Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection.
SLAS Discov
; 27(2): 79-85, 2022 03.
Article
in En
| MEDLINE
| ID: mdl-35063690
ABSTRACT
Covalent inhibitors targeting the main protease (Mpro, 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 Mpro. These acrylamide containing molecules were discovered using our covalent DNA-encoded library (DEL) screening platform. Following selection against SARS-CoV-2 Mpro, 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 11 (covalent) binding stoichiometry between our hit molecules and SARS-CoV-2 Mpro. Fluorescent staining assay for covalent binding in the presence of cell lysate suggests reasonable selectivity for SARS-CoV-2 Mpro. And lastly, inhibition of enzymatic activity was also observed against a panel of 3CLpro enzymes from different coronavirus strains, with IC50 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Protease Inhibitors
/
DNA
/
Drug Discovery
/
Coronavirus 3C Proteases
/
SARS-CoV-2
Limits:
Humans
Language:
En
Journal:
SLAS Discov
Year:
2022
Type:
Article
Affiliation country:
China