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

Abstract

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 (3CL^pro) in a post-translational processing step that is critical for coronavirus replication. The 3CL^pro 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 3CL^pro employing ligand-protease structures solved by X-ray crystallography led to the identification of <b>3</b> and <b>4</b>. Preclinical experiments reveal <b>4</b> (<b>PF-00835231</b>) as a potent inhibitor of CoV-2 3CL^pro with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.