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Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection.

Authors :
Ge R
Shen Z
Yin J
Chen W
Zhang Q
An Y
Tang D
Satz AL
Su W
Kuai L
Source :
SLAS discovery : advancing life sciences R & D [SLAS Discov] 2022 Mar; Vol. 27 (2), pp. 79-85. Date of Electronic Publication: 2022 Jan 19.
Publication Year :
2022

Abstract

Covalent inhibitors targeting the main protease (M <superscript>pro</superscript> , or 3CLpro) of SARS-CoV-2 have shown promise in preclinical investigations. Herein, we report the discovery of two new series of molecules that irreversibly bind to SARS-CoV-2 M <superscript>pro</superscript> . These acrylamide containing molecules were discovered using our covalent DNA-encoded library (DEL) screening platform. Following selection against SARS-CoV-2 M <superscript>pro</superscript> , off-DNA compounds were synthesized and investigated to determine their inhibitory effects, the nature of their binding, and to generate preliminary structure-activity relationships. LC-MS analysis indicates a 1:1 (covalent) binding stoichiometry between our hit molecules and SARS-CoV-2 M <superscript>pro</superscript> . Fluorescent staining assay for covalent binding in the presence of cell lysate suggests reasonable selectivity for SARS-CoV-2 M <superscript>pro</superscript> . And lastly, inhibition of enzymatic activity was also observed against a panel of 3CLpro enzymes from different coronavirus strains, with IC <subscript>50</subscript> values ranging from inactive to single digit micromolar. Our results indicate that DEL selection is a useful approach for identifying covalent inhibitors of cysteine proteases.<br />Competing Interests: Declaration of Conflicting Interests The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors were employed by WuXi AppTec, and their research and authorship of this article was completed within the scope of their employment with WuXi AppTec.<br /> (Copyright © 2022. Published by Elsevier Inc.)

Details

Language :
English
ISSN :
2472-5560
Volume :
27
Issue :
2
Database :
MEDLINE
Journal :
SLAS discovery : advancing life sciences R & D
Publication Type :
Academic Journal
Accession number :
35063690
Full Text :
https://doi.org/10.1016/j.slasd.2022.01.001