Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells Journal Article
| Authors: | Nguyenla, X.; Wehri, E.; Van Dis, E.; Biering, S. B.; Yamashiro, L. H.; Zhu, C.; Stroumza, J.; Dugast-Darzacq, C.; Graham, T. G. W.; Wang, X.; Jockusch, S.; Tao, C.; Chien, M.; Xie, W.; Patel, D. J.; Meyer, C.; Garzia, A.; Tuschl, T.; Russo, J. J.; Ju, J.; Näär, A. M.; Stanley, S.; Schaletzky, J. |
| Article Title: | Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells |
| Abstract: | SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with significant mortality and morbidity. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, 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. This 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 5A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir’s apparent potency > 25-fold. We report that HCV NS5A inhibitors act on the SARS-CoV-2 exonuclease proofreader, providing a possible explanation for the synergy observed with nucleoside analog remdesivir. FDA-approved Hepatitis C therapeutics Epclusa® (velpatasvir/sofosbuvir) and Zepatier® (elbasvir/grazoprevir) could be further optimized to achieve potency and pharmacokinetic properties that support clinical evaluation in combination with remdesivir. © 2022, The Author(s). |
| Keywords: | hepatitis c; lung; antivirus agent; alanine; hepacivirus; nucleoside; antiviral agents; adenosine phosphate; adenosine monophosphate; nucleosides; humans; human; covid-19; sars-cov-2; remdesivir; sofosbuvir; grazoprevir; velpatasvir |
| Journal Title: | Scientific Reports |
| Volume: | 12 |
| ISSN: | 2045-2322 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-11-02 |
| Start Page: | 18506 |
| Language: | English |
| DOI: | 10.1038/s41598-022-21034-5 |
| PUBMED: | 36323770 |
| PROVIDER: | scopus |
| PMCID: | PMC9628577 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
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