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A New Methodology for Incorporating Chiral Linkers into Stapled Peptides
Author(s) -
Serrano Juan C.,
Sipthorp James,
Xu Wenshu,
Itzhaki Laura S.,
Ley Steven V.
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700075
Subject(s) - peptide , combinatorial chemistry , affinities , chemistry , peptidomimetic , protease , binding affinities , in vitro , stereochemistry , computational biology , biochemistry , biophysics , receptor , enzyme , biology
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.