Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells

Nguyenla, X.; Wehri, E.; Van Dis, E.; Biering, S.; Yamashiro, L. H.; Stroumza, J.; Dugast-Darzacq, C.; Graham, T.; Stanley, S.; Schaletzky, J.

doi:10.1101/2020.09.18.302398

bioRxiv · 10.1101/2020.09.18.302398

Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells

Nguyenla, X.·Wehri, E.·Van Dis, E.·Biering, S.·Yamashiro, L. H.·Stroumza, J.·Dugast-Darzacq, C.·Graham, T.·Stanley, S.·Schaletzky, J.

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Abstract

The SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with currently 29 million confirmed cases and close to a million deaths. At this time, there are no FDA-approved vaccines or therapeutics for COVID-19, but Emergency Use Authorization has been granted for remdesivir, a broad-spectrum antiviral nucleoside analog. However, remdesivir is only moderately efficacious against SARS-CoV-2 in the clinic, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. We identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5 A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivirs apparent potency 25-fold. We therefore suggest that the FDA-approved Hepatitis C therapeutics Epclusa (velpatasvir/sofosbuvir) and Zepatier (elbasvir/grazoprevir) should be fast-tracked for clinical evaluation in combination with remdesivir to improve treatment of acute SARS-CoV-2 infections.

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Nguyenla, X., Wehri, E., Van Dis, E., Biering, S., Yamashiro, L. H., Stroumza, J., Dugast-Darzacq, C., Graham, T., Stanley, S., Schaletzky, J.. 2020-09-18. Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells. https://doi.org/10.1101/2020.09.18.302398

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