Discovery of highly potent covalent SARS-CoV-2 3CLpro inhibitors bearing 2-sulfoxyl-1,3,4-oxadiazole scaffold for combating COVID-19
发布时间：2025-11
点击次数：
- 发布时间：
- 2025-11
- 影响因子：
- 6.0
- DOI码：
- 10.1016/j.ejmech.2023.115721
- 论文名称：
- Discovery of highly potent covalent SARS-CoV-2 3CLpro inhibitors bearing 2-sulfoxyl-1,3,4-oxadiazole scaffold for combating COVID-19
- 发表刊物：
- EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
- 摘要：
- 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 (3CLpro) 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 3CLpro. 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 (IC50 = 0.030 & mu;M) against SARS-CoV-2 3CLpro, 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 3CLpro. 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-1,3,4oxadiazole scaffold as a novel cysteine reactive warhead would provide valuable insights into the design of potent covalent 3CLpro inhibitors for COVID-19 treatment.
- 第一作者：
- zhangfumao,huangting,wangfeng
- 论文类型：
- 期刊论文
- 通讯作者：
- gaodingding,赵金存,田平
- 卷号：
- 260
- ISSN号：
- 0223-5234
- 是否译文：
- 否
- 发表时间：
- 2023-11
- 他引次数：
- 13