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

Juhye Kang,Tae-Hyuk Kwon,Jung Seung Nam,Mi Hee Lim,Hyuck Jin Lee,Geewoo Nam,Hyun-Woo Rhee

doi:10.1039/c9sc00931k

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.

Highlights

A substantial amount of research effort has been dedicated towards identifying the association of amyloidogenic peptides with the pathologies of neurodegenerative diseases
Chemical approaches to modify amyloidogenic peptides would be valuable in advancing our molecular-level understanding of their involvement in neurodegeneration
Through our multidisciplinary studies, presented in this work, we demonstrate the development of new chemical tactics for modi cation of amyloidogenic peptides using transition metal complexes, useful for identifying their properties, such as aggregation, at the molecular level

Summary

Introduction

A substantial amount of research effort has been dedicated towards identifying the association of amyloidogenic peptides with the pathologies of neurodegenerative diseases. Ab modi cations, achieved by our rationally engineered Ir(III) complexes, include two events: (i) complexation with Ab in the absence of light; (ii) Ab oxidation upon coordination and photoactivation, which can signi cantly regulate their aggregation and toxicity.

Results

Conclusion