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Remdesivir potently 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 III, 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, View ORCID ProfileTimothy P. Sheahan
doi: https://doi.org/10.1101/2020.04.27.064279
Andrea J. Pruijssers
1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
2Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA
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  • For correspondence: ardina.pruijssers@vumc.org sheahan@email.unc.edu
Amelia S. George
1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
2Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA
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Alexandra Schäfer
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Sarah R. Leist
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Lisa E. Gralinksi
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Kenneth H. Dinnon III
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
4Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Boyd L. Yount
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Maria L. Agostini
1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
2Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA
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Laura J. Stevens
1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
2Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA
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James D. Chappell
1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
2Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA
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Xiaotao Lu
1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
2Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA
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Tia M. Hughes
1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
2Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA
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Kendra Gully
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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David R. Martinez
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Ariane J. Brown
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Rachel L. Graham
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Jason K. Perry
5Gilead Sciences, Inc, Foster City, CA, 94404, USA
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Venice Du Pont
5Gilead Sciences, Inc, Foster City, CA, 94404, USA
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Jared Pitts
5Gilead Sciences, Inc, Foster City, CA, 94404, USA
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Bin Ma
5Gilead Sciences, Inc, Foster City, CA, 94404, USA
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Darius Babusis
5Gilead Sciences, Inc, Foster City, CA, 94404, USA
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Eisuke Murakami
5Gilead Sciences, Inc, Foster City, CA, 94404, USA
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Joy Y. Feng
5Gilead Sciences, Inc, Foster City, CA, 94404, USA
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John P. Bilello
5Gilead Sciences, Inc, Foster City, CA, 94404, USA
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Danielle P. Porter
5Gilead Sciences, Inc, Foster City, CA, 94404, USA
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Tomas Cihlar
5Gilead Sciences, Inc, Foster City, CA, 94404, USA
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Ralph S. Baric
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
4Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Mark R. Denison
1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
2Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA
6Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
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Timothy P. Sheahan
3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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  • ORCID record for Timothy P. Sheahan
  • For correspondence: ardina.pruijssers@vumc.org sheahan@email.unc.edu
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SUMMARY

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent of the novel pandemic viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug of an adenosine analog, potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). Weaker activity was observed in Vero E6 cells (EC50 = 1.65 μM) due to 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 chimeric virus, therapeutic RDV administration diminished lung viral load and improved pulmonary function as compared to vehicle treated animals. These data provide evidence that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19.

Competing Interest Statement

The authors affiliated with Gilead Sciences, Inc. are employees of the company and own company stock. The other authors have no conflict of interest to report.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Remdesivir potently 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 III, 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
bioRxiv 2020.04.27.064279; doi: https://doi.org/10.1101/2020.04.27.064279
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Remdesivir potently 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 III, 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
bioRxiv 2020.04.27.064279; doi: https://doi.org/10.1101/2020.04.27.064279

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