Design of helical peptides : from Cys–Cys stapling to new Cys–Lys methodologies
(2026)
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- (en) Peptide stapling consists in covalently linking two amino acid side chains. By increasing peptide helicity, stapling has become a widely used strategy for mimicking α-helical protein segments and designing inhibitors of protein–protein interactions. Numerous chemical methods have been developed for the preparation of stapled peptides using either natural or unnatural amino acids. Among them, approaches involving two cysteine residues as anchoring points (“Cys–Cys stapling”) are the most widely used but are limited to the installation of symmetrical linkers. On the other hand, “Cys–Lys stapling” exploits the difference in nucleophilicity between the thiol and amine groups of cysteine and lysine residues, respectively. This approach enables the incorporation of non-symmetrical linkers, thereby expanding structural diversity. However, Cys–Lys stapling remains relatively underexplored, and novel methodologies are still needed. In this work, a new Cys–Lys stapling methodology was developed based on sequential S-alkylation and intramolecular reductive amination. After optimization of the one-pot procedure, the scope of the method was evaluated using a range of peptides and aldehyde-based reagents. Preservation of the nucleophilicity of the lysine side chain enabled bicyclization and post-stapling derivatization, further increasing structural diversity. As suggested by circular dichroism studies, the thiol-to-amine stapling method described in this work may represent a promising strategy for enhancing the helicity, and potentially the binding affinity, of bioactive peptides.
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Pierrard, F. (2026). Design of helical peptides : from Cys–Cys stapling to new Cys–Lys methodologies. https://hdl.handle.net/2078.5/278909