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

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Sci Rep


. 2022 Nov 2;12(1):18506.
doi: 10.1038/s41598-022-21034-5.
Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells


Xammy Nguyenla ^{# 1} , Eddie Wehri ^{# 2} , Erik Van Dis ^{# 3} , Scott B Biering ^{# 1} , Livia H Yamashiro ^{# 1 3} , Chi Zhu ^{4 5} , Julien Stroumza ² , Claire Dugast-Darzacq ⁶ , Thomas G W Graham ⁶ , Xuanting Wang ^{7 8} , Steffen Jockusch ^{7 9} , Chuanjuan Tao ^{7 8} , Minchen Chien ^{7 8} , Wei Xie ¹⁰ , Dinshaw J Patel ¹⁰ , Cindy Meyer ¹¹ , Aitor Garzia ¹¹ , Thomas Tuschl ¹¹ , James J Russo ^{7 8} , Jingyue Ju ^{7 8 12} , Anders M Näär ^{4 5} , Sarah Stanley ^{13 14} , Julia Schaletzky ¹⁵



Affiliations

• PMID: 36323770
• DOI: 10.1038/s41598-022-21034-5

Free article

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.