Structure-guided design of potent inhibitors of SARS-CoV-2 3CL protease: Structural, biochemical, and cell-based studies

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Authors
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.
Advisors
Issue Date
2021-12-01
Type
Article
Keywords
SARS-CoV-2 , Assays , Inhibitors , Alcohols , Peptides and proteins
Research Projects
Organizational Units
Journal Issue
Citation
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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Description
This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Publisher
American Chemical Society
Journal
Book Title
Series
Journal of Medicinal Chemistry;
PubMed ID
DOI
ISSN
0022-2623
1520-4804
EISSN