Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies

Chamandi S Dampalla; Athri D Rathnayake; Krishani Dinali Perera; Abdul-Rahman M Jesri; Harry Nhat Nguyen; Matthew J Miller; Hayden A Thurman; Jian Zheng; Maithri M Kashipathy; Kevin P Battaile; Scott Lovell; Stanley Perlman; Yunjeong Kim; William C Groutas; Kyeong-Ok Chang

doi:10.1021/acs.jmedchem.1c01037

Back

Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies

Journal article

Peer reviewed

Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies

Chamandi S Dampalla, Athri D Rathnayake, Krishani Dinali Perera, Abdul-Rahman M Jesri, Harry Nhat Nguyen, Matthew J Miller, Hayden A Thurman, Jian Zheng, Maithri M Kashipathy, Kevin P Battaile, …

Journal of medicinal chemistry, Vol.64(24)

12/05/2021

DOI: 10.1021/acs.jmedchem.1c01037

PMCID: PMC8673480

PMID: 34865476

Files and links (1)

url

https://www.osti.gov/biblio/1859294View

Open Access

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.

COVID-19

pandemic

Details

Title: Subtitle: Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies
Creators: Chamandi S Dampalla - Wichita State University
Athri D Rathnayake - Wichita State University
Krishani Dinali Perera - Kansas State University
Abdul-Rahman M Jesri - Wichita State University
Harry Nhat Nguyen - Wichita State University
Matthew J Miller - Wichita State University
Hayden A Thurman - Wichita State University
Jian Zheng - University of Iowa
Maithri M Kashipathy - University of Kansas
Kevin P Battaile - New York Structural Biology Center
Scott Lovell - University of Kansas
Stanley Perlman - University of Iowa
Yunjeong Kim - Kansas State University
William C Groutas - Wichita State University
Kyeong-Ok Chang - Kansas State University
Resource Type: Journal article
Publication Details: Journal of medicinal chemistry, Vol.64(24)
DOI: 10.1021/acs.jmedchem.1c01037
PMID: 34865476
PMCID: PMC8673480
NLM abbreviation: J Med Chem
ISSN: 0022-2623
eISSN: 1520-4804
Grant note: DOI: 10.13039/100000009, name: Foundation for the National Institutes of Health, award: R01 AI109039, S10RR024664; DOI: 10.13039/100006132, name: Office of Science, award: DE-AC02-06CH11357, DE-SC0012704; DOI: 10.13039/100000015, name: U.S. Department of Energy, award: KP1605010; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: P30GM110761, P30GM133893; DOI: 10.13039/100000001, name: National Science Foundation, award: 1625923; name: Hauptman-Woodward Medical Research Institute
Language: English
Date published: 12/05/2021
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9984201535602771

Metrics

21 Record Views

29 Times Cited - Web of Science