A novel pyridazinone derivative inhibits hepatitis B virus replication by inducing genome-free capsid formation.
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 to combat chronic HBV infection.
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Ya-Juan
YJ
Wang
Laboratory of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Dong
D
Lu
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Yi-Bin
YB
Xu
Laboratory of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Wei-Qiang
WQ
Xing
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Xian-Kun
XK
Tong
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Gui-Feng
GF
Wang
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Chun-Lan
CL
Feng
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Pei-Lan
PL
He
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China yangli@simm.ac.cn tangwei@simm.ac.cn yhhu@simm.ac.cn.
Li
L
Yang
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China yangli@simm.ac.cn tangwei@simm.ac.cn yhhu@simm.ac.cn.
Wei
W
Tang
Laboratory of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China yangli@simm.ac.cn tangwei@simm.ac.cn yhhu@simm.ac.cn.
You-Hong
YH
Hu
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Jian-Ping
JP
Zuo
D000998:Antiviral Agents / Q000494:pharmacology*; D002213:Capsid / Q000378:metabolism*; D036022:Capsid Proteins / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral; D006515:Hepatitis B virus / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D036022:Capsid Proteins; D004279:DNA, Viral