Modulating Insulin Aggregation with Charge Variable Cholic Acid-Derived Polymers.

Area of Science:

• Polymer Chemistry
• Biophysical Chemistry
• Materials Science

Background:

• Protein aggregation, particularly insulin fibrillation, is linked to various diseases.
• Developing effective strategies to control protein aggregation is crucial for therapeutic applications.
• Cholic acid (CA)-based polymeric architectures offer potential for modulating biological processes.

Purpose of the Study:

• To design and synthesize charge-variable polymers containing cholate side chains.
• To investigate the effect of these polymers on insulin fibrillation.
• To elucidate the mechanism by which CA-based polymers modulate insulin aggregation.

Main Methods:

• Synthesis of anionic, cationic, and neutral copolymers using reversible addition-fragmentation chain transfer (RAFT) polymerization.
• Biophysical techniques including spectroscopic (tyrosine fluorescence, Nile red fluorescence, circular dichroism) and microscopic analyses.
• Isothermal titration calorimetry (ITC) to study polymer-protein interactions.

Main Results:

• The CA-based cationic polymer (CP-10) significantly inhibited insulin fibrillation in a dose-dependent manner.
• Anionic (AP-10) and neutral (NP-10) copolymers showed negligible effects on insulin aggregation.
• Hydrophobic and electrostatic polar interactions were identified as key mechanisms for CP-10's inhibitory activity.

Conclusions:

• CA-based cationic polymers are effective anti-amyloidogenic agents capable of controlling insulin aggregation.
• The charge and specific interactions (hydrophobic and electrostatic) of the polymer are critical for its anti-aggregation efficacy.
• This study presents a novel approach using CA-based cationic polymers for protein aggregation modulation.