1. Academic Validation
  2. Pyrimidotriazine derivatives as selective inhibitors of HBV capsid assembly

Pyrimidotriazine derivatives as selective inhibitors of HBV capsid assembly

  • Virus Res. 2019 Oct 2;271:197677. doi: 10.1016/j.virusres.2019.197677.
Masaaki Toyama 1 Norikazu Sakakibara 2 Midori Takeda 3 Mika Okamoto 1 Koichi Watashi 4 Takaji Wakita 4 Masaya Sugiyama 5 Masashi Mizokami 5 Masanori Ikeda 3 Masanori Baba 6
Affiliations

Affiliations

  • 1 Division of Antiviral Chemotherapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, Japan.
  • 2 Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki, Japan.
  • 3 Division of Biological Information Technology, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, Japan.
  • 4 Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
  • 5 The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
  • 6 Division of Antiviral Chemotherapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, Japan. Electronic address: m-baba@m2.kufm.kagoshima-u.ac.jp.
Abstract

Chronic hepatitis B virus (HBV) Infection is currently treated with nucleoside/nucleotides analogs. They are potent inhibitors of HBV DNA Polymerase, which also functions as Reverse Transcriptase. Although nucleoside/nucleotide analogs efficiently suppress HBV replication in liver cells, they cannot eradicate HBV DNA from liver cells and cure the disease. Therefore, it is still mandatory to identify and develop effective inhibitors that target a step other than reverse transcription in the viral replication cycle. HBV capsid assembly is a critical step for viral replication and an attractive target for inhibition of HBV replication. We conducted in silico screening of compounds expected to bind to the HBV capsid dimer-dimer interaction site. The selected compounds were further examined for their anti-HBV activity in vitro. Among the test compounds, novel pyrimidotriazine derivatives were found to be selective inhibitors of HBV replication in HepG2.2.15.7 cells. Among the compounds, 2-[(2,3-dichlorophenyl)amino]-4-(4-tert-butylphenyl)-8-methyl-4H,9H-pyrimido[1,2-a][1,3,5]triazin-6-one was the most active against HBV replication. Studies on its mechanism of action revealed that the compound interfered with HBV capsid assembly determined by a cell-free capsid assembly system. Thus, the pyrimidotriazine derivatives are considered to be potential leads for novel HBV capsid assembly inhibitors.

Keywords

Antiviral; Capsid assembly; HBV; Pyrimidotriazine.

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