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
doi: https://doi.org/10.1101/2020.03.12.989186
Abstract
SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency. 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. 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.
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