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

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

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.

Figures
Products