共价键
化学
蛋白酵素
DNA
蛋白酶
酶
小分子
半胱氨酸
生物化学
严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)
2019年冠状病毒病(COVID-19)
医学
病理
有机化学
传染病(医学专业)
疾病
作者
Rui Ge,Zuyuan Shen,Jian Yin,Wen‐Hua Chen,Qi Zhang,Yulong An,Dewei Tang,Alexander L. Satz,Wenji Su,Letian Kuai
标识
DOI:10.1016/j.slasd.2022.01.001
摘要
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 1:1 (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.
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