Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells PMID: 36323770

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
14. Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, 94720, USA. [email protected].
15. The Henry Wheeler Center for Emerging and Neglected Diseases, 344 Li Ka Shing, Berkeley, CA, 94720, USA. [email protected].
# 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.