PhD Studentship: Understanding Intrinsically Disordered Protein-Protein Interactions Using Peptidomimetics

University of Birmingham; Birmingham; On-site; GBP 18,000 - 23,000; Full time

Job summary

University of Birmingham is offering a PhD studentship focused on understanding and modulating protein-protein interactions (PPIs). The project will explore peptidomimetics designed to inhibit β-strand-mediated PPIs, employing N-alkylation and thioamide substitutions to enhance stability and cell uptake.

Supervisors include Professor Andy Wilson and Professor Teresa Carlomagno. The studentship is part of a collaborative program with Midlands Integrated Biosciences Training Partnership and

Responsibilities

• Develop methods to target interactions of intrinsically disordered regions engaged in PPIs.
• Systematically explore backbone amide modification across peptidomimetics designed to inhibit β-strand-mediated PPIs.
• Use N-alkylation and amide thioamide substitution to enhance cell uptake and proteolysis resistance.
• Apply automated solid-phase peptide synthesis and structural biophysical methods to study conformational ensembles.

Job description

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;
• (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

https://admissions.bham.ac.uk/applicant-home/applications/courses/coursedetails/?programmeid=178130b3-6c66-ed11-9561-0022481b589a

References:

1. J. F. Greenblatt, B. M. Alberts and N. J. Krogan, Cell, 2024, 187, 6501–6517.
2. H. Lu, Q. Zhou, J. He, Z. Jiang, C. Peng, R. Tong and J. Shi, Signal Transduct. Target Ther., 2020, 5, 213.
3. A. M. Watkins and P. S. Arora, ACS Chem. Biol., 2014, 9, 1747–1754.
4. E. E. Cawood, E. Baker, T. A. Edwards, D. N. Woolfson, T. K. Karamanos and A. J. Wilson, Chem. Sci., 2024, 15, 10237–10245.
5. T. Kremsmayr, A. Aljnabi, J. B. Blanco-Canosa, H. N. T. Tran, N. B. Emidio and M. Muttenthaler, J. Med. Chem., 2022, 65, 6191–6206.