Azole γ‐Peptides Helix Switching via Heterocycle Substitutions
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.
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BibTeX
@article{chaise2026azole,
title = {{Azole γ‐Peptides Helix Switching via Heterocycle Substitutions}},
author = {Samantha Chaise and Claude Didierjean and Audrey Gacogne and Maxime Fillaudeau and Young Kee Kang and Aurélien Lebrun and Jean‐louis Bantignies and Dominique Housset and Muriel Amblard and Ludovic T Maillard and Baptiste Legrand},
journal = {Angewandte Chemie International Edition},
year = {2026},
month = jul,
doi = {10.1002/anie.9299244},
url = {https://hal.science/hal-05849567v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Azole γ‐Peptides Helix Switching via Heterocycle Substitutions
AU - Samantha Chaise
AU - Claude Didierjean
AU - Audrey Gacogne
AU - Maxime Fillaudeau
AU - Young Kee Kang
AU - Aurélien Lebrun
AU - Jean‐louis Bantignies
AU - Dominique Housset
AU - Muriel Amblard
AU - Ludovic T Maillard
AU - Baptiste Legrand
PY - 2026
DA - 2026/07/16
JO - Angewandte Chemie International Edition
DO - 10.1002/anie.9299244
UR - https://hal.science/hal-05849567v1
AB - 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.
SN - 1433-7851
SN - 1521-3773
ER -