tetano
Editor, Senior Moderator
SLAS Discov
. 2022 Jan 18;S2472-5552(22)00006-5.
doi: 10.1016/j.slasd.2022.01.001. Online ahead of print.
Discovery of SARS-CoV-2 Main Protease Covalent Inhibitors from a DNA-Encoded Library Selection
Rui Ge[SUP] 1 [/SUP], Zuyuan Shen[SUP] 1 [/SUP], Jian Yin[SUP] 1 [/SUP], Wenhua Chen[SUP] 1 [/SUP], Qi Zhang[SUP] 1 [/SUP], Yulong An[SUP] 1 [/SUP], Dewei Tang[SUP] 1 [/SUP], Alexander L Satz[SUP] 2 [/SUP], Wenji Su[SUP] 3 [/SUP], Letian Kuai[SUP] 4 [/SUP]
Affiliations
Abstract
Covalent inhibitors targeting the main protease (M[SUP]pro[/SUP], 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[SUP]pro[/SUP]. These acrylamide containing molecules were discovered using our DNA-encoded library (DEL) screening platform. Following selection against SARS-CoV-2 M[SUP]pro[/SUP], off-DNA compounds were synthesized and investigated to determine their inhibitory effects, the nature of their binding, and generate preliminary structure-activity relationships. LC-MS analysis indicates a 1:1 (covalent) binding stoichiometry between our hit molecules and SARS-CoV-2 M[SUP]pro[/SUP]. Fluorescent staining assay for covalent binding in the presence of cell lysate suggests reasonable selectivity for SARS-CoV-2 M[SUP]pro[/SUP]. And lastly, inhibition of enzymatic activity was also observed against a panel of 3CLpro enzymes from different coronavirus strains, with IC[SUB]50[/SUB] 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.
Keywords: COVID-19; Covalent inhibitor; SARS-CoV-2 M(pro); covalent DEL selection.
. 2022 Jan 18;S2472-5552(22)00006-5.
doi: 10.1016/j.slasd.2022.01.001. Online ahead of print.
Discovery of SARS-CoV-2 Main Protease Covalent Inhibitors from a DNA-Encoded Library Selection
Rui Ge[SUP] 1 [/SUP], Zuyuan Shen[SUP] 1 [/SUP], Jian Yin[SUP] 1 [/SUP], Wenhua Chen[SUP] 1 [/SUP], Qi Zhang[SUP] 1 [/SUP], Yulong An[SUP] 1 [/SUP], Dewei Tang[SUP] 1 [/SUP], Alexander L Satz[SUP] 2 [/SUP], Wenji Su[SUP] 3 [/SUP], Letian Kuai[SUP] 4 [/SUP]
Affiliations
- PMID: 35063690
- DOI: 10.1016/j.slasd.2022.01.001
Abstract
Covalent inhibitors targeting the main protease (M[SUP]pro[/SUP], 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[SUP]pro[/SUP]. These acrylamide containing molecules were discovered using our DNA-encoded library (DEL) screening platform. Following selection against SARS-CoV-2 M[SUP]pro[/SUP], off-DNA compounds were synthesized and investigated to determine their inhibitory effects, the nature of their binding, and generate preliminary structure-activity relationships. LC-MS analysis indicates a 1:1 (covalent) binding stoichiometry between our hit molecules and SARS-CoV-2 M[SUP]pro[/SUP]. Fluorescent staining assay for covalent binding in the presence of cell lysate suggests reasonable selectivity for SARS-CoV-2 M[SUP]pro[/SUP]. And lastly, inhibition of enzymatic activity was also observed against a panel of 3CLpro enzymes from different coronavirus strains, with IC[SUB]50[/SUB] 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.
Keywords: COVID-19; Covalent inhibitor; SARS-CoV-2 M(pro); covalent DEL selection.