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  Synthesis of novel metal chelators against Parkinson’s Disease (ref: SF22/HLS/APP/TETARD)


   Faculty of Health and Life Sciences

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  Dr D Tetard  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The involvement of iron in the development of Parkinson’s Disease is now well recognised. Iron seems to be accumulating in the neurons of sufferers and is involved in the formation of reactive oxygen species that cause oxidative damage to neurons, resulting in their death.

For this reason, numerous research groups are actively involved in the development of novel selective iron(III) chelators that could prevent its involvement in the electron-transfer reaction that cause these oxidative damages to lipids, enzymes and DNA.

However, this strategy to fight Parkinson’s Disease is not a straightforward accomplishment. First of all, iron(III) is ubiquitous in living organisms, including human and is involved in numerous enzymes. Also, metal chelators are usually not totally selective and might bind metals other than the metal of choice. It is therefore necessary to design chelators that are selective for iron(III) over other biologically relevant metals (e.g. Mg(II), Cu(II), Zn(II), etc.) and importantly. that will not be so strong as to inhibit enzymes that include iron as co-factor. Another complication is that the chelator must be capable of reaching the brain to be effective. The central nervous system is shielded from exogenous molecules by an effective protective membrane called the Blood Brain Barrier (BBB). Any chelator must therefore be capable of crossing the BBB in a large enough concentration to be biologically effective.

We have designed numerous classes of chelators based on the hydroxypyridinone family of powerful and selective iron(III) chelators and demonstrated their potential in protecting neuron models against oxidative damage.1-5 Some of our first generation of chelators were simple molecules designed only to chelate iron(III) with no in-built means to cross the BBB. Others were designed to chelate iron(III) but also use the amino acid transporter LAT-1 as a mean to penetrate the brain though the BBB. Other molecules were designed to cross the BBB via passive diffusion but provide two modes of action beneficial against Parkinson’s Disease.

The project will progress further in these two latter directions by synthesising second generation versions of these molecules to build on the learning gained so far and develop toward a lead candidate that could assessed in clinical trials.

The candidate must have a background in organic synthesis with lab experience and be comfortable with inorganic chemistry, physical chemistry and biochemistry. The student must also be willing to learn biological screening techniques on cells. 

Eligibility and How to Apply:

Please note eligibility requirement:

•      Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non- UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above)

•      Appropriate IELTS score, if required

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 note: All applications must include a covering letter (up to 1000 words maximum) including why you are interested in this PhD, a summary of the relevant experience you can bring to this project and of your understanding of this subject area with relevant references (beyond the information already provided in the advert). Applications that do not include the advert reference (e.g. SF22/…) will not be considered.

 

Deadline for applications: Ongoing

Start Date: 1st October and 1st March are the standard cohort start dates each year.

Northumbria University is committed to creating an inclusive culture where we take pride in, and value, the diversity of our doctoral students. We encourage and welcome applications from all members of the community. The University hold a bronze Athena Swan award in recognition of our commitment to advancing gender equality, we are a Disability Confident Employer, a member of the Race Equality Charter and are participating in the Stonewall Diversity Champion Programme. We also hold the HR Excellence in Research award for implementing the concordat supporting the career development of researchers.

Informal enquiries to Dr David Tétard ([Email Address Removed])

Chemistry (6)

Funding Notes

This project is fully self-funded and available to applicants worldwide. Tuition fees will depend on the running cost of the individual project, in line with University fee bands found at https://www.northumbria.ac.uk/study-at-northumbria/fees-funding/. The fee will be discussed and agreed at interview stage.
Please note: to be classed as a Home student, candidates must meet the following criteria:
Be a UK National (meeting residency requirements), or
have settled status, or
have pre-settled status (meeting residency requirements), or
have indefinite leave to remain or enter.
If a candidate does not meet the criteria above, they would be classed as an International student.

References

1. Gutbier, S.; Kyriakou, S.; Schildknecht, S.; Uckert, A. K.; Brull, M.; Lewis, F.; Dickens, D.; Pearson, L.; Elson, J. L.; Michel, S.; Hubscher-Bruder, V.; Brandel, J.; Tétard, D.; Leist, M.; Pienaar, I. S., Design and evaluation of bi-functional iron chelators for protection of dopaminergic neurons from toxicants. Arch. Toxicol. 2020, 94 (9), 3105-3123.
2. Lewis, F. W.; Fairooz, S.; Elson, J. L.; Hubscher-Bruder, V.; Brandel, J.; Soundararajan, M.; Smith, D.; Dexter, D. T.; Tetard, D.; Pienaar, I. S., Novel 1-hydroxypyridin-2-one metal chelators prevent and rescue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson's disease. Arch. Toxicol. 2020, 94 (3), 813-831.
3. Lewis, F. W.; Bird, K.; Navarro, J.-P.; El Fallah, R.; Brandel, J.; Hubscher-Bruder, V.; Tsatsanis, A.; Duce, J. A.; Tétard, D.; Bourne, S.; Maina, M.; Pienaar, I. S., Synthesis, Physicochemical Characterization and Neuroprotective Evaluation of Novel 1-hydroxypyrazin-2(1H)-one Iron Chelators in an In Vitro Cell Model of Parkinson’s Disease. Dalton Trans. 2022, Accepted for publication.
4. Workman, D. G.; Tsatsanis, A.; Lewis, F. W.; Boyle, J. P.; Mousadoust, M.; Hettiarachchi, N. T.; Hunter, M.; Peers, C.; Tétard, D.; Duce, J. A., Protection from Neurodegeneration in the 6-Hydroxydopamine (6-OHDA) Model of Parkinson’s with Novel 1-Hydroxypyridin-2-one Metal Chelators. Metallomics 2015, 7, 867-876.
5. Bergin, J. C. J.; Tan, K. K.; Nelson, A. K.; Amarandei, C. A.; Hubscher-Bruder, V.; Brandel, J.; Voinarovska, V.; Dejaegere, A.; Stote, R. H.; Tetard, D., 1-Hydroxy-2(1H)-pyridinone-Based Chelators with Potential Catechol O-Methyl Transferase Inhibition and Neurorescue Dual Action against Parkinson's Disease. Molecules 2022, 27 (9).

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