Dual Functional Amphiphilic Sugar-Coated AIE-Active Fluorescent Organic Nanoparticles for the Monitoring and Inhibition of Insulin Amyloid Fibrillation Based on Carbohydrate-Protein Interactions
Dual Functional Amphiphilic Sugar-Coated AIE-Active Fluorescent Organic Nanoparticles for the Monitoring and Inhibition of Insulin Amyloid Fibrillation Based on Carbohydrate-Protein Interactions
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双功能两亲糖衣 AIE 活性荧光有机纳米颗粒，用于基于碳水化合物-蛋白质相互作用监测和抑制胰岛素淀粉样纤维颤动
DOI：
10.1039/d2tb01070d
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Guo-wen Xing
中科院分区：
文献类型：
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作者：
Yan-Ming Ji;Wenyan Zhang;Jing-Dong Zhang;Xia-Fen Li;Fan-Dong Yu;Cui-Yun Li;Guang-jian Liu;Guo-wen Xing
淀粉样蛋白相关疾病，如阿尔茨海默氏病，都被认为与淀粉样蛋白原纤维在体内的沉积有关。胰岛素是一种蛋白质激素，容易发生聚集和原纤化，形成毒性更强的淀粉样原纤维。迄今为止，开发一种新的方法来研究淀粉样蛋白纤维化的异位检测和原位抑制仍然具有挑战性。本文报道了一种模块化合成策略，以葡糖胺（G）、甘露糖（M）或唾液酸（S）为亲水性部分，四苯乙烯（TPE）为疏水性AIE核，构建了9种两亲性糖包被AIE活性荧光有机纳米颗粒（FONs，TPE 2/3/4X，X = G，M或S）。用荧光光谱、圆二色谱和透射电镜研究了TPE 2/3/4X与胰岛素的糖蛋白相互作用。在9种FON AIEgens中，筛选出TPE 2G作为用于胰岛素纤维化过程的离体检测和原位抑制的最佳双功能FON，表明糖基部分在胰岛素纤维化的检测/抑制中表现出关键作用。分子动力学模拟结果表明TPE 2G与胰岛素的结合机制是通过以货车德瓦尔斯相互作用为主、氢键相互作用为辅的弱相互作用来稳定胰岛素A链的一个α-螺旋，从而抑制胰岛素原纤化过程。本研究为淀粉样蛋白相关疾病的糖-蛋白相互作用的进一步研究提供了有力的实验平台。
Amyloid-related diseases, such as Alzheimer's disease, are all considered to be related to the deposition of amyloid fibrils in the body. Insulin is a protein hormone that easily undergoes aggregation and fibrillation to form more toxic amyloid-like fibrils. So far, it is still challenging to develop a new protocol to study the ex situ detection and in situ inhibition of amyloid fibrillation. Here, we reported a modular synthetic strategy to construct nine amphiphilic sugar-coated AIE-active fluorescent organic nanoparticles (FONs, TPE2/3/4X, X = G, M or S) with glucosamine (G), mannose (M) or sialic acid (S) as a hydrophilic moiety and tetraphenylethylene (TPE) as a hydrophobic AIE core. The carbohydrate-protein interactions between insulin and TPE2/3/4X were investigated by fluorescence spectroscopy, circular dichroism spectroscopy and transmission electron microscopy. Among the nine FON AIEgens, TPE2G was screened out as the best dual functional FON for the ex situ detection and in situ inhibition of the insulin fibrillation process, indicating that the glycosyl moiety exhibited a crucial effect on the detection/inhibition of insulin fibrillation. The molecular dynamics simulation results showed that the binding mechanism between TPE2G and native insulin was through weak interactions dominated by van der Waals interactions and supplemented by hydrogen bonding interactions to stabilize an alpha-helix of the insulin A chain, thereby inhibiting the insulin fibrillation process. This work provides a powerful protocol for the further research of amyloid-related diseases based on carbohydrate-protein interactions.