Stapled peptides are conformationally restricted peptides which adopt well-defined secondary structures due to the cross-linking of unnatural amino acid side chains. These cyclic peptides are strong candidates for  addressing traditionally 'undruggable' drug targets such as protein-protein interactions due to their inherent binding selectivity, enhanced cell permeability and proteolytic resistance.We report the efficient synthesis of a range of diazidopeptides, their macrocyclisation with external linkers using either a double Staudinger ligation or Cu-catalysed azide-alkyne cycloaddition, and the resulting secondary structures induced by the macrocyclisations. This synthetic approach enables the conjugation of other functional domains to stapled peptides in a convergent route, ranging from simple fluorescent tags to organelle-targeting motifs.

Azide-based macrocyclisation strategies towards functionalised stapled peptides

243rd National Meeting (2012)

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