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Although nucleot(s)ide analogs are used as main treatment for HBV infection, the emergence of the drug\u2010resistant viruses has become a problem. To discover novel antivirals with low side effects and low risk of emergence of resistant viruses, screening for anti\u2010HBV compounds was performed with compound libraries of inhibitors targeting G\u2010protein\u2010coupled receptors (GPCRs). HepG2\u2010hNTCP C4 cells infected with HBV were treated with various GPCR inhibitors and harvested at 14 day postinfection for quantification of core protein in the first screening or relaxed circular DNA in the second screening. Finally, we identified a cannabinoid receptor 1 inhibitor, rimonabant, as a candidate showing anti\u2010HBV effect. In HepG2\u2010hNTCP C4 cells, treatment with rimonabant suppressed HBV propagation at the viral RNA transcription step but had no effect on entry or covalently closed circular DNA level. The values of half maximal inhibitory concentration, half maximal effective concentration, and selectivity index of rimonabant in primary human hepatocyte (PHH) are 2.77\u2009\u03bcm, 40.4\u2009\u03bcm, and 14.6, respectively. Transcriptome analysis of rimonabant\u2010treated primary hepatocytes by RNA sequencing revealed that the transcriptional activity of hepatocyte nuclear factor 4\u03b1 (HNF4\u03b1), which is known to stimulate viral RNA synthesis, was depressed. By treatment of PHH with rimonabant, the expression level of HNF4\u03b1 protein and the production of the messenger RNAs (mRNAs) of downstream factors promoted by HNF4\u03b1 were reduced while the amount of HNF4\u03b1 mRNA was not altered. These results suggest that treatment with rimonabant suppresses HBV propagation through the inhibition of HNF4\u03b1 activity.<\/jats:p>","DOI":"10.1111\/1348-0421.12777","type":"journal-article","created":{"date-parts":[[2020,1,25]],"date-time":"2020-01-25T09:20:17Z","timestamp":1579944017000},"page":"345-355","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Rimonabant suppresses RNA transcription of hepatitis B virus by inhibiting hepatocyte nuclear factor 4\u03b1"],"prefix":"10.1111","volume":"64","author":[{"given":"Asuka","family":"Sato","sequence":"first","affiliation":[{"name":"Department of Molecular Virology, Research Institute for Microbial Diseases Osaka University Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chikako","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Research Institute for Microbial Diseases Osaka University 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