Remdesivir Metabolite GS-441524 Efficiently Inhibits SARS-CoV-2 Infection in Mouse Model

Li, Y.; Cao, L.; Li, G.; Cong, F.; Sun, J.; Luo, Y.; Chen, G.; Wang, P.; Xing, F.; Ji, Y.; Zhao, J.; Zhang, Y.; Guo, D.; Zhang, X.

doi:10.1101/2020.10.26.353300

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bioRxiv · 10.1101/2020.10.26.353300

Remdesivir Metabolite GS-441524 Efficiently Inhibits SARS-CoV-2 Infection in Mouse Model

Li, Y.·Cao, L.·Li, G.·Cong, F.·Sun, J.·Luo, Y.·Chen, G.·Wang, P.·Xing, F.·Ji, Y.·Zhao, J.·Zhang, Y.·Guo, D.·Zhang, X.

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Abstract

The outbreak of coronavirus disease 2019 (COVID-19) rapidly spreads across worldwide and becomes a global pandemic. Remdesivir is the only COVID-19 treatment approved by U.S. Food and Drug Administration (FDA); however, its effectiveness is still under questioning as raised by the results of a large WHO Solidarity Trial. Herein, we report that the parent nucleotide of remdesivir, GS-441524, potently inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero E6 and other cells. It exhibits good plasma distribution and longer half-life (t1/2=4.8h) in rat PK study. GS-441524 is highly efficacious against SARS-CoV-2 in AAV-hACE2 transduced mice and murine hepatitis virus (MHV) in mice, reducing the viral titers in CoV-attacked organs, without noticeable toxicity. Given that GS-441524 was the predominant metabolite of remdesivir in the plasma, the anti-COVID-19 effect of remdesivir may partly come from the effect of GS-441524. Our results also supported that GS-441524 as a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases.

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Li, Y., Cao, L., Li, G., Cong, F., Sun, J., Luo, Y., Chen, G., Wang, P., Xing, F., Ji, Y., Zhao, J., Zhang, Y., Guo, D., Zhang, X.. 2020-10-27. Remdesivir Metabolite GS-441524 Efficiently Inhibits SARS-CoV-2 Infection in Mouse Model. https://doi.org/10.1101/2020.10.26.353300

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