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Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection.
- 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.)
- Subjects :
- Antiviral Agents chemistry
Cell Line
Feasibility Studies
Humans
Protease Inhibitors chemistry
SARS-CoV-2 enzymology
Structure-Activity Relationship
Antiviral Agents pharmacology
Coronavirus 3C Proteases antagonists & inhibitors
DNA chemistry
Drug Discovery methods
Protease Inhibitors pharmacology
SARS-CoV-2 drug effects
Subjects
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