Simeprevir Potently Suppresses SARS-CoV‑2 Replication\nand Synergizes with Remdesivir
Ho Sing Lo, Kenrie Pui Yan Hui, H. M. Lai, Xu He (685343), Khadija Shahed Khan, Simranjeet Kaur, Junzhe Huang, Zhongqi Li, Anthony Chan, Hayley Hei-Yin Cheung, Ka‐Chun Ng, John Chi Wang Ho, Yu Wai Chen, Bowen Ma, Peter Man-Hin Cheung, Dong Hyuk Shin, Kaidao Wang, Meng-Hsuan Lee, Barbara Selisko, Cécilia Eydoux, Jean‐Claude Guillemot, Bruno Canard, Kuen‐Phon Wu, Po‐Huang Liang, Ivan Đikić, Zhong Zuo, Francis K.L. Chan, David S.C. Hui, Vincent Mok, Kam‐Bo Wong, Chris Ka Pun Mok (7538165), Ho Ko, Wei Shen Aik, Michael C. W. Chan, Wai‐Lung Ng
Abstract
The outbreak of coronavirus\ndisease 2019 (COVID-19), caused by\nthe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),\nis a global threat to human health. Using a multidisciplinary approach,\nwe identified and validated the hepatitis C virus (HCV) protease inhibitor\nsimeprevir as an especially promising repurposable drug for treating\nCOVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple\norders of magnitude and synergizes with remdesivir <i>in vitro</i>. Mechanistically, we showed that simeprevir not only inhibits the\nmain protease (M<sup>pro</sup>) and unexpectedly the RNA-dependent\nRNA polymerase (RdRp) but also modulates host immune responses. Our\nresults thus reveal the possible anti-SARS-CoV-2 mechanism of simeprevir\nand highlight the translational potential of optimizing simeprevir\nas a therapeutic agent for managing COVID-19 and future outbreaks\nof CoV.