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

ABSTRACT: Covalent inhibitors targeting the main protease (M^pro, 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^pro. These acrylamide containing molecules were discovered using our covalent DNA-encoded library (DEL) screening platform. Following selection against SARS-CoV-2 M^pro, 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^pro. Fluorescent staining assay for covalent binding in the presence

SUBMITTER: Ge R 

PROVIDER: S-EPMC8767972 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature