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A New Methodology for Incorporating Chiral Linkers into Stapled Peptides.

ABSTRACT: 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.

SUBMITTER: Serrano JC

PROVIDER: S-EPMC5488175 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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A New Methodology for Incorporating Chiral Linkers into Stapled Peptides.

Serrano Juan C JC Sipthorp James J Xu Wenshu W Itzhaki Laura S LS Ley Steven V SV

Chembiochem : a European journal of chemical biology 20170518 12

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 s ...[more]

PMID: 28388005

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