文献类型：期刊文献

中文题名：基于氯虫苯甲酰胺结构的PROTACs分子设计、合成及杀虫活性研究

英文题名：Design,synthesis,and insecticidal activity evaluation of PROTACs based on the structure of chlorantraniliprole

作者：张振国[1];付稳[1];李忠[1];邵旭升[1]

机构：[1]华东理工大学药学院,上海市化学生物学(芳香杂环)重点实验室,上海200237

年份：2025

卷号：27

期号：4

起止页码：628

中文期刊名：农药学学报

外文期刊名：Chinese Journal of Pesticide Science

收录：;EI(收录号：20253619097481);北大核心:【北大核心2023】；

基金：国家自然科学基金(No.32472610)。

语种：中文

中文关键词：蛋白降解靶向嵌合体;鱼尼丁受体;氯虫苯甲酰胺;泊马度胺;结构改造;杀虫活性

外文关键词：PROTACs;ryanodine receptor;chlorantraniliprole;pomalidomide;structural renovation;insecticidal activity

摘要：蛋白降解靶向嵌合体(proteolysis-targeting chimeras,PROTACs)技术作为生物医药前沿技术,可通过“事件驱动”(event driven)降解模式,特异性清除靶蛋白,因其高选择性和独特机制,现已成为医药和农药等领域研究热点。本研究基于PROTACs技术,引入烷基链或聚乙二醇链,将氯虫苯甲酰胺和泊马度胺偶联,构建了8个靶向昆虫鱼尼丁受体(RyR)的PROTACs分子。生物活性测定结果显示,目标化合物A1~A8对鳞翅目害虫小菜蛾及东方黏虫均表现出了较好的杀虫活性,在50 mg/L质量浓度下致死率均大于80%。其中化合物A8对小菜蛾的LC_(50)值为0.50μmol/L,化合物A5对东方黏虫的LC_(50)值为1.13μmol/L,但相比氯虫苯甲酰胺的杀虫活性仍分别下降了5.6和28倍。蛋白免疫印迹实验结果表明,所有目标化合物均未能诱导RyR蛋白降解,推测可能是因为配体亲和力或泛素转移效率低所致,后续拟进行E3连接酶配体及连接链的优化。本研究可为PROTACs技术在农药创制研究中的应用探索提供理论指导。
As a cutting-edge approach in biomedicine,proteolysis-targeting chimeras(PROTACs)technology eliminates target proteins through an event driven degradation mode.Its high selectivity and unique mechanism have made it a research hotspot in medicine,agrochemistry,and other fields.In this study,PROTACs were leveraged to conjugate chlorantraniliprole and pomalidomide via alkyl chains or polyethylene glycol chains to constructeight novel PROTACs molecules targeting the ryanodine receptor(RyR).Biological activity assays showed that the target compounds A1-A8 exhibited good insecticidal activity against the Lepidopteran pests Plutella xylostella and Mythimna separata,with the lethality both exceeding 80%at the concentration of 50 mg/L.Among them,LC_(50) values of 0.50μmol/L for compound A8 against P.xylostella and 1.13μmol/L for A5 against M.separata,representing 5.6-fold and 28-fold reductions in potency compared to chlorantraniliprole,respectively.Western blot analysis indicated that none of the compounds induced RyR degradation,potentially due to insufficient ligand binding affinity or inefficient ubiquitin transfer.Subsequent optimization should focus on E3 ligase ligands and linker structures.This work lays a foundation for applying PROTACs technology to pesticide development.