Azole γ-Peptides Helix Switching via Heterocycle Substitutions

Area of Science:

• Chemical Biology
• Polymer Chemistry
• Organic Chemistry

Background:

• Controlling peptide backbone folding via non-covalent interactions is crucial for foldamer design.
• Heterocyclic amino acids offer unique structural possibilities for foldamer development.

Purpose of the Study:

• To demonstrate how heteroatom substitutions in azole γ-peptides program conformational switching.
• To investigate the role of stereoelectronic effects and intramolecular hydrogen bonds in dictating foldamer conformation.

Main Methods:

• Design and synthesis of conformationally constrained thiazole- and oxazole-based γ-amino acids.
• Analysis of intramolecular hydrogen bonding patterns (C9, C7) and electrostatic interactions (X···O).
• Structural characterization of resulting oligomers using solution-state methods.

Main Results:

• Permutation of S and N in thiazole γ-peptides induced a stretched helical structure with alternating C7-turns and extended conformations, driven by H-bonds and S···N interactions.
• Oxazole-derived oligomers (S→O substitution) adopted a stable 7-Helix stabilized by a continuous seven-membered H-bond network.
• Stereoelectronic effects and specific non-covalent interactions dictate the observed helical structures.

Conclusions:

• Simple heteroatom permutation or substitution provides precise control over heterocyclic γ-peptide folding.
• This control expands foldamer design possibilities for applications in molecular recognition, catalysis, and biomedicine.