Development and application of approaches for discovery of orthosteric protein-protein interaction inhibitors


Contact Professor Andy Wilson to discuss this project further informally.

Project description

Protein-protein interactions (PPIs) control all cellular processes relevant to health and disease.1 Selective inhibition of individual PPIs would thus facilitate both a greater understanding of biological mechanisms; and provide new opportunities for therapeutic intervention. Yet, PPI inhibitors represent a minute fraction of current small molecule drugs, largely because of specific challenges associated with development of inhibitors for these targets.  

In previous work, we developed and exploited generic scaffolds that mimic the presentation of the amino acid side chains from an -helix (e.g. i, i+4, i+7).2-5  The potential of the approach was demonstrated through the discovery of potent, selective and cell-permeable inhibitors of a range of -helix-mediated PPIs. This research demonstrated that secondary structure mimetics can be used to inhibit PPIs related by structure, however small molecule scaffolds are currently not available to target constellations of side chains relevant to many other PPI classes.  

We are currently pursuing a major 5-year programme focused on developing tools to facilitate discovery of inhibitors of many PPI classes (together with our partners at Bristol and a range of drug discovery organisations). The programme will develop and exploit new computational tools to allow identification of PPIs that may be inhibited by small molecules. We will design, prepare and evaluate novel small molecule scaffolds that allow specific classes of PPIs to be targeted and ultimately exploit the new tools for discovery of cell-permeable inhibitors of a range of PPIs. The synthesis of these small molecule inhibitors will exploit synthetic approaches that we have developed to target diverse and novel lead-like chemical space.2  

As part of this programme, we are recruiting additional PhD students to the team; the students will undertake interdisciplinary projects as part of the programme and there will be multiple opportunities for personal development (including team-working), and possibly secondments to our industrial and academic partners. Indicative combinations of experimental and computational approaches to be used are as follows:
•    peptide design and synthesis; 
•    biophysics and structural biology; 
•    diversity- and lead-oriented synthesis; and
•    evaluation of the cellular function of novel PPI inhibitors.

Overall, the PhD students will contribute to the development, validation and exemplification of new tools that will facilitate the discovery of inhibitors of a wide range of biologically-relevant PPIs.

Further information about this project (pdf)

References 1. V Azzarito, K. Long, N. S. Murphy and A. J. Wilson*: Inhibition of a-Helix Mediated Protein-Protein Interactions Using Designed Molecules, Nature Chem., 2013, 5, 161-173 2. C. M. Grison, G. M. Burslem, J. A. Miles, L. K. A. Pilsl, D. J. Yeo, Z. Imani, S. L. Warriner, M. E. Webb, A. J. Wilson: Double Quick, Double Click Reversible Peptide “Stapling”, Chem. Sci., 2017, 8, 5166-5171. 3. J. A. Miles, D. J. Yeo, Philip Rowell, S. Rodriguez-Marin, C. M. Pask, S. L. Warriner, T. A. Edwards*, A. J. Wilson*: Hydrocarbon Constrained Peptides – Understanding Preorganization and Binding Affinity, Chem. Sci., 2016, 7, 3694-3702 4. C.M. Grison, J. A. Miles, S. Robin, A. J. Wilson*, D. J. Aitken*: An α-Helix-Mimicking 12,13-Helix: Designed α/β/γ-Foldamers as Selective Inhibitors of Protein–Protein Interactions, Angew. Chem. Int. Ed., 2016, 55, 11096–11100. 5. A Barnard, K. Long, H. L. Martin, J. A. Miles, T. A. Edwards, D. C. Tomlinson, A. Macdonald,* A. J. Wilson*: Selective and Potent Proteomimetic Inhibitors of Intracellular Protein-Protein Interactions, Angew. Chem. Int. Ed., 2015, 54, 2960-2965

Entry requirements

Applications are invited from candidates with, or expecting, a minimum of the equivalent of a UK upper second class honours degree (2:1) in a relevant discipline, a Master's degree in a relevant discipline, or both.

How to apply

Formal applications for research degree study should be made online through the university's website. Please state clearly in the research information section that the PhD you wish to be considered for is the ‘Development and application of approaches for discovery of orthosteric  protein-protein interaction inhibitors’ as well as Professor Andy Wilson as your proposed supervisor.

If English is not your first language, you must provide evidence that you meet the University’s minimum English Language requirements.

If you require any further information please contact the Graduate School Office

We welcome scholarship applications from all suitably-qualified candidates, but UK black and minority ethnic (BME) researchers are currently under-represented in our Postgraduate Research community, and we would therefore particularly encourage applications from UK BME candidates.  All scholarships will be awarded on the basis of merit.