A Novel Methodology for the Incorporation of Chiral Linkers in Stapled Peptides
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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.
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1439-7633
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Engineering and Physical Sciences Research Council (EP/M004120/1)
Medical Research Council (G1002329)
Medical Research Council (MC_PC_13059)
MRC (MC_PC_14116 v2)