Long-lived azobispyrazole stapled peptides for light-activated inhibition of protein–protein interactions
- 1Department of Chemistry, Molecular Sciences Research Hub, Imperial College London 82 Wood Lane London W12 0BZ UK
- 2Department of Chemistry, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK
- 3Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR) 30 Biopolis Street, #07-01 Matrix Singapore 138671 Singapore
Abstract
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 Bak72–87 and p5317–28 peptides. Photoisomerisation (E → Z) of the stapled peptides enhanced helical content and led to an increase in binding affinity for target proteins Bcl-xL 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-Bak72–87 (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.
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BibTeX
@article{mccann2026longlived,
title = {{Long-lived azobispyrazole stapled peptides for light-activated inhibition of protein–protein interactions}},
author = {Sinead McCann and Davia Prischich and Kira Scobel and Dennis J. Worm and Aditya R. Thawani and Marie Mori and Yaw Sing Tan and Anna Barnard and Matthew J. Fuchter},
journal = {Chemical Science},
year = {2026},
month = nov,
doi = {10.1039/d6sc06137k},
url = {https://doi.org/10.1039/d6sc06137k},
note = {CC BY 3.0},
}
RIS
TY - JOUR
TI - Long-lived azobispyrazole stapled peptides for light-activated inhibition of protein–protein interactions
AU - Sinead McCann
AU - Davia Prischich
AU - Kira Scobel
AU - Dennis J. Worm
AU - Aditya R. Thawani
AU - Marie Mori
AU - Yaw Sing Tan
AU - Anna Barnard
AU - Matthew J. Fuchter
PY - 2026
DA - 2026/11/02
JO - Chemical Science
DO - 10.1039/d6sc06137k
UR - https://doi.org/10.1039/d6sc06137k
AB - 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 Bak72–87 and p5317–28 peptides. Photoisomerisation (E → Z) of the stapled peptides enhanced helical content and led to an increase in binding affinity for target proteins Bcl-xL 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-Bak72–87 (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.
SN - 2041-6520
SN - 2041-6539
ER -