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

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 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.
Competing Interest Statement
CUHK and HKU have filed a US provisional patent application based on the finding of this manuscript. W.L.N., M.C.W.C., K.P.Y.H., H.S.L., K.S.K., H.K. and H.M.L. are inventors of the patent. F.K.L.C. has served as a consultant to Eisai, Pfizer, Takeda and Otsuka, and has been paid lecture fees by Eisai, Pfizer, AstraZeneca and Takeda.
Footnotes
Updated RdRP assay data; provided additional RNA-seq results.
Subject Area
- Biochemistry (13876)
- Bioengineering (10577)
- Bioinformatics (33610)
- Biophysics (17319)
- Cancer Biology (14384)
- Cell Biology (20375)
- Clinical Trials (138)
- Developmental Biology (10988)
- Ecology (16218)
- Epidemiology (2067)
- Evolutionary Biology (20523)
- Genetics (13519)
- Genomics (18814)
- Immunology (13944)
- Microbiology (32523)
- Molecular Biology (13533)
- Neuroscience (70886)
- Paleontology (533)
- Pathology (2222)
- Pharmacology and Toxicology (3779)
- Physiology (5959)
- Plant Biology (12161)
- Synthetic Biology (3403)
- Systems Biology (8242)
- Zoology (1871)