A Novel Methodology for the Incorporation of Chiral Linkers in Stapled Peptides
Chembiochem : a European journal of chemical biology
John Wiley & Sons Ltd.
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Serrano, J., Sipthorp, J., Xu, W., Itzhaki, L., & Ley, S. (2017). A Novel Methodology for the Incorporation of Chiral Linkers in Stapled Peptides. Chembiochem : a European journal of chemical biology, 18 (12), 1066-1071. https://doi.org/10.1002/cbic.201700075
Stapled peptides have arisen as a new class of chemical probe and potential therapeutic agents to modulate protein-protein interactions. Here, we report the first two-component i,i+7 stapling methodology using two orthogonal, on-resin stapling reactions to incorporate linkers bearing a chiral center on a p53-derived stapled peptide. Post-stapling modifications to the staple chain were performed on-resin, enabling rapid access to various peptide derivatives from a single staple. The stapled peptides have increased helicity, protease stability and in vitro binding affinities to MDM2 compared to the unstapled peptide. This approach can be used to generate a diverse library of stapled peptides with differing properties starting from a single stapled peptide, with scope for much greater functional diversity than that provided by existing stapling methodologies.
chiral linkers, protein–protein interactions, solid-phase synthesis, stapled peptides, two-component stapling
This work was supported by Engineering and Physical Sciences Research Council (EPSRC) grants EP/K009494/1, EP/M004120/1 and EP/K/039520/1. JCS acknowledges a scholarship from the Gates Cambridge Trust. LSI acknowledges the support of a Senior Fellowship from the Medical Research Foundation.
MRC (MC_PC_14116 v2)
External DOI: https://doi.org/10.1002/cbic.201700075
This record's URL: https://www.repository.cam.ac.uk/handle/1810/263622
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/