Small-Molecule-Functionalized Hyperbranched Polyglycerol Dendrimers for Inhibiting Protein Aggregation.

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.