LAUSR

While foldamers have been extensively studied as protein mimics and especially as α‐helix mimics, their use as capping motif to enhance α‐helix propensity remains comparatively much limited. In this study, we leverage the structural similarities between urea‐based helical foldamers and α‐helix to investigate the efficacy of oligoureas as N‐ or C‐caps for reinforcing α‐helical structures in water. Short oligoureas, comprising 3 to 4 residues, were strategically introduced at the N‐ or C‐terminus of two peptide sequences (S‐peptide and an Ala‐rich model sequence). The impact of these foldamer insertions on peptide conformation was examined using electronic circular dichroism (ECD) and solution NMR. This research identifies specific foldamer sequences capable of promoting α‐helicity when incorporated at either terminus of the peptides. Not only does this work broaden the application scope of foldamers, but it also provides valuable insights into novel strategies for modulating peptide conformation in aqueous environments. The findings presented in this study may have implications for peptide design and the development of bioactive foldamer‐based peptide mimics.