Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19

The novel coronavirus disease COVID-19
that emerged in 2019 is
caused by the virus SARS CoV-2 and named for its close genetic similarity
to SARS CoV-1 that caused severe acute respiratory syndrome (SARS)
in 2002. Both SARS coronavirus genomes encode two overlapping large
polyproteins, which are cleaved at specific sites by a 3C-like cysteine
protease (3CLpro) in a post-translational processing step
that is critical for coronavirus replication. The 3CLpro sequences for CoV-1 and CoV-2 viruses are 100% identical in the
catalytic domain that carries out protein cleavage. A research effort
that focused on the discovery of reversible and irreversible ketone-based
inhibitors of SARS CoV-1 3CLpro employing ligand-protease
structures solved by X-ray crystallography led to the identification
of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2
3CLpro with suitable pharmaceutical properties to warrant
further development as an intravenous treatment for COVID-19.