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Therefore, new antiviral strategies interfering with other HBV replication steps are required, especially those that could efficiently inhibit HBsAg production. Here, we identified novel anti\u2010HBV compounds that could potently block HBsAg expression from cccDNA by screening a natural compound library derived from Chinese traditional medical plants by a novel screening strategy. The combination of ELISA assay detecting the HBsAg and real\u2010time PCR detecting HBV RNAs as indicator for cccDNA transcriptional activity were used. The antiviral activity of a candidate compound and underlying mechanism were evaluated in HBV\u2010infected cells and a humanized liver mouse model. Herein, we selected a highly effective low\u2010cytotoxic compound sphondin, which could effectively inhibit both intracellular HBsAg production and HBV RNAs levels. Moreover, we found that sphondin markedly inhibited cccDNA transcriptional activity without affecting cccDNA level. Mechanistic study found sphondin preferentially bound to HBx protein by residue Arg72, which led to increased 26S proteasome\u2010mediated degradation of HBx. Sphondin treatment significantly reduced the recruitment of HBx to cccDNA, which subsequently led to inhibition of cccDNA transcription and HBsAg expression. The absence of HBx or R72A mutation potently abrogated the antiviral effect induced by sphondin in HBV\u2010infected cells. Collectively, sphondin may be considered as a novel and natural antiviral agent directly targeting HBx protein, which effectively inhibited cccDNA transcription and HBsAg expression.<\/jats:p>","DOI":"10.1002\/jmv.28578","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T09:54:39Z","timestamp":1677491679000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Sphondin efficiently blocks HBsAg production and cccDNA transcription through promoting HBx degradation"],"prefix":"10.1002","volume":"95","author":[{"given":"Fang","family":"Ren","sequence":"first","affiliation":[{"name":"The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital Chongqing Medical University  Chongqing China"},{"name":"Chongqing Key Laboratory of 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases The Children's Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieli","family":"Hu","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital Chongqing Medical University  Chongqing 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