Exploring Structural and Chemical Reactivity of γ-Amino Acids in the Design of Peptide Foldamers and Small Molecule Peptidomimetics

Abstract

The progress in the field of foldamers constructed from the unnatural amino acid building blocks revealed that the folding phenomenon is not restricted to proteins. The advancement in the foldamer research has opened doors to various remarkable structures available to the oligomers of non-natural amino acids. Perhaps, β-and γ-peptides are among the most extensively studied unnatural oligomers. In addition to the various types of synthetic unnatural γ-amino acids, a variety of backbone functionalized, relatively unexplored γ-amino acids have been frequently found in many biologically active peptide natural products. In our previous studies, we have shown the utility of naturally occurring E-vinylogous γ-amino acids in the design of β-hairpins, β-double helices, β-meanders, and multi-stranded β-sheets. In the present study, we have examined the conformational properties and chemical reactivity of α,β-unsaturated γ-amino acids and their utility in the design of novel peptide foldamers, small molecule peptidomimetics and β-double helices. We have demonstrated the direct transformation of unusual planar α,γ-hybrid peptides composed of alternating α- and E-vinylogous γ-amino acids into 12-helical structures through a base mediated γ,β to β,γ double bond migration. Further, we have shown the transformation of E-vinylogous amino amides into new γ-lactams through a molecular rearrangement involving consecutive multiple double bond migrations. Moreover, we have examined the impact of dialkyl substituents (Thorpe–Ingold effect) in the design of β-sheet mimetics versus β-double helices from the homo-oligomers of E-vinylogous γ-amino acids. In addition to the geometrically constrained γ-amino acids, we have also examined conformations of saturated γ-amino acids in α,γ-hybrid peptide sequences. We have designed and studied the conformations of γαα-hybrid peptides embedded with crown-ethers and studied their ion transporting activities. Overall, the chemistry and conformational properties of unsaturated γ-amino acids reported here open wide opportunities to further explore them as building blocks for the foldamers design as well as templates to perform various organic reactions on peptides.