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

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

  • Sci Rep. 2022 Nov 2;12(1):18506. doi: 10.1038/s41598-022-21034-5.
Xammy Nguyenla # 1 Eddie Wehri # 2 Erik Van Dis # 3 Scott B Biering # 1 Livia H Yamashiro # 1 3 Chi Zhu 4 5 Julien Stroumza 2 Claire Dugast-Darzacq 6 Thomas G W Graham 6 Xuanting Wang 7 8 Steffen Jockusch 7 9 Chuanjuan Tao 7 8 Minchen Chien 7 8 Wei Xie 10 Dinshaw J Patel 10 Cindy Meyer 11 Aitor Garzia 11 Thomas Tuschl 11 James J Russo 7 8 Jingyue Ju 7 8 12 Anders M Näär 4 5 Sarah Stanley 13 14 Julia Schaletzky 15
Affiliations

Affiliations

  • 1 Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, 94720, USA.
  • 2 The Henry Wheeler Center for Emerging and Neglected Diseases, 344 Li Ka Shing, Berkeley, CA, 94720, USA.
  • 3 Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, 94720, USA.
  • 4 Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, 94720, USA.
  • 5 Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA.
  • 6 Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, University of California, Berkeley, CA, 94720, USA.
  • 7 Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA.
  • 8 Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA.
  • 9 Department of Chemistry, Columbia University, New York, NY, 10027, USA.
  • 10 Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
  • 11 Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY, 10065, USA.
  • 12 Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, 10032, USA.
  • 13 Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, 94720, USA. sastanley@berkeley.edu.
  • 14 Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, 94720, USA. sastanley@berkeley.edu.
  • 15 The Henry Wheeler Center for Emerging and Neglected Diseases, 344 Li Ka Shing, Berkeley, CA, 94720, USA. jschaletzky@berkeley.edu.
  • # Contributed equally.
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.

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