Structure-guided design of potent inhibitors of SARS-CoV-2 3CL protease: Structural, biochemical, and cell-based studies
Date
2021-12-01Author
Dampalla, Chamandi S.
Rathnayake, Athri D.
Perera, Krishani Dinali
Jesri, Abdul Rahman M.
Nguyen, Harry Nhat
Miller, Matthew J.
Thurman, Hayden A.
Zheng, Jian
Kashipathy, Maithri M.
Battaile, Kevin P.
Lovell, Scott
Perlman, Stanley
Metadata
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J. Med. Chem. 2021, 64, 24, 17846–17865 Publication Date:December 5, 2021 https://doi.org/10.1021/acs.jmedchem.1c01037
Abstract
The COVID-19 pandemic is having a major impact on public health worldwide, and there is an urgent need for the creation of an armamentarium of effective therapeutics, including vaccines, biologics, and small-molecule therapeutics, to combat SARS-CoV-2 and emerging variants. Inspection of the virus life cycle reveals multiple viral- and host-based choke points that can be exploited to combat the virus. SARS-CoV-2 3C-like protease (3CLpro), an enzyme essential for viral replication, is an attractive target for therapeutic intervention, and the design of inhibitors of the protease may lead to the emergence of effective SARS-CoV-2-specific antivirals. We describe herein the results of our studies related to the application of X-ray crystallography, the Thorpe–Ingold effect, deuteration, and stereochemistry in the design of highly potent and nontoxic inhibitors of SARS-CoV-2 3CLpro.
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