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Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA\u2010approved hepatitis C drug EPCLUSA (Sofosbuvir\/Velpatasvir) should inhibit coronaviruses, including SARS\u2010CoV\u20102. Here, using model polymerase extension experiments, we demonstrate that the active triphosphate form of Sofosbuvir is incorporated by low\u2010fidelity polymerases and SARS\u2010CoV RNA\u2010dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the active triphosphate form of Sofosbuvir is not incorporated by a host\u2010like high\u2010fidelity DNA polymerase. Using the same molecular insight, we selected 3\u2019\u2010fluoro\u20103\u2019\u2010deoxythymidine triphosphate and 3\u2019\u2010azido\u20103\u2019\u2010deoxythymidine triphosphate, which are the active forms of two other anti\u2010viral agents, Alovudine and AZT (an FDA\u2010approved HIV\/AIDS drug) for evaluation as inhibitors of SARS\u2010CoV RdRp. We demonstrate the ability of two of these HIV reverse transcriptase inhibitors to be incorporated by SARS\u2010CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS\u2010CoV and SARS\u2010CoV\u20102 RdRps, we expect these nucleotide analogues would also inhibit the SARS\u2010CoV\u20102 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad\u2010spectrum anti\u2010coronavirus agents.<\/jats:p>","DOI":"10.1002\/prp2.674","type":"journal-article","created":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T05:15:21Z","timestamp":1604034921000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Nucleotide analogues as inhibitors of SARS\u2010CoV Polymerase"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4974-4241","authenticated-orcid":false,"given":"Jingyue","family":"Ju","sequence":"first","affiliation":[{"name":"Center for Genome Technology and Biomolecular Engineering Columbia University New York New York USA"},{"name":"Department of Chemical Engineering Columbia University New York NY USA"},{"name":"Department of Molecular Pharmacology and Therapeutics Columbia University New York NY 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Columbia University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minchen","family":"Chien","sequence":"additional","affiliation":[{"name":"Center for Genome Technology and Biomolecular Engineering Columbia University New York New York USA"},{"name":"Department of Chemical Engineering Columbia University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanjuan","family":"Tao","sequence":"additional","affiliation":[{"name":"Center for Genome Technology and Biomolecular Engineering Columbia University New York New York USA"},{"name":"Department of Chemical Engineering Columbia University New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Morozova","sequence":"additional","affiliation":[{"name":"Center for Genome Technology and Biomolecular Engineering Columbia University New York New York USA"},{"name":"Department of Chemical Engineering Columbia University New York NY 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