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http://conacyt.repositorioinstitucional.mx/jspui/handle/1000/4662| Nucleotide Analogues as Inhibitors of SARS-CoV Polymerase | |
| Jingyue Ju. Xiaoxu Li. Shiv Kumar. Steffen Jockusch. Minchen Chien. Chuanjuan Tao. Irina Morozova. Sergey Kalachikov. Robert Kirchdoerfer. James J. Russo. | |
| Acceso Abierto | |
| Atribución-NoComercial-SinDerivadas | |
| 10.1101/2020.03.12.989186 | |
| SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency.1 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-approved heptatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2.2 Here, using model polymerase extension experiments, we demonstrate that the activated triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the activated triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected two other anti-viral agents, Alovudine and AZT (an FDA approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two HIV reverse transcriptase inhibitors, 3-fluoro-3-deoxythymidine triphosphate and 3-azido-3-deoxythymidine triphosphate (the active triphosphate forms of Alovudine and AZT), to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents. | |
| www.biorxiv.org | |
| 2020 | |
| Artículo | |
| https://www.biorxiv.org/content/10.1101/2020.03.12.989186v1.full.pdf | |
| Inglés | |
| VIRUS RESPIRATORIOS | |
| Aparece en las colecciones: | Artículos científicos |
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