Inhibition of insulin amyloid fibrillogenesis using antioxidant copolymers with dopamine pendants.

Abstract

Amyloid aggregation, intricately related to various neurodegenerative and metabolic diseases, presents a significant growing health challenge. Dopamine, a potent antioxidant, plays a pivotal role in modulating protein misfolding by leveraging its potent anti-amyloidogenic and neuroprotective properties. However, its biological applications are limited by poor aqueous solubility and suboptimal biocompatibility. To address these challenges, water-soluble copolymers (DP1-DP3) featuring dopamine and glucose side-chain pendants are fabricated and investigated for their efficacy in inhibiting amyloid fibril formation from insulin and amyloid beta (Aβ42) peptide. The effects of DP1-DP3 copolymers on amyloid fibrillation are assessed using several biophysical techniques, which demonstrate excellent radical scavenging properties and the remarkable efficacy of DP3 copolymer in suppressing insulin amyloid fibrillation, achieving ≈97% inhibition. Isothermal titration calorimetry (ITC) and fluorescence binding experiments are carried out to quantify the insulin-DP3 complex formation. Molecular dynamics simulations validate the ability of DP3 to prevent amyloid fibrillogenesis of both insulin and Aβ42. These studies demonstrate beneficial interactions between DP3 and amyloidogenic protein/peptide, facilitating the stability of the resulting complexes. Overall, the present findings suggest that dopamine-based antioxidant polymers hold significant potential as advanced therapeutic agents for preventing amyloidogenic disorders.