PT  - JOURNAL ARTICLE
AU  - Ma, Chunlong
AU  - Hurst, Brett
AU  - Hu, Yanmei
AU  - Szeto, Tommy
AU  - Tarbet, Bart
AU  - Wang, Jun
TI  - Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
AID  - 10.1101/2020.04.20.051581
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.20.051581
4099  - http://biorxiv.org/content/early/2020/04/20/2020.04.20.051581.short
4100  - http://biorxiv.org/content/early/2020/04/20/2020.04.20.051581.full
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.