Glycosylated Pro-drugs for Metal Passivation in Neurodegenerative Diseases
The amyloid hypothesis seeks to explain the aetiology of Alzheimer’s disease (AD) by linking irregularities present in the affected brain, insoluble aggregates of β-amyloid (Aβ) protein and elevated levels of redox active metal ions, with the observed symptoms of oxidative stress and brain tissue damage. β-amyloid is a ubiquitous, normal brain protein that, in the case of AD, becomes pathogenic through an unknown mechanism. While currently available therapeutic strategies such as the administration of cholinesterase inhibitors focus on relief of symptoms of AD (in this example, reduced neuronal activity), we have developed a strategy which seeks to target together two brain pathologies described in the amyloid hypothesis: elevated levels of metal ions and oxidative stress.
Our strategy seeks to obtain synergistic benefits from multifunctional drugs that bind and passivate redox active metal ions, particularly Cu(II), while also being potent inhibitors of the free radical oxidative processes that can lead to neurological tissue destruction. In addition, glucose substituents are incorporated into the compounds to promote prodrug uptake by the brain.Every compound is designed to include: 1) carbohydrate substituent(s) for improved central nervous system (CNS) access; 2) antioxidant functionality for reduction of oxidative stress conditions; 3) metal chelation capabilities to sequester excess CNS metal ions; and 4) amyloid targeting substituents.
Two prototype compound families have been synthesized, characterized, studied and patented in order to compare multiple variations of the two classes of designed multi-functional compounds through cell cytotoxicity and pharmacokinetic profiling, to identify lead compounds that can be used in further in vitro and in vivo studies.
This novel strategy has potential synergistic benefits for both prevention and treatment of neurological disorders, including Alzheimer’s and Parkinson’s diseases, and goes well beyond currently proposed therapies that either target reactive oxygen species (ROS), or non-specifically bind excess metal ions in the tissues of neurodegenerative disease patients.