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

Lo, Ho Sing; Hui, Kenrie Pui Yan; Lai, Hei-Ming; He, Xu; Khan, Khadija Shahed; Kaur, Simranjeet; Huang, Junzhe; Li, Zhongqi; Chan, Anthony K. N.; Cheung, Hayley Hei-Yin; Ng, Ka-Chun; Ho, John Chi Wang; Chen, Yu Wai; Ma, Bowen; Cheung, Peter Man-Hin; Shin, Donghyuk; Wang, Kaidao; Lee, Meng-Hsuan; Selisko, Barbara; Eydoux, Cecilia; Guillemot, Jean-Claude; Canard, Bruno; Wu, Kuen-Phon; Liang, Po-Huang; Dikic, Ivan; Zuo, Zhong; Chan, Francis K. L.; Hui, David S. C.; Mok, Vincent C. T.; Wong, Kam-Bo; Mok, Chris Ka Pun; Ko, Ho; Aik, Wei Shen; Chan, Michael Chi Wai; Ng, Wai-Lung

[Image: see text] 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 (M(pro)) 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.