State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease, Nankai University, Tianjin 300353, People's Republic of China.
Key Laboratory of Special Pathogens and Biosafety, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, People's Republic of China.
J Med Chem. 2024 Oct 10;67(19):17124-17143. doi: 10.1021/acs.jmedchem.4c00656. Epub 2024 Sep 18.
Cathepsin L (CatL) is a promising antiviral drug target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as an important protease for cleaving the SARS-CoV-2 spike protein and enhancing viral entry to cells. We identified a tripeptide aldehyde candidate, , which exhibited inhibitory effects against SARS-CoV-2 in Vero E6 cells. The protease screening analysis and protein pull-down assays demonstrated the direct binding of to CatL. Guided by molecular docking, we synthesized 72 analogues. Upon analyzing the structure-activity relationships of these inhibitors, the series was developed. Among them, functioned as the most potent CatL inhibitor (IC = 0.27 nM, EC = 0.26 μM). effectively blocked the CatL function and substantially hindered the entry of the SARS-CoV-2 pseudovirus to cells. Our work presented novel compounds for targeting and inhibiting CatL, offering valuable insights into the development of SARS-CoV-2 antivirals.
组织蛋白酶 L (CatL) 是严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的一种有前途的抗病毒药物靶点，它是一种重要的蛋白酶，可切割 SARS-CoV-2 的刺突蛋白并增强病毒进入细胞的能力。我们鉴定了一种三肽醛候选物 ，它对 Vero E6 细胞中的 SARS-CoV-2 表现出抑制作用。蛋白酶筛选分析和蛋白质下拉实验表明 与 CatL 直接结合。在分子对接的指导下，我们合成了 72 个类似物。在分析这些抑制剂的构效关系后，开发了 系列。其中， 作为最有效的 CatL 抑制剂发挥作用（IC = 0.27 nM，EC = 0.26 μM）。 有效地阻断了 CatL 的功能，并显著阻碍了 SARS-CoV-2 假病毒进入细胞。我们的工作为靶向和抑制 CatL 提供了新的化合物，为开发 SARS-CoV-2 抗病毒药物提供了有价值的见解。
