Design, synthesis, and structural characterization of helix-forming aliphatic homo-δ-peptides based on conformational restriction due to the structural characteristics of cyclopropane

Abstract

Considerable effort has been directed toward developing artificial peptide-based oligomers that fold into a specific secondary structure, i.e., peptide foldamers. To date, however, detailed structural analysis of crystals of δ-peptide foldamers consisting of aliphatic δ-amino acids, which have a more extended carbon backbone compared with well-studied β- and γ-amino acids, have not been reported. We rationally designed aliphatic homo-δ-peptide foldamers forming a stable helical structure utilizing a chiral cyclopropane δ-amino acid as a monomer unit whose conformation was tightly restricted by the structural characteristics of cyclopropane depending on its stereochemistry. We stereoselectively synthesized the cyclopropane δ-amino acid monomer and prepared its various homo-oligomers. Structural analysis of the homo-δ-peptides using nuclear magnetic resonance, circular dichroism, and infrared spectroscopy revealed that they form a stable 14-helical structure in solution. Furthermore, the effective conformational regulation of the backbone due to the characteristics of cyclopropane allowed us to achieve X-ray crystallographic analysis of the homo-δ-peptides, showing their common right-handed 14-helical structures. The helical structures were consistent with both those predicted by theoretical calculations and those obtained based on nuclear magnetic resonance spectroscopy in solution. A critical point is that the helical structures of these δ-peptides are theoretically predictable by calculations. To our knowledge, this is the first example of aliphatic homo-δ-peptide foldamers forming a stable helical structure both in solution and in crystal.