2. Academic Validation
  3. Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir

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

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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