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Scientific Reports

Scientific Reports

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

Published:2 November 2022 DOI: 10.1038/s41598-022-21034-5 PMID: 36323770
Xammy Huu Wrynla,?Eddie Wehri,?Erik Van Dis,?Scott B Biering,?Livia H Yamashiro,?Chi Zhu,?Julien Stroumza,?Claire Dugast-Darzacq,?Thomas G W Graham,?Xuanting Wang,?Steffen Jockusch,?Chuanjuan Tao,?Minchen Chien,?Wei Xie,?Dinshaw J Patel,?Cindy Meyer,?Aitor Garzia,?Thomas Tuschl,?James J Russo,?Jingyue Ju,?Anders M N??r,?Sarah Stanley,?Julia Schaletzky

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.

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Materials Related products
Procduct Name CAS Molecular Formula Supplier Price
Remdesivir 1809249-37-3 C27H35N6O8P 366 suppliers $10.00-$13340.00
Remdesivir 1809249-37-3 C27H35N6O8P 366 suppliers $10.00-$13340.00
Remdesivir 1809249-37-3 C27H35N6O8P 366 suppliers $10.00-$13340.00
Remdesivir 1809249-37-3 C27H35N6O8P 366 suppliers $10.00-$13340.00
GS 5734 1809249-37-3 C27H35N6O8P - Inquiry
GS 5734 1809249-37-3 C27H35N6O8P - Inquiry

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