A Novel Methodology for the Incorporation of Chiral Linkers in Stapled Peptides

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.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