A New Methodology for Incorporating Chiral Linkers into Stapled Peptides

作者：Serrano Juan C; Sipthorp James; Xu Wenshu; Itzhaki Laura S; Ley Steven V

来源：ChemBioChem, 2017, 18(12): 1066-1071.

DOI：10.1002/cbic.201700075

• chiral linkers
• protein-protein interactions
• solid-phase synthesis
• stapled peptides
• two-component stapling

Stapled peptides have arisen as a new class of chemical probe and potential therapeutic agents for modulating protein-protein interactions. Here, we report the first two-component i,i+7 stapling methodology that makes use of two orthogonal, on-resin stapling reactions to incorporate linkers bearing a chiral centre into a p53-derived stapled peptide. Post-stapling modifications to the chain were performed on-resin and enabled 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 equivalent unstapled peptide. This approach can be used to generate a library of diverse stapled peptides with different properties starting from a single stapled peptide, with scope for much greater functional diversity than that provided by existing stapling methodologies.

• 出版日期2017-6-19