Chemical strategies to modify amyloidogenic peptides using iridium(iii) complexes: coordination and photo-induced oxidation

Abstract

Amyloidogenic peptides are considered central pathological contributors towards neurodegeneration as observed in neurodegenerative disorders [e.g., amyloid-β (Aβ) peptides in Alzheimer's disease (AD)]; however, their roles in the pathologies of such diseases have not been fully elucidated since they are challenging targets to be studied due to their heterogeneous nature and intrinsically disordered structure. Chemical approaches to modify amyloidogenic peptides would be valuable in advancing our molecular-level understanding of their involvement in neurodegeneration. Herein, we report effective chemical strategies for modification of Aβ peptides (i.e., coordination and coordination-/photo-mediated oxidation) implemented by a single Ir(III) complex in a photo-dependent manner. Such peptide variations can be achieved by our rationally designed Ir(III) complexes (Ir-Me, Ir-H, Ir-F, and Ir-F2) leading to significantly modulating the aggregation pathways of two main Aβ isoforms, Aβ₄₀ and Aβ₄₂, as well as the production of toxic Aβ species. Overall, we demonstrate chemical tactics for modification of amyloidogenic peptides in an effective and manageable manner utilizing the coordination capacities and photophysical properties of transition metal complexes.