Functionalised staple linkages for modulating the cellular activity of stapled peptides

Yu Heng Lau, Peterson De Andrade, Soo Tng Quah, Maxim Rossmann, Luca Laraia, Niklas Sköld, Tze Jing Sum, Pamela J. E. Rowling, Thomas L. Joseph, Chandra Verma, Marko Hyvönen, Laura S. Itzhaki, Ashok R. Venkitaraman, Christopher J. Brown, David P. Lane, David R. Spring

Research output: Contribution to journalJournal articleResearchpeer-review


Stapled peptides are a promising class of alpha-helix mimetic inhibitors for protein-protein interactions. We report the divergent synthesis of "functionalised" stapled peptides via an efficient two-component strategy. Starting from a single unprotected diazido peptide, dialkynyl staple linkers bearing different unprotected functional motifs are introduced to create different alpha-helical peptides in one step, functionalised on the staple linkage itself. Applying this concept to the p53/MDM2 interaction, we improve the cell permeability and p53 activating capability of an otherwise impermeable p53 stapled peptide by introducing cationic groups on the staple linkage, rather than modifying the peptide sequence.
Original languageEnglish
JournalChemical Science
Issue number5
Pages (from-to)1804-1809
Publication statusPublished - 2014
Externally publishedYes

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