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Chemical tools as modulators of amyloid formation


Project Description

The inherent ability of proteins to aggregate into amyloid fibrils underlies more than fifty human diseases. The misassembly of soluble proteins into toxic aggregates underlies a variety of conditions including AD and Type-2 diabetes. Amylin (hIAPP) and 2m are two proteins of interest in understanding the mechanism of protein misfolding.

The project aims to apply our considerable expertise in the protein misfolding and small molecule inhibitor fields to identify small chemical probes of hIAPP and 2m. Such a compound will be used to provide new opportunities to understand how and why proteins form amorphous aggregates or self-assemble into amyloid and to potentially develop therapeutics to treat disease.

The project brings together our established robust assays for measuring the binding and inhibition of amyloid formation of prototype compounds and access to target expertise around the structural biology of hIAPP and 2m proteins with distinct and complementary approaches for the identification of small molecules able to bind to and inhibit amyloid formation.

The specific aims of the project are to: (i) identify novel chemical modulators through screening of repurposing libraries, (ii) use medicinal chemistry tool and techniques to demonstrate the ability to rationally design chemical modulators of intrinsically disordered proteins, (iii) demonstrate the potential for incorporation of a structural hypothesis to binding based on in silico design and structural biology, (iv) optimise inhibitors for drug-likeness and pharmaceutical and pharmacokinetic properties consistent with a bioavailable agent

Funding Notes

White Rose BBSRC Doctoral Training Partnership in Mechanistic Biology
4 year fully-funded programme of integrated research and skills training, starting Oct 2019:
• Research Council Stipend
• UK/EU Tuition Fees
• Conference allowance
• Research Costs

Requirements:
At least a 2:1 honours degree or equivalent. We welcome students with backgrounds in biological, chemical or physical sciences, or mathematical backgrounds with an interest in biological questions.
EU candidates require 3 years of UK residency in order to receive full studentship

Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process.

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References

RF:
Saunders, J.C., Young, L.M., Mahood, R.A., Revill, C.H., Foster, R.J., Jackson, M.P., Smith, D.A.M., Ashcroft, A.E., Brockwell, D.J. & Radford, S.E. (2016) An in vivo platform for identifying inhibitors of protein aggregation Nature Chem. Biol., 12, 94-101

Schumann S, Jackson BR, Yule I, Whitehead SK, Revill C, Foster R, Whitehouse A Targeting the ATP-dependent formation of herpesvirus ribonucleoprotein particle assembly as an antiviral approach Nature Microbiology 2 -, 2016

Read C, Fitzpatrick CM, Yang P, Kuc RE, Maguire JJ, Glen RC, Foster R, Davenport AP Cardiac action of the first G protein biased small molecule apelin agonist Biochemical Pharmacology 116 63-72, 2016


Young, L.M., Saunders, J.C., Mahood, R.A., Revill, C.H., Foster R.J., Tu, L.-H., Raleigh, D.P., Radford, S.E. & Ashcroft, A.E. (2015) Screening and classifying small molecule inhibitors of amyloid formation using ion mobility spectrometry-mass spectrometry. Nature Chemistry, 1, 73-81

SER:
Saunders, J.C., Young, L.M., Mahood, R.A., Revill, C.H., Foster, R.J., Jackson, M.P., Smith, D.A.M., Ashcroft, A.E., Brockwell, D.J. & Radford, S.E. (2016) An in vivo platform for identifying inhibitors of protein aggregation Nature Chem. Biol., 12, 94-101

Stull, F., Koldewey, P., Humes, J.R., Radford, S.E. & Bardwell, J.C.A. (2016) Substrate protein folds while it is bound to the ATP-independent chaperone Spy Nat. Struct. Mol. Biol. 1, 53-59

Young, L.M., Saunders, J.C., Mahood, R.A., Revill, C.H., Foster R.J., Tu, L.-H., Raleigh, D.P., Radford, S.E. & Ashcroft, A.E. (2015) Screening and classifying small molecule inhibitors of amyloid formation using ion mobility spectrometry-mass spectrometry. Nature Chemistry, 1, 73-81

Tipping, K.W., Karamanos, T.K., Jakhria, T., Iadanza, M.G., Goodchild, S.C., Tuma, R., Ranson, N.A., Hewitt, E.W. & Radford, S.E. (2015) pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers. PNAS, 112, 5691-5696

Related Subjects

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FTE Category A staff submitted: 34.40

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