Coronavirus Inhibitors

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.

Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19
Robert L. Hoffman*, Robert S. Kania, Mary A. Brothers, Jay F. Davies, Rose A. Ferre, Ketan S. Gajiwala, Mingying He, Robert J. Hogan, Kirk Kozminski, Lilian Y. Li, Jonathan W. Lockner, Jihong Lou, Michelle T. Marra, Lennert J. Mitchell Jr., Brion W. Murray, James A. Nieman, Stephen Noell, Simon P. Planken, Thomas Rowe, Kevin Ryan, George J. Smith III, James E. Solowiej, Claire M. Steppan, and Barbara Taggart
J. Med. Chem. 2020, 63, 21, 12725–12747

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