Design, Synthesis and Study of Hybrid Cyclic Peptides and Peptide Nucleic Acids from Delta Amino Acids

Abstract

Self-assembling cyclic peptides are important building blocks for constructing synthetic nanotubes. They can be primarily classified into D, L-cyclic peptides, cyclic β-peptides, cyclic α, γ-peptides, and cyclic peptides incorporating δ- or ε-amino acids based on their composition. Our research focuses on the design of novel cyclic peptides derived from β(O)-δ5-amino acid residues, consisting of a hybrid structure of crown ether and peptide macrocycles. These peptides exhibit unique self-assembly, forming hollow sub-nanotubular structures with unidirectional hydrogen bonds. These cyclic dipeptides, adopting non-centrosymmetric space groups, display significant anisotropy, suggesting potential macroscopic dipole extensions. Furthermore, their inherent macrodipole orientation inspires investigation into their piezoelectric properties, opening new avenues for diverse applications. Additionally, we have synthesized size-variant macrocycles featuring β(O)-δ5-amino acid residues, which also fold into self-assembled sub-nanotubes in solution and gas phase. These supramolecular sizevariant sub-nanotubes act as anion-selective transporters. The ion channel activity and selective ion transport activity of these cyclic peptides may have great potential in the construction of functional artificial transmembrane transporters. We further explored these δ-amino acids to design novel Peptide Nucleic Acids (PNAs), aiming to enhance solubility, binding affinity, and specificity to DNA/RNA. We have synthesized new PNAs and conducted UV-Tm studies to assess their thermal stability and binding affinity against ssDNA and ssRNA. Remarkably, the new PNAs bind to both ssDNA and ssRNA similarly to the aeg peptide nucleic acids. The advantage of these new δ-amino acid-based peptide nucleic acids over the aegPNAs is that they are easy to synthesize and scale up using solid-phase methods. Additionally, compared to age peptide nucleic acids, the new PNAs are highly soluble in aqueous solution. These new peptide nucleic acids may serve as alternatives to existing aeg-peptide nucleic acids. Overall, we designed and studied new cyclic peptides and peptide nucleic acids from β(O)-δ5- amino acid residues. The new hybrid crown ether-cyclic peptide mimetics and peptide nucleic acids described here can serve as piezo-electronic materials, transmembrane channel-forming candidates, and DNA/RNA-binding proteolytically stable biomolecules.