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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 (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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Hoffman RL,Kania RS,Brothers MA,Davies JF,Ferre RA,Gajiwala KS,He M,Hogan RJ,Kozminski K,Li LY,Lockner JW,Lou J,Marra MT,Mitchell LJ Jr,Murray BW,Nieman JA,Noell S,Planken SP,Rowe T,Ryan K,Smith GJ 3rd,Solowiej

doi

10.1021/acs.jmedchem.0c01063

subject

Has Abstract

pub_date

2020-11-12 00:00:00

pages

12725-12747

issue

21

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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