Lo HS, Hui KPY, Lai HM, He X, Khan KS, Kaur S, Huang J, Li Z, Chan AKN, Cheung HH, Ng KC, Ho JCW, Chen YW, Ma B, Cheung PM, Shin D, Wang K, Lee MH, Selisko B, Eydoux C, Guillemot JC, Canard B, Wu KP, Liang PH, Dikic I, Zuo Z, Chan FKL, Hui DSC, Mok VCT, Wong KB, Mok CKP, Ko H, Aik WS, Chan MCW, Ng WL
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.