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The present study aimed to identify small molecules as novel capsid assembly modulators with antiviral activity. Structure-based virtual screening of an integrated compound library led to the identification of several types of HBV inhibitors. Among these inhibitors, N-sulfonylpiperidine-3-carboxamides (SPCs) potently reduced the amount of secreted HBV DNA. Through structure\u2013activity relationship studies, we identified an SPC derivative, namely, C-39, which exhibited the highest antiviral activity without causing cytotoxicity. Mechanism studies showed that C-39 dose-dependently inhibited the formation of HBV capsid, synthesis of cccDNA, e antigen (HBeAg), viral pregenomic RNA (pgRNA), and HBV DNA levels, thereby restraining HBV replication. In summary, SPCs represent a new class of capsid assembly modulators. Further optimization of SPCs is expected to obtain new antiviral drugs against HBV infection.<\/jats:p>","DOI":"10.3390\/v14020348","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T23:42:20Z","timestamp":1644363740000},"page":"348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Structure-Based Discovery of N-Sulfonylpiperidine-3-Carboxamides as Novel Capsid Assembly Modulators for Potent Inhibition of HBV Replication"],"prefix":"10.3390","volume":"14","author":[{"given":"Yang","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Yin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Hu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"Cai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieli","family":"Hu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xia","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0137-1247","authenticated-orcid":false,"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0377-877X","authenticated-orcid":false,"given":"Luyi","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S2468-1253(18)30056-6","article-title":"Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: A modelling study","volume":"3","author":"Gamkrelidze","year":"2018","journal-title":"Lancet Gastroenterol. 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