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

  • J Med Chem. 2020 Nov 12;63(21):12725-12747. doi: 10.1021/acs.jmedchem.0c01063.
Robert L Hoffman  1 ,  Robert S Kania  1 ,  Mary A Brothers  1 ,  Jay F Davies  1 ,  Rose A Ferre  1 ,  Ketan S Gajiwala  1 ,  Mingying He  1 ,  Robert J Hogan  2 ,  Kirk Kozminski  1 ,  Lilian Y Li  1 ,  Jonathan W Lockner  1 ,  Jihong Lou  1 ,  Michelle T Marra  1 ,  Lennert J Mitchell Jr  1 ,  Brion W Murray  1 ,  James A Nieman  1 ,  Stephen Noell  1 ,  Simon P Planken  1 ,  Thomas Rowe  2 ,  Kevin Ryan  1 ,  George J Smith 3rd  1 ,  James E Solowiej  1 ,  Claire M Steppan  1 ,  Barbara Taggart  2
Affiliations
  • 1. Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121 United States.
  • 2. Southern Research Institute, 2000 9th Avenue South, Birmingham, Alabama 35205 United States.
PMID: 33054210 DOI: 10.1021/acs.jmedchem.0c01063
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 (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.

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