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JMC submission_COVID19_manuscript.pdf (1.45 MB)

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

submitted on 09.07.2020, 15:17 and posted on 22.07.2020, 10:24 by Robert Hoffman, Robert S. Kania, Mary A. Brothers, Jay F. Davies, Rose A. Ferre, Ketan S. Gajiwala, Mingying He, Robert Jeff Hogan, Kirk Kozminski, Lilian Y. Li, Jonathan W. Lockner, Jihong Lou, Michelle T. Marra, Lennert J. Mitchell 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, Barbara Taggart
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 cysteine 3C-like 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.


Email Address of Submitting Author


Pfizer, inc


United States of America

ORCID For Submitting Author


Declaration of Conflict of Interest

No conflicts of Interest

Version Notes

This version of the manuscript is currently under review by the Journal of Medicinal Chemistry. Upon publication a link to the publlished paper via the Digital Object Identified (DOI) will be provided.