Peptide and peptoid foldamers in medicinal chemistry

Introduction: Proteins and other biologics comprise emerging therapeutic class with efficacies against targets for which development of small-molecule antagonists has been unsuccessful. The biological function of a protein is intimately tied to its sequence-dependent folding. A variety of unnatural oligomer backbones show folding behavior analogous to proteins. Often termed ‘foldamers,’ these compounds have the potential to provide the benefits of existing protein therapeutics while overcoming some drawbacks, such as protease susceptibility. Areas covered: This review surveys work toward the development of foldamer therapeutics based on β-peptides, α-peptoids, β-peptoids and heterogeneous backbones composed of mixtures of these monomers with natural α-residues. Bioactivities targeted by foldamers are diverse but can be broadly divided into two categories: i) functions that require the simple separation of charged and hydrophobic functional groups and ii) functions that require a precise and complex three-dimensional display of side chains in the folded state. Expert opinion: A long-term goal in research on foldamers is to recreate the entire range of structure and function manifested by natural proteins on unnatural backbones. Successes in the development of bioactive foldamers not only show their promise, but also highlight the challenges associated with the invention of general and reliable design strategies. While there is still a long way to go to a clinically used foldamer drug, significant advances in recent years demonstrate the potential of such scaffolds for use in the discovery of new therapeutics.