School of Chemistry Colloquium: Dr Chris Coxon Fluoroaromatics as tools to define and probe peptide & protein conformations

Perfluoroaromatic reagents are valuable but underexplored tools with which to modify peptides and proteins. They are attractive for bioconjugation due principally to their facile nucleophilic substitution chemistry, the ability for their reactivity to be tuned towards specific nucleophiles and their tendency to undergo multiple nucleophilic substitutions [1]. In this talk, we will discuss our work on the optimisation of fluoroaromatic reagents for applications in chemoselective ‘tagging', stapling and macrocyclisation of peptides. Specifically, we will discuss the reactions of perfluoroaromatic reagents with cysteine side chains of peptides to lock peptides into alpha-helices as protein-protein interaction inhibitors [2], macrocycles with skin-penetrating properties and fluorescent multicycles [3].

Organic fluorine is almost absent in nature and, therefore, provides an excellent tool to incorporate into biomacromolecules to study their behaviour in native-like conditions using 19F NMR. Proline cis-trans isomerism plays a key role in protein folding and conformational switching and proline is over-represented in intrinsically disordered protein regions. Therefore, new ways to probe the conformation of prolines is valuable towards understanding protein folding and misfolding in diseases such as Parkinson's disease. We recently designed a peptide model that incorporates a 4-fluorophenylalanine residue distal to a proline (up to 6 amino acids away). Using this model, we were able to quantify how the amino acids proximal to proline affect its preference for cis or trans conformations, and therefore, understand how we can tune the local peptide sequence to control the conformational properties in small peptides [4]. Finally, we will return to the initial focus of the talk to discuss some possible new approaches to study larger native peptides/proteins in (or close to) their natural environments by ‘fluorine tagging' in combination with 19F NMR.

1. Brittain, W.D. Chem. Eur. J, 2022, 28, e202103305.
2. Verhoork, S.J. Chem. Eur. J., 2019, 25, 177-182.
3. Dognini, P. Chem. Eur. J., 2023, e202301410.
4. Killoran, P.M. Chem. Eur. J., 2023, 29, e202203017.