro-Signaling Regulation Technology Unit, RIKEN CLST, Wako, Japan.
authors.forename: Senko
authors.initials: S
authors.lastname: Tsukuda
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.|Department of Applied Biological Science, Tokyo University of Science, Noda, Japan.|CREST, Japan Science and Technology Agency (JST), Saitama, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.affiliation: Department of Advanced Science and Engineering, Graduate School of Engineering, Osaka Electro-Communication University, Neyagawa, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Hojima
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Isogawa
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: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Omagari
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: Micro-Signaling Regulation Technology Unit, RIKEN CLST, Wako, Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Kojima
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: Department of Advanced Science and Engineering, Graduate School of Engineering, Osaka Electro-Communication University, Neyagawa, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Saito
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: D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology; D005544:Forecasting; D005838:Genotype; D006509:Hepatitis B / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics; D003699:Hepatitis D / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D003698:Hepatitis Delta Virus / Q000187:drug effects / Q000235:genetics; D006801:Humans; D058990:Molecular Targeted Therapy / Q000639:trends; D044945:Proanthocyanidins / Q000008:administration & dosage*; D015678:Viral Structural Proteins / Q000187:drug effects* / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D044945:Proanthocyanidins; D015678:Viral Structural Proteins; C013221:proanthocyanidin