RT Journal Article
SR Electronic
T1 Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.20.051581
DO 10.1101/2020.04.20.051581
A1 Ma, Chunlong
A1 Hurst, Brett
A1 Hu, Yanmei
A1 Szeto, Tommy
A1 Tarbet, Bart
A1 Wang, Jun
YR 2020
UL http://biorxiv.org/content/early/2020/04/20/2020.04.20.051581.abstract
AB A novel coronavirus SARS-CoV-2, also called novel coronavirus 2019 (nCoV-19), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.4% as of April 15, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (Mpro). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, calpain inhibitors II, XII, and MG-132 were identified to have potent activity with single-digit to submicromolar IC50 values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies and thermal shift binding assays. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC50 values ranging from 0.49 to 3.37 μM. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known Mpro inhibitors. Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics.Competing Interest StatementJ. W. and C. M. are inventors of a pending patent that claims the use of the identified compounds for COVID-19.