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

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

  • J Med Chem. 2021 Dec 23;64(24):17846-17865. doi: 10.1021/acs.jmedchem.1c01037.
Chamandi S Dampalla 1,  Athri D Rathnayake 1,  Krishani Dinali Perera 2,  Abdul-Rahman M Jesri 1,  Harry Nhat Nguyen 1,  Matthew J Miller 1,  Hayden A Thurman 1,  Jian Zheng 3,  Maithri M Kashipathy 4,  Kevin P Battaile 5,  Scott Lovell 4,  Stanley Perlman 3,  Yunjeong Kim 2,  William C Groutas 1,  Kyeong-Ok Chang 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United States.
  • 2 Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United States.
  • 3 Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa 52242, United States.
  • 4 Protein Structure Laboratory, The University of Kansas, Lawrence, Kansas 66047, United States.
  • 5 NYX, New York Structural Biology Center, Upton, New York 11973, United States.
PMID: 34865476 DOI: 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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