Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir

  • ACS Cent Sci. 2021 May 26;7(5):792-802. doi: 10.1021/acscentsci.0c01186.
Ho Sing Lo  1 ,  Kenrie Pui Yan Hui  2  3 ,  Hei-Ming Lai  4  5  6 ,  Xu He  1 ,  Khadija Shahed Khan  1 ,  Simranjeet Kaur  7 ,  Junzhe Huang  5  6 ,  Zhongqi Li  5  6 ,  Anthony K N Chan  8 ,  Hayley Hei-Yin Cheung  9 ,  Ka-Chun Ng  2 ,  John Chi Wang Ho  2 ,  Yu Wai Chen  10 ,  Bowen Ma  1 ,  Peter Man-Hin Cheung  11 ,  Donghyuk Shin  12  13 ,  Kaidao Wang  14 ,  Meng-Hsuan Lee  15 ,  Barbara Selisko  16 ,  Cecilia Eydoux  16 ,  Jean-Claude Guillemot  16 ,  Bruno Canard  16 ,  Kuen-Phon Wu  15 ,  Po-Huang Liang  15 ,  Ivan Dikic  12 ,  Zhong Zuo  1 ,  Francis K L Chan  5  17 ,  David S C Hui  5  18 ,  Vincent C T Mok  5  19 ,  Kam-Bo Wong  9 ,  Chris Ka Pun Mok  20 ,  Ho Ko  4  5  6  19  21  22 ,  Wei Shen Aik  7 ,  Michael Chi Wai Chan  2  3 ,  Wai-Lung Ng  1
Affiliations
  • 1. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 2. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
  • 3. Centre for Immunology and Infection (C2I), Hong Kong Science Park, Hong Kong, SAR, China.
  • 4. Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 5. Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 6. Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 7. Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
  • 8. Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California 91010, United States.
  • 9. School of Life Sciences, Centre for Protein Science and Crystallography, State Key Laboratory of Agrobiotechnology, Faculty of Science, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 10. Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Hong Kong.
  • 11. School of Public Health, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 12. Buchmann Institute for Molecular Life Sciences, Goethe University, 60323 Frankfurt am Main, Germany.
  • 13. Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
  • 14. Protein Production Department, GenScript Biotech Corporation, Nanjing, Jiangsu Province 211100, China.
  • 15. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 115.
  • 16. Laboratoire d'Architecture et Fonction des Macromolécules Biologiques (AFMB), Centre National de la Recherche Scientifique, Aix-Marseille Université, 13007 Marseille, France.
  • 17. Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 18. Stanley Ho Center for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 19. Gerald Choa Neuroscience Centre, Margaret K. L. Cheung Research Centre for Management of Parkinsonism, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 20. HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Shatin, Hong Kong.
  • 21. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 22. Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
PMID: 34075346 DOI: 10.1021/acscentsci.0c01186
Abstract

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro. Mechanistically, we showed that simeprevir not only inhibits the main protease (Mpro) and unexpectedly the RNA-dependent RNA polymerase (RdRp) but also modulates host immune responses. Our results thus reveal the possible anti-SARS-CoV-2 mechanism of simeprevir and highlight the translational potential of optimizing simeprevir as a therapeutic agent for managing COVID-19 and future outbreaks of CoV.

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