Exploring the Holdase Activity of Supramolecular Chaperones with Amyloid-Forming Peptides and Insulin

Protein folding is essential for maintaining cellular homeostasis. When proteins misfold, aggregation can occur, contributing to a variety of diseases. Amphiphilic naphthyl-benzyl ether dendrons were recently reported to mimic natural chaperone systems by reducing the extent of fibrillation of an amyloid beta (Aβ) peptide fragment. Herein we develop this system using a slower-aggregating mutant Aβ peptide and the essential therapeutic protein, insulin. We show that amphiphilic dendrons strictly mimic the holdase function of chaperones by preventing aggregation, rather than slowing aggregation or disaggregating preformed fibrils. We demonstrate that the activity of these molecules tolerates minor changes to their structure and translates from the model Aβ peptide to insulin without structural optimization. Moreover, second-generation dendron 2 effectively eliminates insulin aggregation for multiple days in the presence of chemical and mechanical stressors. These findings expand both our understanding and the potential therapeutic relevance of amphiphilic dendrons as an emerging approach to tackle protein aggregation.