School of Material Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India.
School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
Biomacromolecules. 2020 Aug 10;21(8):3270-3278. doi: 10.1021/acs.biomac.0c00713. Epub 2020 Jul 27.
Amyloid protein aggregation is responsible for a variety of neurodegenerative diseases, and antiamyloidogenic small molecules are identified for inhibiting such protein aggregation at extra-/intracellular space. We show that the nanoparticle form of small molecules offers better antiamyloidogenic performance via enhanced bioavailability and multivalent binding with protein. Here, we report hyperbranched polyglycerol dendrimers terminated with antiamyloidogenic small molecules such as gallate, tyrosine, and trehalose and their potential in inhibiting lysozyme/huntingtin protein aggregation under intra-/extracellular space. The synthesized functional dendrimers are ∼5 nm in size having an average molecular weight of ∼2000 Da, and they are highly biocompatible in nature. We found that functional dendrimers are efficient in micromolar doses with respect to molecular forms that are effective at millimolar concentration. It is observed that the trehalose-terminated dendrimer is more effective in inhibiting protein aggregation, whereas the gallate-terminated dendrimer is more effective in disintegrating mature protein fibrils. This approach can be used to design functional dendrimers as potential nanodrugs for the treatment of various neurodegenerative diseases.
淀粉样蛋白聚集是多种神经退行性疾病的原因，已鉴定出抗淀粉样蛋白小分子，以抑制细胞外/细胞内空间中的这种蛋白聚集。我们表明，小分子的纳米颗粒形式通过增强生物利用度和与蛋白质的多价结合提供了更好的抗淀粉样蛋白性能。在这里，我们报告了用具有抗淀粉样蛋白特性的小分子如没食子酸、酪氨酸和海藻糖终止的超支化聚甘油树状大分子及其在细胞内/细胞外空间抑制溶菌酶/亨廷顿蛋白聚集的潜力。合成的功能树突状大分子的尺寸约为 5nm，平均分子量约为 2000Da，本质上具有高度的生物相容性。我们发现，对于在毫摩尔浓度下有效的分子形式，功能树突状大分子在微摩尔剂量下是有效的。观察到海藻糖末端的树突状大分子在抑制蛋白质聚集方面更有效，而没食子酸末端的树突状大分子在分解成熟的蛋白质原纤维方面更有效。这种方法可用于设计功能性树突状大分子作为治疗各种神经退行性疾病的潜在纳米药物。
