Targeting recognition surfaces on natural proteins with peptidic foldamers

Molecules intended to antagonize protein-protein interactions or augment polypeptide-based signaling must bind tightly to large and specific surfaces on target proteins. Some types of unnatural oligomers with discrete folding propensities ('foldamers') have recently been shown to display this capability. This review covers important recent advances among several classes of foldamers, including α-peptides with secondary structures stabilized by covalent bonds, d-α-peptides, α/β-peptides and oligo-oxopiperazines. Recent advances in this area have involved enhancing membrane permeability to provide access to intracellular protein targets, improving pharmacokinetics and duration of action in vivo, and developing strategies appropriate for targeting large and irregularly-shaped protein surfaces.