College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China.
Department of Chemistry and Chemical Engineering, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, P. R. China.
J Mater Chem B. 2022 Jul 27;10(29):5602-5611. doi: 10.1039/d2tb01070d.
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 detection and 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 detection and 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 α-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.
淀粉样相关疾病，如阿尔茨海默病，都被认为与体内淀粉样纤维的沉积有关。胰岛素是一种蛋白质激素，容易发生聚集和纤维形成，形成更有毒的类淀粉样纤维。到目前为止，开发一种新的方案来研究淀粉样纤维的检测和抑制仍然具有挑战性。在这里，我们报告了一种模块化的合成策略，用于构建九个具有两亲性糖涂层的 AIE 活性荧光有机纳米粒子（FON，TPE2/3/4X，X = G、M 或 S），其中葡萄糖胺（G）、甘露糖（M）或唾液酸（S）作为亲水部分，四苯乙烯（TPE）作为疏水 AIE 核心。通过荧光光谱、圆二色光谱和透射电子显微镜研究了胰岛素与 TPE2/3/4X 之间的碳水化合物-蛋白质相互作用。在这九个 FON AIEgen 中，筛选出 TPE2G 作为检测和抑制胰岛素纤维形成过程的最佳双重功能 FON，表明糖基部分对胰岛素纤维形成的检测/抑制具有重要作用。分子动力学模拟结果表明，TPE2G 与天然胰岛素的结合机制是通过范德华相互作用为主、氢键相互作用为辅的弱相互作用，稳定胰岛素 A 链的α-螺旋，从而抑制胰岛素纤维形成过程。这项工作为基于碳水化合物-蛋白质相互作用的淀粉样相关疾病的进一步研究提供了一种强大的方案。
