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It has been reported that it has anti-conronaviruses activities including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we assemble three <jats:italic>Stephania<\/jats:italic> genomes (<jats:italic>S. japonica<\/jats:italic>, <jats:italic>S. yunnanensis<\/jats:italic>, and <jats:italic>S. cepharantha<\/jats:italic>), propose the cepharanthine biosynthetic pathway, and assess the antiviral potential of compounds involved in the pathway. Among the three genomes, <jats:italic>S. japonica<\/jats:italic> has a near telomere-to-telomere assembly with one remaining gap, and <jats:italic>S. cepharantha<\/jats:italic> and <jats:italic>S. yunnanensis<\/jats:italic> have chromosome-level assemblies. Following by biosynthetic gene mining and metabolomics analysis, we identify seven cepharanthine analogs that have broad-spectrum anti-coronavirus activities, including SARS-CoV-2, Guangxi pangolin-CoV (GX_P2V), swine acute diarrhoea syndrome coronavirus (SADS-CoV), and porcine epidemic diarrhea virus (PEDV). We also show that two other genera, <jats:italic>Nelumbo<\/jats:italic> and <jats:italic>Thalictrum<\/jats:italic>, can produce cepharanthine analogs, and thus have the potential for antiviral compound discovery. Results generated from this study could accelerate broad-spectrum anti-coronavirus drug discovery.<\/jats:p>","DOI":"10.1038\/s41467-024-45690-5","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T12:04:44Z","timestamp":1708430684000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug 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