A Peptoid with Extended Shape in Water

Abstract

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.

Peptoids with Substituents on the Backbone Carbons as Conformationally Constrained Synthetic Oligoamides

“…42 So far, comparative studies of oligo NSA and N methylated peptides have not been reported, but the literature suggests their similarities and differences regarding conformational preferences. The crystal structures of the two molecules 36,43 implies that they form similar extended backbone conformations (Figure 10a and b). However, the preferred orientations of their substituents appeared to be different.…”

“…However, they also incorporated NSA alternately, not consecutively. 35 36 Inspired by the reports by Kodadek and other pioneers, we initiated a more detailed conformational analysis of oligo NSA.…”

“…The major conformation of oligoproline in water is the polyproline type II helix. A comparison of the crystal structures of oligoproline 46 and oligo NSA 36 indicated the conformational differences between the two oligomers. Oligoproline favors (φ, ψ) ( 70 , 150 ), which is clearly different from the (φ, ψ) ( 120 , 90 ), preferred by oligo NSA.…”

De Novo Design of Cell‐Penetrating Foldamers

“…[76,77] Furthermore, several studies have recently reported that the conformations of peptoids can be constrained by adding a methyl group to an α-carbon atom. [78,79] Most peptoids exhibit resistant to proteases because their backbones are composed of unnatural sequences and display low cytotoxicity, which are attractive properties for biological applications as cell-permeable molecules. Cell-penetrating peptoids (CPPos) containing an Arg-like side chain at the N-…”

Increasing the Functional Group Diversity in Helical β-Peptoids: Achievement of Solvent- and pH-Dependent Folding

“…Inspired by detailed studies of the trans-cis-amide equilibria of proline residues, [35][36][37][38] efforts have also been directed towards the development of methods to control these ratios in and -peptoids. [39][40][41][42][43][44][45][46][47][48][49] Still, only a limited number of examples of high-resolution structures of folded oligomers have been solved, [50][51][52][53][54][55][56][57][58] underlining the continued challenge of achieving structure-based design of oligomeric peptoids. We reported the N-(S)-1-(1-naphthyl)ethyl (Ns1npe, 1) side chain to promote formation of triangular prism-shaped -peptoid helical structure of oligomer 2, 31,53 and recently elaborated upon this highly cis-amide bond-inducing side chain to incorporate longer hydrocarbons (3) and amino groups.…”