Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3CL Protease.

Autor:	Dampalla CS; Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United States., Kim Y; Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United States., Bickmeier N; Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United States., Rathnayake AD; Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United States., Nguyen HN; Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United States., Zheng J; Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, United States., Kashipathy MM; Protein Structure Laboratory, The University of Kansas, Lawrence, Kansas 66047, United States., Baird MA; Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United States., Battaile KP; NYX, New York Structural Biology Center, Upton, New York 11973, United States., Lovell S; Protein Structure Laboratory, The University of Kansas, Lawrence, Kansas 66047, United States., Perlman S; Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, United States., Chang KO; Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United States., Groutas WC; Department of Chemistry, Wichita State University, Wichita, Kansas 67260, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Jul 22; Vol. 64 (14), pp. 10047-10058. Date of Electronic Publication: 2021 Jul 02.
DOI:	10.1021/acs.jmedchem.1c00319
Abstrakt:	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.
Databáze:	MEDLINE
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