Facially Amphiphilic Cholate-Conjugated Polymers for Regulating Insulin Fibrillation

Area of Science:

• Polymer Chemistry
• Biophysical Chemistry
• Materials Science

Background:

• Protein misfolding and aggregation, such as insulin fibrillation (IF), are implicated in various diseases.
• Facially amphiphilic polymers (FAPs) are emerging as potential therapeutic agents for modulating protein aggregation.

Purpose of the Study:

• To synthesize and evaluate cholate-based FAPs for their efficacy in inhibiting insulin fibrillation.
• To elucidate the mechanisms underlying the interaction between FAPs and insulin during fibrillation.

Main Methods:

• Synthesis of cationic, anionic, and zwitterionic cholate-based FAPs and control polymers.
• Biophysical characterization using spectroscopic techniques (ThT, NR, Tyr fluorescence), UV-vis turbidity, DLS, CD, and microscopy.
• Isothermal titration calorimetry (ITC) and hemolytic assays to study polymer-protein interactions and toxicity.

Main Results:

• The zwitterionic FAP (PFCASB) demonstrated superior antiamyloidogenic activity against insulin fibrillation.
• Spectroscopic and ITC data indicated that hydrophobic and electrostatic interactions are crucial for PFCASB's inhibitory mechanism.
• PFCASB effectively prevented insulin fibril-induced erythrocyte damage.

Conclusions:

• Facially amphiphilic zwitterionic polymers, specifically PFCASB, are highly effective in inhibiting insulin fibrillation.
• The study provides insights into the role of polymer structure and amphiphilicity in modulating protein aggregation.
• This work offers a new perspective for developing polymer-based strategies against protein aggregation diseases.