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.
【초록키워드】 COVID-19, SARS-CoV-2, Efficacy, Mortality, Antiviral, antivirals, Remdesivir, drug, virus, HCV, global pandemic, Protein, clinical evaluation, human lung, morbidity, therapeutic, hepatitis C, SARS Coronavirus, inhibitor, synergy, moderate, SARS-CoV-2 replication, pharmacokinetic, exonuclease, Combination, treatment strategy, Support, approved drug, Compound, profiles, NS5A, Effect, concentrations, identify, caused, conducted, epithelial cell line, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, Antiviral, Remdesivir, synergy, approved drug, human lung cell,