tetano
Editor, Senior Moderator
Chem Biodivers
. 2024 Aug 7:e202401034.
doi: 10.1002/cbdv.202401034. Online ahead of print. Discovery of a Highly Promising Disulfide Derivative Scaffold as Inhibitor of SARS-CoV-2 main protease
Yin-Sui Xu[SUP] 1 [/SUP], Yang Xiang[SUP] 2 [/SUP], Le Zhai[SUP] 3 [/SUP], Cheng Chen[SUP] 4 [/SUP], Xiao-Rong Wu[SUP] 4 [/SUP], Wei-Ya Chen[SUP] 4 [/SUP], Lu Liu[SUP] 4 [/SUP], Mu-Han Zhao[SUP] 4 [/SUP], Xiao-Long Liu[SUP] 5 [/SUP], Ke-Wu Yang[SUP] 6 [/SUP]
Affiliations
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.
Keywords: SARS-CoV-2; disulfide derivative; dithiocarbamate-Cu(II) complex; inhibitor; main protease.
. 2024 Aug 7:e202401034.
doi: 10.1002/cbdv.202401034. Online ahead of print. Discovery of a Highly Promising Disulfide Derivative Scaffold as Inhibitor of SARS-CoV-2 main protease
Yin-Sui Xu[SUP] 1 [/SUP], Yang Xiang[SUP] 2 [/SUP], Le Zhai[SUP] 3 [/SUP], Cheng Chen[SUP] 4 [/SUP], Xiao-Rong Wu[SUP] 4 [/SUP], Wei-Ya Chen[SUP] 4 [/SUP], Lu Liu[SUP] 4 [/SUP], Mu-Han Zhao[SUP] 4 [/SUP], Xiao-Long Liu[SUP] 5 [/SUP], Ke-Wu Yang[SUP] 6 [/SUP]
Affiliations
- PMID: 39109873
- DOI: 10.1002/cbdv.202401034
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.
Keywords: SARS-CoV-2; disulfide derivative; dithiocarbamate-Cu(II) complex; inhibitor; main protease.