Project No. 2452
Dr Gregory Perry – University of Southampton
Prof Michelle D. Garret – University of Kent
Dr Matthias G. J. Baud – University of Southampton
Covalent small molecules are a powerful tool in protein modification and drug development.
Sulfur-fluoride exchange (SuFEx) – a technology based on the reactivity of sulfonyl fluorides – has come to the forefront of this field. Though powerful, SuFEx is restricted to the use of fluoride as a leaving group – the fluoride group cannot be modified which limits reactivity, selectivity and binding affinity.
We will establish sulfur-pyrrole exchange (SuPEx) as an approach to advance the current state-of-the-art. Whereas the leaving group in SuFEx chemistry (the fluoride) cannot be modified, the leaving group in our sulfonyl pyrrole reagents (the pyrrole) can be modified. This will allow us to tune the reactivity and specificity of our SuPEx reagents. This project will build on preliminary results in the group that have investigated the reactivity of sulfonyl pyrroles in organic synthesis and establish SuPEx as a tool in chemical biology. As a proof of concept, we will investigate the utility of our SuPEx reagents in the labelling of proteins that contain nucleophilic residues (e.g. cysteines) in their active site, for example EGFR or mutant RAS (G12C mutation).
SuPEx will provide better tools for chemical biology, for example they will lead to improved selectivity in protein labelling/modification, and improved specificity and binding affinity in covalent inhibition. This will aid developments in determining protein function and drug discovery.
Candidate Qualities: The candidate will display a passion for solving problems at the boundaries between chemistry and biology. They will be interested in developing their skills in synthetic organic chemistry and applying this knowledge in a biological context to help gain a better understanding of the rules of life and the development of more potent pharmaceuticals.