A novel pyridazinone derivative inhibits hepatitis B virus replication by inducing genome-free capsid formation

Antimicrobial Agents and Chemotherapy
Ya-Juan WangJian-Ping Zuo

Abstract

Here we first identified a novel pyridazinone derivative, compound 3711, as a nonnucleosidic hepatitis B virus (HBV) inhibitor in a cell model system. 3711 decreased extracellular HBV DNA levels by 50% (50% inhibitory concentration [IC50]) at 1.5 ± 0.2 μM and intracellular DNA levels at 1.9 ± 0.1 μM, which demonstrated antiviral activity at levels far below those associated with toxicity. Both the 3TC/ETV dually resistant L180M/M204I mutant and the adefovir (ADV)-resistant A181T/N236T mutant were as susceptible to 3711 as wild-type HBV. 3711 treatment induced the formation of genome-free capsids, a portion of which migrated faster on 1.8% native agarose gel. The induced genome-free capsids sedimented more slowly in isopycnic CsCl gradient centrifugation without significant morphological changes. 3711 treatment decreased levels of HBV DNA contained in both secreted enveloped virion and naked virus particles in supernatant. 3711 could interfere with capsid formation of the core protein (Cp) assembly domain. A Cp V124W mutant, which strengthens capsid interdimer interactions, recapitulated the effect of 3711 on capsid assembly. Pyridazinone derivative 3711, a novel chemical entity and HBV inhibitor, may provide a new opportunity t...Continue Reading

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Citations

Jan 7, 2016·Virus Research·Ya-Juan WangJian-Ping Zuo
Nov 1, 2016·Expert Opinion on Drug Discovery·Liudi TangJu-Tao Guo
May 24, 2017·Physical Biology·Marcus Thomas, Russell Schwartz
Mar 11, 2016·F1000Research·Wade Blair, Christopher Cox
Nov 25, 2017·Frontiers of Medicine·Shuye ZhangZheng Zhang
Jul 1, 2017·Drugs·Altaf DawoodRobert G Gish
Mar 16, 2021·Bioorganic & Medicinal Chemistry·Yuan WangTingjun Hou
May 1, 2021·European Journal of Medicinal Chemistry·Peng ZhuYong Ling
Jan 26, 2018·ACS Infectious Diseases·Song FengHong C Shen
Dec 12, 2018·ACS Infectious Diseases·Xuexiang ZhangJinhong Chang
Jul 22, 2020·Journal of Medicinal Chemistry·Wuhong ChenYouhong Hu

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