Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice

• Published in: Cell reports (Cambridge) Vol. 32; no. 3; p. 107940
• Main Authors: Pruijssers, Andrea J., George, Amelia S., Schäfer, Alexandra, Leist, Sarah R., Gralinksi, Lisa E., Dinnon, Kenneth H., Yount, Boyd L., Agostini, Maria L., Stevens, Laura J., Chappell, James D., Lu, Xiaotao, Hughes, Tia M., Gully, Kendra, Martinez, David R., Brown, Ariane J., Graham, Rachel L., Perry, Jason K., Du Pont, Venice, Pitts, Jared, Ma, Bin, Babusis, Darius, Murakami, Eisuke, Feng, Joy Y., Bilello, John P., Porter, Danielle P., Cihlar, Tomas, Baric, Ralph S., Denison, Mark R., Sheahan, Timothy P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.07.2020; The Authors
• Subjects: antiviral; coronavirus; COVID-19; GS-441524; mouse; RdRp; remdesivir; RNA-dependent RNA polymerase; SARS-CoV-2; therapeutic; COVID-19; therapeutic; mouse; SARS-CoV-2; GS-441524; RdRp; RNA-dependent RNA polymerase; antiviral; coronavirus; remdesivir
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107940

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the novel viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV) potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). Weaker activity is observed in Vero E6 cells (EC50 = 1.65 μM) because of their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase of SARS-CoV-2. In mice infected with the chimeric virus, therapeutic RDV administration diminishes lung viral load and improves pulmonary function compared with vehicle-treated animals. These data demonstrate that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19. [Display omitted] •Remdesivir binding of active site of polymerase is conserved across all human CoVs•Remdesivir inhibits SARS-CoV-2 in primary and continuous human lung cell cultures•Remdesivir potency depends on cell-type-specific metabolism to its active form•Therapeutic remdesivir reduces viral loads and improves outcomes in mice SARS-CoV-2 causes severe lung disease (COVID-19) in humans. Pruijssers et al. demonstrate that the antiviral drug remdesivir potently inhibits SARS-CoV-2 in human lung cell cultures. Therapeutic treatment of infected mice with remdesivir reduces viral loads and improves clinical outcomes, further supporting use of remdesivir for the treatment of COVID-19.