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Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells.
Nguyenla, Xammy; Wehri, Eddie; Van Dis, Erik; Biering, Scott B; Yamashiro, Livia H; Zhu, Chi; Stroumza, Julien; Dugast-Darzacq, Claire; Graham, Thomas G W; 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.
  • Nguyenla X; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, 94720, USA.
  • Wehri E; The Henry Wheeler Center for Emerging and Neglected Diseases, 344 Li Ka Shing, Berkeley, CA, 94720, USA.
  • Van Dis E; Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, 94720, USA.
  • Biering SB; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, 94720, USA.
  • Yamashiro LH; Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, 94720, USA.
  • Zhu C; Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, 94720, USA.
  • Stroumza J; Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, 94720, USA.
  • Dugast-Darzacq C; Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA.
  • Graham TGW; The Henry Wheeler Center for Emerging and Neglected Diseases, 344 Li Ka Shing, Berkeley, CA, 94720, USA.
  • Wang X; Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, University of California, Berkeley, CA, 94720, USA.
  • Jockusch S; Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, University of California, Berkeley, CA, 94720, USA.
  • Tao C; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA.
  • Chien M; Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA.
  • Xie W; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA.
  • Patel DJ; Department of Chemistry, Columbia University, New York, NY, 10027, USA.
  • Meyer C; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA.
  • Garzia A; Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA.
  • Tuschl T; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA.
  • Russo JJ; Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA.
  • Ju J; Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
  • Näär AM; Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
  • Stanley S; Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY, 10065, USA.
  • Schaletzky J; Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY, 10065, USA.
Sci Rep ; 12(1): 18506, 2022 Nov 02.
Article in English | MEDLINE | ID: covidwho-2096786
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Hepatitis C / COVID-19 Drug Treatment Type of study: Experimental Studies / Prognostic study Limits: Humans Language: English Journal: Sci Rep Year: 2022 Document Type: Article Affiliation country: S41598-022-21034-5

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Hepatitis C / COVID-19 Drug Treatment Type of study: Experimental Studies / Prognostic study Limits: Humans Language: English Journal: Sci Rep Year: 2022 Document Type: Article Affiliation country: S41598-022-21034-5