Development of Small Molecules as Chemical Tools for Investigating the Role of Metal-Protein Interactions in Neurodegenerative Diseases.

Abstract

Metals play an essential part in biological processes in humans. When these beneficial metal ions become misregulated, the resulting metal ion dyshomeostasis can be catastrophic. This occurs in several neurodegenerative diseases where the aberrant interactions of metal ions with proteins can lead to their abnormal aggregation, production of oxidative stress, and neuronal death (reactivity). To better understand the role of metal−protein complexes in the pathogenesis of these diseases, small molecules have been developed as chemical tools that target these complexes and mediate their reactivity.

In this thesis, first, design considerations along with the approaches of developing and studying the activity of such molecules were discussed in the context of the most prevalent neurodegenerative diseases, Alzheimer’s disease (AD). Next, one such compound, L2-b, was demonstrated to target metal complexes of amyloid-beta (Abeta), an AD pathological feature, over metal-free Abeta, and reduce the reactivity of these species using biochemical and biophysical techniques. Upon application of L2-b to 5XFAD AD model mice, metal−Abeta was targeted and modulated in the brain; amyloid pathology was reduced; and AD-associated cognitive deficits were improved. These in vivo studies are the first time experimental evidence has directly linked metal−Abeta to AD pathogenesis.

Subsequent investigations developed new small molecules that could target and mediate abnormal metal-free and metal-induced reactivity. Initial studies began with a small series of stilbene-based compounds that were found to have different activity toward controlling metal-free Abeta and metal−Abeta reactivity despite their structural similarity. In-depth (bio)chemical and DFT calculations were also performed to propose modes of action for these molecules. This knowledge was then used to create a library of chemical tools that have different abilities toward mediating abnormal metal-free and metal-induced Abeta reactivity. Additionally, two more frameworks were developed and their ability to control metal−Abeta reactivity was explored.

Overall, the small molecules designed and analyzed here demonstrate that increased mechanistic understanding of their activity allows for the development of compounds with targeted abilities to control the reactivity of metal−protein complexes. Application of such compounds in vivo could lead to the elucidation of the pathogenesis of these devastating diseases, which could result in effective therapeutic discovery.