Journal article
Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus‑2 3CL Protease
Journal of medicinal chemistry, Vol.64(14), pp.10047-10058
07/02/2021
DOI: 10.1021/acs.jmedchem.1c00319
PMID: 34213885
Abstract
A series of nondeuterated and deuterated dipeptidyl aldehyde and masked aldehyde inhibitors that incorporate in their structure a conformationally constrained cyclohexane moiety was synthesized and found to potently inhibit severe acute respiratory syndrome coronavirus-2 3CL protease in biochemical and cell-based assays. Several of the inhibitors were also found to be nanomolar inhibitors of Middle East respiratory syndrome coronavirus 3CL protease. The corresponding latent aldehyde bisulfite adducts were found to be equipotent to the precursor aldehydes. High-resolution cocrystal structures confirmed the mechanism of action and illuminated the structural determinants involved in binding. The spatial disposition of the compounds disclosed herein provides an effective means of accessing new chemical space and optimizing pharmacological activity. The cellular permeability of the identified inhibitors and lack of cytotoxicity warrant their advancement as potential therapeutics for COVID-19.
Details
- Title: Subtitle
- Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus‑2 3CL Protease
- Creators
- Chamandi S Dampalla - Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United StatesYunjeong Kim - Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United StatesNaemi Bickmeier - Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United StatesAthri D Rathnayake - Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United StatesHarry Nhat Nguyen - Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United StatesJian Zheng - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, United StatesMaithri M Kashipathy - Protein Structure Laboratory, The University of Kansas, Lawrence, Kansas 66047, United StatesMatthew A Baird - Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United StatesKevin P Battaile - NYX, New York Structural Biology Center, Upton, New York 11973, United StatesScott Lovell - Protein Structure Laboratory, The University of Kansas, Lawrence, Kansas 66047, United StatesStanley Perlman - Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, United StatesKyeong-Ok Chang - Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United StatesWilliam C Groutas - Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United States
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.64(14), pp.10047-10058
- Publisher
- American Chemical Society
- DOI
- 10.1021/acs.jmedchem.1c00319
- PMID
- 34213885
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Grant note
- DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases, award: P01 AI060699, R01 AI109039, R01 AI129269
- Language
- English
- Date published
- 07/02/2021
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
- Record Identifier
- 9984095142602771
Metrics
20 Record Views