The strategic replacement of four alpha-amino acid residues of a cyclo-(alpha alpha alpha alpha alpha)(2) peptide by beta-, beta(2)- or beta(3)-amino acids residues provided a series of novel 2:1 alpha/beta-mixed peptides that were designed to adopt cyclic hairpin-like structures. It was shown that conformationally stable cyclo-(alpha beta alpha beta alpha)(2) isomers can be obtained using both enantiomers of the central two basic alpha-amino acid residues, a known alpha-amino acid turn sequence and several combinations of facing beta-amino acid residues with no side chain or a hydrophobic side chain having specific regio- and stereochemistry. The X-ray analysis of two derivatives provides molecular details of the intra-molecular hydrogen bonding interaction, dihedral angles of the backbone and side chain positioning of the novel cyclic hairpin-like structures. One of these isomers forms an unprecedented hexagon-shaped nano-channel assembly in the crystal structure. Well-defined cyclic hairpin-like structures as described here and derivatives that can be readily designed based on this research can be used as scaffolds onto which functional groups can be grafted in a spatially controlled manner and as beta-hairpin mimics with specific biological properties. (C) 2012 Elsevier Ltd. All rights reserved.