School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
Microbial Research Institute of Liaoning Province, Chaoyang 122000, China.
Molecules. 2023 Feb 16;28(4):1883. doi: 10.3390/molecules28041883.
Furin is a potential target protein associated with numerous diseases; especially closely related to tumors and multiple viral infections including SARS-CoV-2. Most of the existing efficient furin inhibitors adopt a substrate analogous structure, and other types of small molecule inhibitors need to be discovered urgently. In this study, a high-throughput screening combining virtual and physical screening of natural product libraries was performed, coupled with experimental validation and preliminary mechanistic assays at the molecular level, cellular level, and molecular simulation. A novel furin inhibitor, permethrin, which is a derivative from pyrethrin I generated by Trev. was identified, and this study confirmed that it binds to a novel allosteric pocket of furin through non-competitive inhibition. It exhibits a very favorable protease-selective inhibition and good cellular activity and specificity. In summary, permethrin shows a new parent nucleus with a new mode of inhibition. It could be used as a highly promising lead compound against furin for targeting related tumors and various resistant viral infections, including SARS-CoV-2.
弗林蛋白酶是一种与多种疾病相关的潜在靶蛋白，尤其是与肿瘤和多种病毒感染（包括 SARS-CoV-2）密切相关。大多数现有的高效弗林蛋白酶抑制剂采用类似底物的结构，迫切需要发现其他类型的小分子抑制剂。在这项研究中，采用高通量筛选技术，结合天然产物库的虚拟筛选和物理筛选，并在分子水平、细胞水平和分子模拟水平进行实验验证和初步的机制研究。鉴定出一种新型弗林蛋白酶抑制剂——除虫菊酯，它是由 Trev. 产生的除虫菊酯 I 的衍生物。本研究证实，它通过非竞争性抑制作用结合弗林蛋白酶的一个新的变构口袋。它表现出非常有利的蛋白酶选择性抑制作用以及良好的细胞活性和特异性。总之，除虫菊酯展示了一种具有新抑制模式的新型母体核。它可以作为一种针对弗林蛋白酶的很有前途的先导化合物，用于靶向相关肿瘤和各种耐药病毒感染，包括 SARS-CoV-2。
