The long-lasting impetus to design novel modes of macrocyclization, and their implementation
into a wide range of bioactive peptides, originates from their contributions to the restriction of conformational
space and the stabilization of preferential bioactive conformations that support higher efficacy
and binding affinity to cognate macromolecular targets, improved specificity and lowering susceptibility
to enzymatic degradation processes. Introducing CuI-catalyzed azide-alkyne cycloaddition
(CuAAC), a prototypical click reaction, to the field of peptide sciences as a bio-orthogonal reaction that
generates a disubstituted-[1,2,3]triazol-1-yl moiety as a pseudopeptidic bond that is peptidomimetic in
nature, paved the way to its widespread application as a new and promising mode of macrocyclization.
This review presents the state-of-art of CuAAC-mediated macrocyclization as it applies to an expansive
range of bioactive peptides and explores the relationship among the structural diversity of CuAACmediated
cyclizations, biological activities and conformations.