Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells
| Autor: | Nguyenla, Xammy, Wehri, Eddie, Van Dis, Erik, Biering, Scott B, Yamashiro, Livia H, Zhu, Chi, Stroumza, Julien, Dugast-Darzacq, Claire, Graham, Thomas GW, Wang, Xuanting, Jockusch, Steffen, Tao, Chuanjuan, Chien, Minchen, Xie, Wei, Patel, Dinshaw J, Meyer, Cindy, Garzia, Aitor, Tuschl, Thomas, Russo, James J, Ju, Jingyue, Näär, Anders M, Stanley, Sarah, Schaletzky, Julia |
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| Rok vydání: | 2022 |
| Předmět: |
Chronic Liver Disease and Cirrhosis
Hepacivirus Antiviral Agents Hepatitis Vaccine Related Hepatitis - C Biodefense Humans Lung Cancer Alanine Multidisciplinary SARS-CoV-2 Prevention Liver Disease Lung Cancer Nucleosides Pneumonia Hepatitis C Adenosine Monophosphate COVID-19 Drug Treatment Infectious Diseases Emerging Infectious Diseases Good Health and Well Being 5.1 Pharmaceuticals Pneumonia & Influenza Development of treatments and therapeutic interventions Sofosbuvir Digestive Diseases Infection |
| Zdroj: | Scientific reports, vol 12, iss 1 |
| ISSN: | 2045-2322 |
| Popis: | 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: | OpenAIRE |
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