Understanding and modulating protein-protein interactions (PPIs) is a key objective in understanding both healthy and disease processes,[1] and, for providing leads to develop new treatments for diseases of unmet medical need.[2] This project will develop methods to target the interactions of intrinsically disordered regions engaged in PPIs.
The β-strand is the second most abundant secondary structure (20-30%) and bioinformatics analyses have established that ~16% of PPIs have an interfacial β-strand.[3] The student will systematically explore backbone amide modification across a series of peptidomimetics designed to inhibit β-strand-mediated PPIs, specifically by: (a) biasing the conformational ensemble towards one that excludes unproductive low energy conformers; and, (b) increasing the rate of target binding. They will use N-alkylation[4] (which is already known to enhance cell-uptake and suppress proteolysis),[5] alongside amides→thioamide substitution. High-resolution structural methods will be used to understand the molecular determinants and mechanism of binding. Peptidomimetics will be prepared using automated solid-phase peptide synthesis and studied with structural biophysical methods to understand their conformational ensembles in the presence and absence of their target protein (using fluorescence anisotropy, surface plasmon resonance isothermal titration calorimetry and cutting edge 2D NMR experiments).
Supervisors: Professor Andy Wilson and Professor Teresa Carlomagno
Funding notes:
This is a PhD studentship with the Midlands Integrated Biosciences Training Partnership, funded by BBSRC and in partnership with the University of Warwick, University of Birmingham, Aston University, Harper Adams University, Coventry University, and the University of Leicester.
For more details please visit: https://warwick.ac.uk/fac/cross_fac/mibtp/ or https://www.birmingham.ac.uk/about/college-of-life-and-environmental-sciences/midlands-integrative-biosciences-training-partnership
References:
- F. Greenblatt, B. M. Alberts and N. J. Krogan, Cell, 2024, 187, 6501–6517.
- Lu, Q. Zhou, J. He, Z. Jiang, C. Peng, R. Tong and J. Shi, Signal Transduct. Target Ther., 2020, 5, 213.
- M. Watkins and P. S. Arora, ACS Chem. Biol., 2014, 9, 1747–1754.
- E. Cawood, E. Baker, T. A. Edwards, D. N. Woolfson, T. K. Karamanos and A. J. Wilson, Chem. Sci., 2024, 15, 10237–10245.
- Kremsmayr, A. Aljnabi, J. B. Blanco-Canosa, H. N. T. Tran, N. B. Emidio and M. Muttenthaler, J. Med. Chem., 2022, 65, 6191–6206.
