Strengthening Peptoid Helicity through Sequence Site-Specific Positioning of Amide cis-Inducing NtBu Monomers

The synthesis of biomimetic helical secondary structures is sought after for the construction of innovative nanomaterials and applications in medicinal chemistry such as the development of protein–protein interaction modulators. Peptoids, a sequence-defined family of oligomers, enable a peptidomimetic strategy, especially considering the easily accessible monomer diversity and peptoid helical folding propensity. However, cis–trans isomerization of the backbone tertiary amides may impair the peptoid’s adoption of stable secondary structures, notably the all-cis polyproline I-like helical conformation. Here, we show that cis-inducing NtBu achiral monomers strategically positioned within chiral sequences may reinforce the degree of peptoid helicity, although with a reduced content of chiral side chains. The design principles presented here will undoubtedly help achieve more conformationally stable helical peptoids with desired functions.