A Peptoid with Extended Shape in Water

The
term “peptoids” was introduced decades ago to
describe peptide analogues that exhibit better physicochemical and
pharmacokinetic properties than peptides. Oligo­(N-substituted glycine) (oligo-NSG) was previously proposed as a peptoid
due to its high proteolytic resistance and membrane permeability.
However, oligo-NSG is conformationally flexible, and ensuring a defined
shape in water is difficult. This conformational flexibility severely
limits the biological application of oligo-NSG. Here, we propose oligo­(N-substituted alanine) (oligo-NSA) as a peptoid that forms
a defined shape in water. The synthetic method established in this
study enabled the first isolation and conformational study of optically
pure oligo-NSA. Computational simulations, crystallographic studies,
and spectroscopic analysis demonstrated the well-defined extended
shape of oligo-NSA realized by backbone steric effects. This new class
of peptoid achieves the constrained conformation without any assistance
of N-substituents and serves as a scaffold for displaying
functional groups in well-defined three-dimensional space in water,
which leads to effective biomolecular recognition.