Structure-guided design of conformationally constrained cyclohexane inhibitors of severe acute respiratory syndrome coronavirus-2 3cl protease

dc.contributor.authorDampalla, Chamandi S.
dc.contributor.authorKim, Yunjeong
dc.contributor.authorBickmeier, Naemi
dc.contributor.authorRathnayake, Athri D.
dc.date.accessioned2021-08-14T23:24:15Z
dc.date.available2021-08-14T23:24:15Z
dc.date.issued2021-07-01
dc.descriptionThis 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 pandemicen_US
dc.description.abstractA 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.en_US
dc.description.sponsorshipThis research was supported in part by grants from the National Institutes of Health (NIH) (R01 AI109039 to K.O.C. and P01 AI060699 and R01 AI129269 to S.P.). The use of the University of Kansas Protein Structure Laboratory was supported by a grant from the National Institute of General Medical Sciences (P30GM110761) of the NIH. The use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. The use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-06CH11357. This research used the AMX beamline of the National Synchrotron Light Source II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory under Contract no. DE-SC0012704. The Center for BioMolecular Structure (CBMS) is primarily supported by the National Institutes of Health, National Institute of General Medical Sciences (NIGMS) through a Center Core P30 grant (P30GM133893), and the DOE Office of Biological and Environmental Research (KP1605010).en_US
dc.identifier.citationDampalla, C. S., Kim, Y., Bickmeier, N., Rathnayake, A. D., Nguyen, H. N., Zheng, J., . . . Groutas, W. C. (2021). Structure-guided design of conformationally constrained cyclohexane inhibitors of severe acute respiratory syndrome coronavirus-2 3CL protease. Journal of Medicinal Chemistry, doi:10.1021/acs.jmedchem.1c00319en_US
dc.identifier.issn0022-2623
dc.identifier.issn1520-4804
dc.identifier.urihttps://doi.org/10.1021/acs.jmedchem.1c00319
dc.identifier.urihttps://soar.wichita.edu/handle/10057/21689
dc.language.isoen_USen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofseriesJournal of Medicinal Chemistry;
dc.rights.holderCopyright © 2021 American Chemical Societyen_US
dc.subjectSARS-CoV-2en_US
dc.subjectInhibitorsen_US
dc.subjectAlcoholsen_US
dc.subjectAldehydesen_US
dc.subjectPeptides and proteinsen_US
dc.titleStructure-guided design of conformationally constrained cyclohexane inhibitors of severe acute respiratory syndrome coronavirus-2 3cl proteaseen_US
dc.typeArticleen_US
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