Simeprevir potently suppresses SARS-CoV-2 replication and synergizes with remdesivir

  1. Ho Sing Lo
  2. Kenrie Pui Yan Hui
  3. Hei-Ming Lai
  4. Khadija Shahed Khan
  5. Simranjeet Kaur
  6. Junzhe Huang
  7. Zhongqi Li
  8. Anthony K. N. Chan
  9. Hayley Hei-Yin Cheung
  10. Ka-Chun Ng
  11. John Chi Wang Ho
  12. Yu Wai Chen
  13. Bowen Ma
  14. Peter Man-Hin Cheung
  15. Donghyuk Shin
  16. Kaidao Wang
  17. Meng-Hsuan Lee
  18. Barbara Selisko
  19. Cecilia Eydoux
  20. Jean-Claude Guillemot
  21. Bruno Canard
  22. Kuen-Phon Wu
  23. Po-Huang Liang
  24. Ivan Dikic
  25. Zhong Zuo
  26. Francis K. L. Chan
  27. David S. C. Hui
  28. Vincent C. T. Mok
  29. Kam-Bo Wong
  30. Ho Ko
  31. Wei Shen Aik
  32. Michael Chi Wai Chan
  33. Wai-Lung Ng
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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 remdesivirin vitro. Mechanistically, we showed that simeprevir inhibits the main protease (Mpro) and unexpectedly the RNA-dependent RNA polymerase (RdRp). Our results thus reveal the viral protein targets of simeprevir, and provide preclinical rationale for the combination of simeprevir and remdesivir for the pharmacological management of COVID-19 patients.

One Sentence Summary

Discovery of simeprevir as a potent suppressor of SARS-CoV-2 viral replication that synergizes with remdesivir.

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