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Variable‐Length Ester‐Based Staples for α‐Helical Peptides by Using A Double Thiol‐ene Reaction
Author(s) -
Paterson Danielle L.,
Flanagan Jack U.,
Shepherd Peter R.,
Harris Paul W. R.,
Brimble Margaret A.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202001478
Subject(s) - peptide , chemistry , thiol , cell permeability , cysteine , combinatorial chemistry , stereochemistry , biochemistry , enzyme
Abstract A novel peptide stapling method effected by a double thiol‐ene reaction between two cysteine residues and a divinyl diester to access stapled peptides with enhanced cell permeability is reported. This diverse chemical tool kit provides facile access to stapled peptides with varying bridge lengths. Stapled Axin mimetics were synthesised by using this stapling method resulting in improved α‐helicity relative to the unstapled peptide. Cell penetrating stapled analogues of the SIGK peptide that targets the protein–protein interaction hotspot of Gβγ proteins were also synthesised that exhibited a moderate increase in α‐helicity and were cell permeable. This chemoselective peptide stapling method is highly amenable as a facile method to easily modify synthetic α‐helical peptides to target intracellular proteins.