A model octapeptide segment derived from vasoactive intestinal peptide (VIP) was utilised to investigate the effect of several conventional cyclisation methods on the α‐helical conformation in short peptide fragments. Three of the classical macrocyclisation techniques (i.e. lactamisation, ring‐closing metathesis and Huisgen cycloaddition) were applied, and the conformations of the resulting cyclic peptides, as well as their linear precursors, were compared by CD analysis. The visibly higher folding propensity of the triazole‐tethered peptide after azide‐alkyne CuAAC macrocyclisation illustrates that the secondary structure of a short peptide fragment can differ significantly depending on the chemical strategy used to covalently cross‐link side chain residues in a ‘helical’ fragment.
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