Type 2 Diabetes Mellitus - where our bodies don’t produce enough insulin, or the insulin that is produced does not function properly, is an increasingly common disorder. Around four million people in the UK are affected by type 2 diabetes and it is estimated that £14 billion pounds is spent a year on treating diabetes and its complications in the UK alone. People with diabetes are up to five times more likely to have cardiovascular disease and their quality of life is likely to be more affected by it than people who don’t have the disease.
This is in part due to diabetes changing the cells that line your blood vessels, leading more toxic molecules in them and a decrease in beneficial molecules such as nitric oxide. We have recently shown that increased levels of a protein called PYK2 is found in the bodies of people with type 2 diabetes. This protein reduces nitric oxide levels by preventing the protein that makes nitric oxide (called eNOS) from working.
We will use fragment-based ligand discovery to identify fragments which modulate the interaction between eNOS and PYK2. These can be elaborated into small molecules. Fragment-based ligand discovery allows greater sampling of chemical space compared with traditional screening techniques, even with a modestly sized compound library. Because of the weaker binding affinities typically exhibited by fragments, sensitive biophysical techniques such as Nuclear Magnetic Resonance are required to detect the binding event. The use of fluorine-containing fragments for Nuclear Magnetic Resonance screening allows increased throughput versus fragments without a fluorine in as the spectra obtained are simplified and easier to read. This gives us the ability to screen mixtures of samples without spectral overlap, allowing cocktails of fragments, with ~10 compounds/tube, to be characterised, maximising efficiency.
This newly discovered interaction offers a novel way to address the cardiovascular complications of type 2 diabetes. The new 4-channel Nuclear Magnetic Resonance probe at Leeds allows fluorine-containing fragment screening for the first time. Results from this work will pave the way to develop therapies to treat type 2 diabetes-targeting a previously unexploited pathway.
This project will deliver training in many quantitative skills including computation and data analytics. The researcher will develop interdisciplinary skills at the interface of chemistry and molecular/structural biology including synthetic chemistry, nuclear magnetic resonance studies, X-ray crystallography, cell culture, western blotting and in vitro assays. The student will be embedded in the Discovery Science and Translational Medicine section in LICAMM and the School of Chemistry, with access to training and development sessions from eminent investigators in metabolic disorders and cardiovascular disease. The studentship will be in partnership with RedBrick Molecular and the candidate will have the opportunity to interact with the company throughout the duration of their PhD.
Lab Websites and Twitter Accounts
@chmkjs
(https://medicinehealth.leeds.ac.uk/medicine/staff/3140/dr-katie-simmons)
@MedicineDean
(https://medicinehealth.leeds.ac.uk/medicine/staff/490/professor-mark-kearney)
@MartinMcPhillie
(https://eps.leeds.ac.uk/chemistry/staff/5234/dr-martin-mcphillie)
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview