Publication in Chemical Science

Our latest work is out now in Chemical Science

Our work on the development of novel photoswitchable stapled peptides is now out in Chemical Science. This was a collaborative project with Professor Matt Fuchter at the University of Oxford and was the work of PhD students in the group Sinead McCann and Kira Scobel. 

Photoswitches can be used to optically control the bioactive conformation of molecules through E–Z photoisomerisation, thereby enabling precise regulation of biological interactions with light. Herein, we describe the first use of a photoswitchable azobispyrazole cross-linker to generate light-responsive (i, i + 7)-stapled Bak^72–87 and p53^17–28 peptides. Photoisomerisation (E →Z) of the stapled peptides enhanced helical content and led to an increase in binding affinity for target proteins Bcl-x_L and MDM2, an effect that was reversible upon back-irradiation to the E isomer. The novel azobispyrazole cross-linker demonstrated excellent photochemical properties including near-quantitative E →Z and Z →E photoisomerisation and long thermal half-life of 65 days at 21 °C. These properties were retained in the stapled peptide form of AzBisPy-Bak^72–87 (0.5-year half-life) and were tolerant to biological assay conditions. Our work expands the repertoire of photoswitches designed for peptide stapling and demonstrates the ability of azobispyrazole-stapled peptides to modulate protein–protein interactions in a system where binding is controlled exclusively by light, independent of thermal relaxation, over a timescale of several weeks.