Brent Stockwell - May 6, 2020

Brent R. Stockwell, PhD, "Discovery and development of SARS-CoV-2 3CL protease inhibitors"

Professor Brent Stockwell introduced new results in a collaborative effort to develop small molecule inhibitors for 3CL protease, the main protease involved in SARS-CoV-2 viral replication. Viral protease inhibitors have been successful therapies for viral infections such as HIV and HCV (hepatitis C virus). SARS-CoV-2 generates two large polyproteins, which must be cleaved at 11 different sites by a chymotrypsin-like cysteine protease known as 3CL (also called Main protease). Importantly, the 3CL substrate binding pocket is similar across 12 different coronaviruses. The group has been focusing on compound 18, as well as GC376 and ebselen, as potential protease inhibitors for SARS-CoV-2. Compound 18 is a modified form of a peptidic inhibitor developed for rhinovirus 3C proteases in the 1990s, and it has activity against coronaviruses, but is inactive against the 2003 SARS-CoV. GC376 is currently in development for feline coronavirus infection, and ebselen is a small molecule that has been tested in clinical studies for hearing loss and reacts covalently with some cystein containing proteins. They tested these 3 compounds with bacterially expressed and purified 3CL SARS-CoV-2 protease using a fluorescent peptide substrate, and found that all three inhibit 3CL protease activity. They also tested for drug stability and found that compound 18 and GC376 are stable in human plasma, although only GC376 is stable in mouse plasma and mouse liver microsomes. Finally, they also found that compound 18, GC376, and ebselen inhibit SARS-CoV-2 viral infection in cell culture. They are optimistic that SARS-CoV-2 3CL protease is amenable to covalent inhibition with small molecules, and hope to modify compound 18, GC376 or ebselen into a clinical candidate with good drug-like properties as treatment for COVID-19.