tetano
Editor, Senior Moderator
Eur J Med Chem
. 2023 Aug 17;260:115721.
doi: 10.1016/j.ejmech.2023.115721. Online ahead of print. Discovery of highly potent covalent SARS-CoV-2 3CL[SUP]pro[/SUP] inhibitors bearing 2-sulfoxyl-1,3,4-oxadiazole scaffold for combating COVID-19
Fu-Mao Zhang[SUP] 1 [/SUP], Ting Huang[SUP] 2 [/SUP], Feng Wang[SUP] 1 [/SUP], Gui-Shan Zhang[SUP] 1 [/SUP], Donglan Liu[SUP] 2 [/SUP], Jun Dai[SUP] 3 [/SUP], Jian-Wei Zhang[SUP] 1 [/SUP], Qing-Hua Li[SUP] 1 [/SUP], Guo-Qiang Lin[SUP] 1 [/SUP], Dingding Gao[SUP] 4 [/SUP], Jincun Zhao[SUP] 5 [/SUP], Ping Tian[SUP] 6 [/SUP]
Affiliations
The coronavirus disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a major public health crisis, posing a significant threat to human well-being. Despite the availability of vaccines, COVID-19 continues to spread owing to the emergence of SARS-CoV-2 mutants. This highlights the urgent need for the discovery of more effective drugs to combat COVID-19. As an important target for COVID-19 treatment, 3C-like protease (3CL[SUP]pro[/SUP]) plays a crucial role in the replication of SARS-CoV-2. In our previous research, we demonstrated the potent inhibitory activities of compound A1, which contains a 2-sulfonyl-1,3,4-oxadiazole scaffold, against SARS-CoV-2 3CL[SUP]pro[/SUP]. Herein, we present a detailed investigation of structural optimization of A1 and conduct a study on the structure-activity relationship. Among the various compounds tested, sulfoxide D6 demonstrates a potent irreversible inhibitory activity (IC[SUB]50[/SUB] = 0.030 μM) against SARS-CoV-2 3CL[SUP]pro[/SUP], as well as a favorable selectivity towards host cysteine proteases such as cathepsin B and cathepsin L. Utilizing mass spectrometry-based peptide profiling, we found that D6 covalently binds to Cys145 of SARS-CoV-2 3CL[SUP]pro[/SUP]. Some representative compounds, namely C11, D9 and D10 also demonstrates antiviral activity against SARS-CoV-2 in Vero E6 cells. Overall, the investigation of the 2-sulfoxyl-1,3,4-oxadiazole scaffold as a novel cysteine reactive warhead would provide valuable insights into the design of potent covalent 3CL[SUP]pro[/SUP] inhibitors for COVID-19 treatment.
Keywords: 2-sulfoxyl-1,3,4-oxadiazole; COVID-19; Covalent inhibitor; SARS-CoV-2 3CL(pro).
. 2023 Aug 17;260:115721.
doi: 10.1016/j.ejmech.2023.115721. Online ahead of print. Discovery of highly potent covalent SARS-CoV-2 3CL[SUP]pro[/SUP] inhibitors bearing 2-sulfoxyl-1,3,4-oxadiazole scaffold for combating COVID-19
Fu-Mao Zhang[SUP] 1 [/SUP], Ting Huang[SUP] 2 [/SUP], Feng Wang[SUP] 1 [/SUP], Gui-Shan Zhang[SUP] 1 [/SUP], Donglan Liu[SUP] 2 [/SUP], Jun Dai[SUP] 3 [/SUP], Jian-Wei Zhang[SUP] 1 [/SUP], Qing-Hua Li[SUP] 1 [/SUP], Guo-Qiang Lin[SUP] 1 [/SUP], Dingding Gao[SUP] 4 [/SUP], Jincun Zhao[SUP] 5 [/SUP], Ping Tian[SUP] 6 [/SUP]
Affiliations
- PMID: 37598484
- DOI: 10.1016/j.ejmech.2023.115721
The coronavirus disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a major public health crisis, posing a significant threat to human well-being. Despite the availability of vaccines, COVID-19 continues to spread owing to the emergence of SARS-CoV-2 mutants. This highlights the urgent need for the discovery of more effective drugs to combat COVID-19. As an important target for COVID-19 treatment, 3C-like protease (3CL[SUP]pro[/SUP]) plays a crucial role in the replication of SARS-CoV-2. In our previous research, we demonstrated the potent inhibitory activities of compound A1, which contains a 2-sulfonyl-1,3,4-oxadiazole scaffold, against SARS-CoV-2 3CL[SUP]pro[/SUP]. Herein, we present a detailed investigation of structural optimization of A1 and conduct a study on the structure-activity relationship. Among the various compounds tested, sulfoxide D6 demonstrates a potent irreversible inhibitory activity (IC[SUB]50[/SUB] = 0.030 μM) against SARS-CoV-2 3CL[SUP]pro[/SUP], as well as a favorable selectivity towards host cysteine proteases such as cathepsin B and cathepsin L. Utilizing mass spectrometry-based peptide profiling, we found that D6 covalently binds to Cys145 of SARS-CoV-2 3CL[SUP]pro[/SUP]. Some representative compounds, namely C11, D9 and D10 also demonstrates antiviral activity against SARS-CoV-2 in Vero E6 cells. Overall, the investigation of the 2-sulfoxyl-1,3,4-oxadiazole scaffold as a novel cysteine reactive warhead would provide valuable insights into the design of potent covalent 3CL[SUP]pro[/SUP] inhibitors for COVID-19 treatment.
Keywords: 2-sulfoxyl-1,3,4-oxadiazole; COVID-19; Covalent inhibitor; SARS-CoV-2 3CL(pro).