化学
二硫键
衍生工具(金融)
严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)
脚手架
蛋白酶抑制剂(药理学)
蛋白酶
2019-20冠状病毒爆发
组合化学
2019年冠状病毒病(COVID-19)
生物化学
病毒学
酶
病毒
生物
病毒载量
医学
疾病
病理
爆发
抗逆转录病毒疗法
传染病(医学专业)
生物医学工程
金融经济学
经济
作者
Yin‐Sui Xu,Jing Wang,Le Zhai,Cheng Chen,Xiaorong Wu,Weiya Chen,Haibo Liu,Mu-Han Zhao,Xiaolong Liu,Ke‐Wu Yang
标识
DOI:10.1002/cbdv.202401034
摘要
The main protease (Mpro) of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) represents a promising target for antiviral drugs aimed at combating COVID-19. Consequently, the development of Mpro inhibitor is an ideal strategy for combating the virus. In this study, we identified twenty-two dithiocarbamates (1a-h), dithiocarbamate-Cu(II) complexes (2a-hCu) and disulfide derivatives (2a-e, 2i) as potent inhibitors of Mpro, with IC50 value range of 0.09-0.72, 0.9-24.7 and 15.1-111 µM, respectively, through FRET screening. The enzyme kinetics, inhibition mode, jump dilution, and DTT assay revealed that 1g may be a partial reversible inhibitor, while 2d and 2f-Cu are the irreversible and dose- and time-dependent inhibitors, potentially covalently binding to the target. Binding of 2d, 2f-Cu and 1g to Mpro was found to decrease the stability of the protein. Additionally, DTT assays and thermal shift assays indicated that 2f-Cu and 2d are the nonspecific and promiscuous cysteine protease inhibitor. ICP-MS implied that the inhibitory activity of 2f-Cu may stem from the uptake of Cu(II) by the enzyme. Cytotoxicity assays demonstrated that 2d and 1g exhibit low cytotoxicity, whereas 2f-Cu show certain cytotoxicity in L929 cells. Overall, this work presents two promising scaffolds for the development of Mpro inhibitors to combat COVID-19.
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