PT  - JOURNAL ARTICLE
AU  - Wayne Vuong
AU  - Muhammad Bashir Khan
AU  - Conrad Fischer
AU  - Elena Arutyunova
AU  - Tess Lamer
AU  - Justin Shields
AU  - Holly A. Saffran
AU  - Ryan T. McKay
AU  - Marco J. van Belkum
AU  - Michael Joyce
AU  - Howard S. Young
AU  - D. Lorne Tyrrell
AU  - John C. Vederas
AU  - M. Joanne Lemieux
TI  - Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
AID  - 10.1101/2020.05.03.073080
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.03.073080
4099  - http://biorxiv.org/content/early/2020/05/05/2020.05.03.073080.short
4100  - http://biorxiv.org/content/early/2020/05/05/2020.05.03.073080.full
AB  - The COVID-19 pandemic, attributed to the SARS-CoV-2 coronavirus infection, resulted in millions infected worldwide and an immediate need for antiviral treatments. The main protease (Mpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide and subsequent viral replication. Feline infectious peritonitis, a fatal infection in cats caused by a coronavirus, was successfully treated previously with a dipeptide-based protease inhibitor. Here we show this drug, GC376, and its analog GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of the SARS-CoV and SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 in cell culture, with EC50 values near one micromolar and little to no toxicity. These protease inhibitors are soluble, non-toxic, and bind reversibly. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals (cats). The work here lays the framework for their use in human trials for the treatment of COVID-19.Competing Interest StatementThe authors have declared no competing interest.