Design, synthesis and structural analysis of mixed α/β-peptides that adopt stable cyclic hairpin-like conformations

Abstract

The strategic replacement of four α-amino acid residues of a cyclo-(ααααα) 2 peptide by β-, β 2- or β 3-amino acids residues provided a series of novel 2:1 α/β-mixed peptides that were designed to adopt cyclic hairpin-like structures. It was shown that conformationally stable cyclo-(αβαβα) 2 isomers can be obtained using both enantiomers of the central two basic α-amino acid residues, a known α-amino acid turn sequence and several combinations of facing β-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 β-hairpin mimics with specific biological properties. © 2012 Elsevier Ltd. All rights reserved.