Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice
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Schäfer, Alexandra, et al. Therapeutic Treatment with an Oral Prodrug of the Remdesivir Parental Nucleoside Is Protective Against Sars-cov-2 Pathogenesis In Mice. 2022. https://doi.org/10.17615/4t8n-4568APA
Schäfer, A., Martinez, D., Won, J., Meganck, R., Moreira, F., Brown, A., Gully, K., Zweigart, M., Conrad, W., May, S., Dong, S., Kalla, R., Chun, K., Du Pont, V., Babusis, D., Tang, J., Murakami, E., Subramanian, R., Barrett, K., Bleier, B., Bannister, R., Feng, J., Bilello, J., Cihlar, T., Mackman, R., Montgomery, S., Baric, R., & Sheahan, T. (2022). Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice. https://doi.org/10.17615/4t8n-4568Chicago
Schäfer, Alexandra, David R Martinez, John J Won, Rita M Meganck, Fernando R Moreira, Ariane J Brown, Kendra L Gully et al. 2022. Therapeutic Treatment with an Oral Prodrug of the Remdesivir Parental Nucleoside Is Protective Against Sars-Cov-2 Pathogenesis In Mice. https://doi.org/10.17615/4t8n-4568- Creator
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Schäfer, Alexandra
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Martinez, David R.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Won, John J.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Meganck, Rita M.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Moreira, Fernando R.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Brown, Ariane J.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Gully, Kendra L.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Zweigart, Mark R.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Conrad, William S.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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May, Samantha R.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Dong, Stephanie
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Kalla, Rao
- Other Affiliation: Gilead Sciences, Inc
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Chun, Kwon
- Other Affiliation: Gilead Sciences, Inc
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Du Pont, Venice
- Other Affiliation: Gilead Sciences, Inc
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Babusis, Darius
- Other Affiliation: Gilead Sciences, Inc
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Tang, Jennifer
- Other Affiliation: Gilead Sciences, Inc
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Murakami, Eisuke
- Other Affiliation: Gilead Sciences, Inc
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Subramanian, Raju
- Other Affiliation: Gilead Sciences, Inc
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Barrett, Kimberly T.
- Other Affiliation: Gilead Sciences, Inc
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Bleier, Blake J.
- Other Affiliation: Gilead Sciences, Inc
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Bannister, Roy
- Other Affiliation: Gilead Sciences, Inc
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Feng, Joy Y.
- Other Affiliation: Gilead Sciences, Inc
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Bilello, John P.
- Other Affiliation: Gilead Sciences, Inc
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Cihlar, Tomas
- Other Affiliation: Gilead Sciences, Inc
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Mackman, Richard L.
- Other Affiliation: Gilead Sciences, Inc
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Montgomery, Stephanie A.
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
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Baric, Ralph S.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Sheahan, Timothy P.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
- Abstract
- The coronavirus disease 2019 (COVID-19) pandemic remains uncontrolled despite the rapid rollout of safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern, with their potential to escape neutralization by therapeutic monoclonal antibodies, emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parent nucleoside of remdesivir, which targets the highly conserved virus RNA-dependent RNA polymerase. GS-621763 exhibited antiviral activity against SARS-CoV-2 in lung cell lines and two different human primary lung cell culture systems. GS-621763 was also potently antiviral against a genetically unrelated emerging coronavirus, Middle East Respiratory Syndrome CoV (MERS-CoV). The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 administration reduced viral load and lung pathology; treatment also improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral which has recently received EUA approval, proved both drugs to be similarly efficacious in mice. These data support the exploration of GS-441524 oral prodrugs for the treatment of COVID-19.
- Date of publication
- 2022
- DOI
- Identifier
- Resource type
- Article
- Rights statement
- In Copyright
- Journal title
- Science Translational Medicine
- Page start
- eabm3410
- Language
- English
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