tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 [/SUP], Eddie Wehri[SUP] #[/SUP][SUP] 2 [/SUP], Erik Van Dis[SUP] #[/SUP][SUP] 3 [/SUP], Scott B Biering[SUP] #[/SUP][SUP] 1 [/SUP], Livia H Yamashiro[SUP] #[/SUP][SUP] 1 3 [/SUP], Chi Zhu[SUP] 4 5 [/SUP], Julien Stroumza[SUP] 2 [/SUP], Claire Dugast-Darzacq[SUP] 6 [/SUP], Thomas G W Graham[SUP] 6 [/SUP], Xuanting Wang[SUP] 7 8 [/SUP], Steffen Jockusch[SUP] 7 9 [/SUP], Chuanjuan Tao[SUP] 7 8 [/SUP], Minchen Chien[SUP] 7 8 [/SUP], Wei Xie[SUP] 10 [/SUP], Dinshaw J Patel[SUP] 10 [/SUP], Cindy Meyer[SUP] 11 [/SUP], Aitor Garzia[SUP] 11 [/SUP], Thomas Tuschl[SUP] 11 [/SUP], James J Russo[SUP] 7 8 [/SUP], Jingyue Ju[SUP] 7 8 12 [/SUP], Anders M Näär[SUP] 4 5 [/SUP], Sarah Stanley[SUP] 13 14 [/SUP], Julia Schaletzky[SUP] 15 [/SUP]
Affiliations
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.
. 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[SUP] #[/SUP][SUP] 1 [/SUP], Eddie Wehri[SUP] #[/SUP][SUP] 2 [/SUP], Erik Van Dis[SUP] #[/SUP][SUP] 3 [/SUP], Scott B Biering[SUP] #[/SUP][SUP] 1 [/SUP], Livia H Yamashiro[SUP] #[/SUP][SUP] 1 3 [/SUP], Chi Zhu[SUP] 4 5 [/SUP], Julien Stroumza[SUP] 2 [/SUP], Claire Dugast-Darzacq[SUP] 6 [/SUP], Thomas G W Graham[SUP] 6 [/SUP], Xuanting Wang[SUP] 7 8 [/SUP], Steffen Jockusch[SUP] 7 9 [/SUP], Chuanjuan Tao[SUP] 7 8 [/SUP], Minchen Chien[SUP] 7 8 [/SUP], Wei Xie[SUP] 10 [/SUP], Dinshaw J Patel[SUP] 10 [/SUP], Cindy Meyer[SUP] 11 [/SUP], Aitor Garzia[SUP] 11 [/SUP], Thomas Tuschl[SUP] 11 [/SUP], James J Russo[SUP] 7 8 [/SUP], Jingyue Ju[SUP] 7 8 12 [/SUP], Anders M Näär[SUP] 4 5 [/SUP], Sarah Stanley[SUP] 13 14 [/SUP], Julia Schaletzky[SUP] 15 [/SUP]
Affiliations
- PMID: 36323770
- DOI: 10.1038/s41598-022-21034-5
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.