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 (A β ₄₂ ) 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 A β ₄₂ . 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.