Exploration of PROTAC technology for the development of broad-spectrum antiviral drugs to trigger the proteolysis of the main viral protease

In 2020, with the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, PROteolysis TArgeting Chimera (PROTAC) degraders acting against the major viral protease 3-chymotrypsin-like protease (3CLPro) were hypothesized to be next-generation anti-coronavirus drugs. 3CLPro is shared by all coronavirus genera as well as by members of the large genus Enterovirus in the Picornavirus family. Combining NMR spectroscopy and X-ray crystallography, we characterize the interaction between our α, β-unsaturated peptidomimetic-based PROTAC with 3CLPro from SARS-CoV-2 and 3CPro from Coxsackievirus B3 (CVB3), the latter being a cardiotropic virus belonging to the Enterovirus genus. The results are compared with those obtained with the PROTAC precursor molecule. Finally, preliminary cellular studies show that the synthetized PROTAC molecule drastically reduces protein levels of SARS-CoV-2 3CLPro in cultured cells.