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

Autor: Xammy Nguyenla, 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. Näär, Sarah Stanley, Julia Schaletzky
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Scientific Reports, Vol 12, Iss 1, Pp 1-17 (2022)
Druh dokumentu: article
ISSN: 2045-2322
DOI: 10.1038/s41598-022-21034-5
Popis: 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.
Databáze: Directory of Open Access Journals
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