PhD Studentship: Development and Application of Enabling Methods for Drug Discovery

Transient protein-protein interactions (PPIs) control all cellular processes relevant to health and disease. Thus, a major problem in life-sciences research is to understand and manipulate PPIs with molecular and temporal resolution. Addressing this challenge will illuminate our understanding of disease development e.g. cell signalling in cancer or aggregation in amyloid disease and provide starting points for drug-discovery. However, methods to interrogate and manipulate PPIs are not well established. Moreover, intrinsically disordered regions – segments of protein with no fixed structure – that undergo disorder-to-order transitions upon formation of the PPI, compound this challenge.

A number of approaches to modulation of PPIs including competitive inhibition, stabilization and allosteric inhibition can be envisioned. Informed by structural and mechanistic understanding of the interactions between IDRs and their client proteins,[1] our group has developed a number of enabling methods that include computational methods[2] constrained peptides,[1] secondary structure mimetics[3] and covalent inhibitors.[4] In tandem we are applying novel fragment discovery methods[5] and developing tag-transfer cross-linking[6] to map ligand binding sites. In this PhD project the student will extend and apply these methods to focussed PPI modulator projects. Current targets include: BH3/BCl-2 family,[1] HIF-1α/p300,[7] interactions of 14-3-3 proteins,[8] (all oncology), and GKAP/SHANK-PDZ (synaptic function).[3]

A range of methods appropriate to the target will be employed including: computational prediction, peptide chemistry, novel fragment-screening technologies, development of new covalent warheads, biophysics and structural-molecular biology. This will allow the design, synthesis and testing of candidate PPI modulators to discover selective and cell-permeable modulator of the target PPI and ultimately chemical probes.[9] You will join a vibrant, diverse and group of researchers to gain skills and knowledge in chemical biology in its broadest sense, and participate in our wider collaborative research.

The project will be supervised by Prof Andy Wilson (https://ajwilsonresearch.com/).

Funding notes:

We offer a fully-funded programme of integrated research and skills training with cross-disciplinary supervision. This studentship includes stipend and tuition fees paid at the UKRI level. Support for conference attendance and research materials will be available.

References:

1. J. Miles, D. Yeo, P. Rowell, S. Rodriguez-Marin, C. Pask, S. Warriner, T. Edwards and A. Wilson, Chem. Sci., 2016, 7, 3694-3702.
2. A. Ibarra, G. Bartlett, Z. Hegedüs, S. Dutt, F. Hobor, K. Horner, K. Hetherington, K. Spence, A. Nelson, T. Edwards, D. Woolfson, R. Sessions and A. Wilson, ACS Chem. Biol., 2019, 14, 2252-2263.
3. S. Celis, F. Hobor, T. James, G. Bartlett, A. Ibarra, D. Shoemark, Z. Hegedüs, K. Hetherington, D. Woolfson, R. Sessions, T. Edwards, D. Andrews, A. Nelson and A. Wilson, Chem. Sci., 2021, 12, 4753-4762.
4. T. Ueda, T. Tamura, M. Kawano, K. Shiono, F. Hobor, A. Wilson and I. Hamachi, J. Am. Chem. Soc., 2021, 143, 4766-4774.
5. E. Cawood, N. Guthertz, J. Ebo, T. Karamanos, S. Radford and A. Wilson, J. Am. Chem. Soc., 2020, 142, 20845-20854.
6. J. Horne, M. Walko, A. Calabrese, M. Levenstein, D. Brockwell, N. Kapur, A. Wilson and S. Radford, Angew. Chem. Int. Ed., 2018, 57, 16688-16692.
7. F. Hóbor, Z. Hegedüs, A. Ibarra, V. Petrovicz, G. Bartlett, R. Sessions, A. Wilson and T. Edwards, RSC. Chem. Biol., 2022, 3, 592-603.
8. S. Srdanovic, M. Wolter, C. Trinh, C. Ottmann, S. Warriner and A. Wilson, FEBS J., 2022, 289 5341-5358.
9. J. Blagg and P. Workman, Cancer Cell, 2017, 32, 9-25.

To apply please email your cv via the above ‘Apply’ button.

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