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 strateg...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-21034-5 |
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| author | 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. Näär Sarah Stanley Julia Schaletzky |
| author_facet | 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. Näär Sarah Stanley Julia Schaletzky |
| author_sort | Xammy Huu Wrynla |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9e4aeb4597b84bd5b8c7f7298e96338a |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-9e4aeb4597b84bd5b8c7f7298e96338a2025-08-20T04:01:35ZengNature PortfolioScientific Reports2045-23222022-11-0112111710.1038/s41598-022-21034-5Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cellsXammy Huu Wrynla0Eddie Wehri1Erik Van Dis2Scott B. Biering3Livia H. Yamashiro4Chi Zhu5Julien Stroumza6Claire Dugast-Darzacq7Thomas G. W. Graham8Xuanting Wang9Steffen Jockusch10Chuanjuan Tao11Minchen Chien12Wei Xie13Dinshaw J. Patel14Cindy Meyer15Aitor Garzia16Thomas Tuschl17James J. Russo18Jingyue Ju19Anders M. Näär20Sarah Stanley21Julia Schaletzky22Division of Infectious Diseases and Vaccinology, School of Public Health, University of CaliforniaThe Henry Wheeler Center for Emerging and Neglected DiseasesDepartment of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of CaliforniaDivision of Infectious Diseases and Vaccinology, School of Public Health, University of CaliforniaDivision of Infectious Diseases and Vaccinology, School of Public Health, University of CaliforniaDepartment of Nutritional Sciences & Toxicology, University of CaliforniaThe Henry Wheeler Center for Emerging and Neglected DiseasesDepartment of Molecular and Cell Biology, Division of Genetics, Genomics and Development, University of CaliforniaDepartment of Molecular and Cell Biology, Division of Genetics, Genomics and Development, University of CaliforniaCenter for Genome Technology and Biomolecular Engineering, Columbia UniversityCenter for Genome Technology and Biomolecular Engineering, Columbia UniversityCenter for Genome Technology and Biomolecular Engineering, Columbia UniversityCenter for Genome Technology and Biomolecular Engineering, Columbia UniversityLaboratory of Structural Biology, Memorial Sloan-Kettering Cancer CenterLaboratory of Structural Biology, Memorial Sloan-Kettering Cancer CenterLaboratory of RNA Molecular Biology, Rockefeller UniversityLaboratory of RNA Molecular Biology, Rockefeller UniversityLaboratory of RNA Molecular Biology, Rockefeller UniversityCenter for Genome Technology and Biomolecular Engineering, Columbia UniversityCenter for Genome Technology and Biomolecular Engineering, Columbia UniversityDepartment of Nutritional Sciences & Toxicology, University of CaliforniaDivision of Infectious Diseases and Vaccinology, School of Public Health, University of CaliforniaThe Henry Wheeler Center for Emerging and Neglected DiseasesAbstract 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.https://doi.org/10.1038/s41598-022-21034-5 |
| spellingShingle | 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. Näär Sarah Stanley Julia Schaletzky Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells Scientific Reports |
| title | Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells |
| title_full | Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells |
| title_fullStr | Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells |
| title_full_unstemmed | Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells |
| title_short | Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells |
| title_sort | discovery of sars cov 2 antiviral synergy between remdesivir and approved drugs in human lung cells |
| url | https://doi.org/10.1038/s41598-022-21034-5 |
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