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

Andrea J Pruijssers; Amelia S George; Alexandra Schäfer; Sarah R Leist; Lisa E Gralinksi; Kenneth H Dinnon 3rd; Boyd L Yount; Maria L Agostini; Laura J Stevens; James D Chappell; Xiaotao Lu; Tia M Hughes; Kendra Gully; David R Martinez; Ariane J Brown; Rachel L Graham; Jason K Perry; Venice Du Pont; Jared Pitts; Bin Ma; Darius Babusis; Eisuke Murakami; Joy Y Feng; John P Bilello; Danielle P Porter; Tomas Cihlar; Ralph S Baric; Mark R Denison; Timothy P Sheahan

doi:10.1016/j.celrep.2020.107940

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

Cell Rep. 2020 Jul 21;32(3):107940. doi: 10.1016/j.celrep.2020.107940. Epub 2020 Jul 7.

Authors

Andrea J Pruijssers¹, Amelia S George², Alexandra Schäfer³, Sarah R Leist³, Lisa E Gralinksi³, Kenneth H Dinnon 3rd⁴, Boyd L Yount³, Maria L Agostini², Laura J Stevens², James D Chappell², Xiaotao Lu², Tia M Hughes², Kendra Gully³, David R Martinez³, Ariane J Brown³, Rachel L Graham³, Jason K Perry⁵, Venice Du Pont⁵, Jared Pitts⁵, Bin Ma⁵, Darius Babusis⁵, Eisuke Murakami⁵, Joy Y Feng⁵, John P Bilello⁵, Danielle P Porter⁵, Tomas Cihlar⁵, Ralph S Baric⁴, Mark R Denison⁶, Timothy P Sheahan⁷

Affiliations

¹ Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN 37232, USA. Electronic address: [email protected].
² Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN 37232, USA.
³ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Gilead Sciences, Inc., Foster City, CA 94404, USA.
⁶ Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁷ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: [email protected].

Abstract

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.

Keywords: COVID-19; GS-441524; RNA-dependent RNA polymerase; RdRp; SARS-CoV-2; antiviral; coronavirus; mouse; remdesivir; therapeutic.

Abstract

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