2026/07/16 by Samantha Chaise, Claude Didierjean, Audrey Gacogne +8 · 1 voice
Biochemistry, Genetics and Molecular Biology · Materials Science · Chemistry · #Chemical Synthesis and Analysis #Supramolecular Self-Assembly in Materials #Click Chemistry and Applications
paper · doi:10.1002/anie.9299244
openalex publication_date 2026/07/16 · openalex created_date 2026/07/18 · openalex updated_date 2026/07/22
ABSTRACT Precise control of peptide backbone folding through non‐covalent interactions remains a major challenge in foldamer design. In this work, we demonstrate that heteroatom substitutions program conformational switching in azole γ‐peptides by tuning intrinsic stereoelectronic effects within heterocyclic γ‐amino acids. Conformationally constrained thiazole‐ and oxazole‐based γ‐amino acids were designed to adopt conformations driven by either a C 9 or a C 7 intramolecular H‐bond depending on key 1,4‐X···O interactions (X = S or N). We previously showed that thiazole‐based oligomers form a well‐characterized canonical 9‐Helix. Here, permutation of the sulfur and nitrogen atoms within the heterocycle induces a stretched helical structure with alternating C 7 ‐turns and residues in extended conformations. This unusual topology arises from competition between seven‐membered intra‐residue H‐bonds and attractive S···N electrostatic‐chalcogen interactions. Reversing this effect through an S→O substitution affords oxazole‐derived oligomers that adopt a stable 7‐Helix stabilized by a continuous seven‐membered H‐bond network in solution. These findings show that simple heteroatom permutation or substitution allows control over heterocyclic γ‐peptide folding, thereby expanding opportunities for foldamer design in molecular recognition, catalysis, and biomedical applications.