Metal-Protein Attenuating Compounds (MPACs) for the Treatment of Alzheimer's Disease

Aberrant metal protein interactions leading to the generation of toxic reactive oxygen species and protein denaturation have been implicated in a number of neurodegenerative diseases. A breakdown in metal homeostasis plays a critical role in these disorders including Alzheimer's disease (AD), where abnormal interactions of copper and zinc ions with ß-amyloid (Aß) may underlie the pathogenesis. We have developed metal-protein attenuating compounds (MPACs) as a novel class of therapeutic agent that target pathogenic interactions of metals with proteins. The prototype for this class of compound is clioquinol (CQ), a small hydrophobic molecule capable of crossing the blood brain barrier. This compound has been shown to have beneficial effects in both a transgenic mouse model of AD and a recently completed small-scale phase II clinical trial.