Developing Enabling Synthetic Methods for Accelerated Peptidomimetic Drug Discovery


   School of Chemistry

   Applications accepted all year round  Funded PhD Project (Students Worldwide)

About the Project

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 and provide starting points for drug-discovery. Many PPIs employ peptides for recognition(1, 2) which represent viable and potentially powerful starting templates for designing PPI inhibitors. However, peptides have drawbacks, including conformational flexibility, poor proteolytic stability, and suboptimal cell uptake.

Our group has developed a number of enabling methods that include in silico tools,(3) constrained peptides,(1) protein or peptide-fragment hybrids(4, 5) and covalent backbone modification.(2) A key next step is to develop sustainable and higher throughput methods to prepare and screen peptidomimetics that exploit these capabilities. In this PhD project the student will explore novel synthetic methods for preparation and screening of peptidomimetics applied to focussed PPI modulator projects. Relevant targets include: SIM/SUMO, interactions of 14-3-3 proteins,(6) and interactions of Aurora A kinase(1) (all oncology). A range of techniques will be employed including: computational prediction, peptide chemistry, novel fragment-screening technologies and biophysics and structural-molecular biology.

You will join a vibrant, diverse and group of researchers to gain skills and knowledge in chemical and structural biology in its broadest sense, and, participate in our wider collaborative research.

Applications will be considered on an ongoing basis until suitable candidate(s) have accepted an offer. Applicants should contact Prof Andy Wilson () for informal inquiries, and before applying (with a CV and cover letter summarising your research interests and previous experience). For more information, please see: https://ajwilsonresearch.com/

Biological Sciences (4) Chemistry (6)

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. R. S. Dawber, D. Gimenez, M. Batchelor, J. A. Miles, M. H. Wright, R. Bayliss and A. J. Wilson, ChemBioChem, n/a, e202300649.
2. E. E. Cawood, E. Baker, T. A. Edwards, D. N. Woolfson, T. K. Karamanos and A. J. Wilson, ChemRxiv, 2023, 10.26434/chemrxiv-22023-xglb26434-v26433.
3. S. Celis, F. Hobor, T. James, G. J. Bartlett, A. A. Ibarra, D. K. Shoemark, Z. Hegedüs, K. Hetherington, D. N. Woolfson, R. B. Sessions, T. A. Edwards, D. M. Andrews, A. Nelson and A. J. Wilson, Chem. Sci., 2021, 12, 4753-4762.
4. E. E. Cawood, N. Guthertz, J. S. Ebo, T. K. Karamanos, S. E. Radford and A. J. Wilson, J. Am. Chem. Soc., 2020, 142, 20845-20854.
5. Z. Hegedüs, F. Hóbor, D. K. Shoemark, S. Celis, L.-Y. Lian, C. H. Trinh, R. B. Sessions, T. A. Edwards and A. J. Wilson, Chem. Sci., 2021, 12, 2286-2293.
6. S. Srdanović, M. Wolter, C. H. Trinh, C. Ottmann, S. L. Warriner and A. J. Wilson, FEBS J., 2022, 289, 5341-5358.

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