Novel Therapeutic Metal Chelators with Dual Modes of action for the Treatment of Neurodegenerative Diseases (HLS/SE/DRFAPP7P/63592)

Alzheimer’s disease is the most common form of dementia today, and is predicted to affect 1 in 85 people globally by 2050. Current therapies for neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease only alleviate the symptoms and do not address the underlying causes. It is known that these diseases are associated with localized high concentrations of redox-active metals (eg: Fe(III) and Cu(II)) in the brain, leading to formation of reactive oxygen species from H2O2 (oxidative stress), protein-metal aggregation, neurotransmitter dysregulation and ultimately neuronal death. Promising new therapeutic approaches to these conditions is the redistribution and passivation of localized high levels of Fe(III) within the brain through chelation therapy.

For chelation therapy, the most promising class of Fe(III) chelators are the hydroxypyridinone (HOPO) ligands. Surprisingly however, few studies have been carried out on the therapeutic application of HOPOs against neurodegenerative diseases. We have recently shown that the less studied and slightly weaker 1-hydroxypyridin-2-one (1,2-HOPO) family of Fe(III) chelators show comparable results to the clinically used Deferiprone (a 3-hydroxypyridin-4-one used in chelation therapy against iron overload) in a cell culture model of Parkinson’s disease.1,2 It is however increasingly accepted that a therapy based on a single mode of action is not likely to be able to stop progress of dementia and that the use of compounds with dual mode of action (e.g. metal chelator associated with monoamine oxidase inhibitor) is more likely to show real benefits.

This collaborative project will be directed at the discovery of therapeutically effective, novel metal chelators through a program of organic synthesis, biological screening and medicinal chemistry optimization. We will synthesize novel derivatives of 1,2-HOPO chelators then synthesise bifunctional derivatives from them that contain additional potential benefits (e.g. BBB penetration, enzyme inhibitors, anti-oxidants). These are designed to provide greater therapeutic relief by their dual mode of action.

The organic synthesis part of the project will be performed at Northumbria University in collaboration with Dr. Frank Lewis. The biological evaluation of the new compounds (in vitro and in vivo) will be carried out on models of neurodegenerative diseases at the University of Leeds in collaboration with Dr. James Duce (School of Biomedical Sciences).
• The studentship will be used to gather data which will be used to leverage future grant applications to funding bodies such as the Wellcome Trust (Seeding Drug Discovery call), BBSRC and Parkinson’s UK.
• The project will have the following potential impacts:
(a) Academic (publication of peer reviewed REFable papers in high impact journals, conference proceedings, dissemination to other beneficiaries such as charities, foundations, etc).
(b) Economic (PI will liase with RBS to patent promising classes of compound. Following this the PI will engage with commercial players such as Eli-Lilly and the MRCT Dementia Consortium regarding licensing of IP if promising compounds are identified).
• Dr. Frank Lewis will be the second supervisor of this project.

Informal Enquiries
Enquiries regarding this studentship should be made to:
Dr David Tétard, [Email Address Removed]

For further details of how to apply, entry requirements and the application form, see
https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

Please ensure you quote the advert reference above on your application form.

Eligibility
For further details of how to apply, entry requirements and the application form, see
https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

Please ensure you quote the advert reference above on your application form.

How to Apply
For further details of how to apply, entry requirements and the application form, see
https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

Please ensure you quote the advert reference above on your application form.