Foldamers with heterogeneous backbones.

The functions performed by proteins and nucleic acids provide the foundation for life. Chemists have recently begun to ask whether it is possible to design synthetic oligomers that approach the structural and functional complexities of these biopolymers. The study of foldamers, non-natural oligomers displaying discrete folding propensities, has demonstrated that there are several synthetic backbones that exhibit biopolymer-like conformational behavior. Early work in this area focused on oligomers comprised of a single type of monomer subunit, but recent efforts have highlighted the potential of mixed or "heterogeneous" backbones to expand the structural and functional repertoire of foldamers. In this Account, we illustrate the promise of heterogeneous backbone foldamers by focusing on examples containing both alpha- and beta-amino acid residues. Some beta-residues bear protein-like side chains, while others have cyclic structures that confer conformational rigidity. The study of heterogeneous backbone foldamers has several advantages over that of their homogeneous backbone counterparts, including access to many new molecular shapes based on variations in the stoichiometries and patterns of the subunit combinations and improved prospects for side chain diversification. Recent efforts to develop alpha/beta-peptide foldamers can be divided into two conceptually distinct classes. The first includes entities prepared using a "block" strategy, in which alpha-peptide segments and beta-peptide segments are combined to form a hybrid oligomer. The second class encompasses designs in which alpha- and beta-amino acid monomers are interspersed in a regular pattern throughout an oligomer sequence. One alpha/beta-peptide helical secondary structure, containing C=O(i)...H-N(i+4) H-bonds analogous to those in the alpha-helix, has been shown via crystallography to form helix bundle quaternary structures. Desirable biological functions have been elicited from alpha/beta-peptide foldamers. Efforts to mimic naturally occurring host-defense alpha-peptides have yielded new antimicrobial agents and have led to a reexamination of the long-held views regarding structure-activity relationships among these alpha-peptides and their analogues. Foldamers offer new platforms for mimicry of the molecular surfaces involved in specific protein-protein recognition events; recent achievements in the preparation of alpha/beta-peptide inhibitors of the protein-protein interactions involved in apoptotic signaling (e.g., between Bcl-xL and pro-apoptotic partners) have revealed the benefits of employing heterogeneous backbones relative to homogeneous backbones for foldamer-based designs. These initial successes in the development of alpha/beta-peptides exhibiting specific biological activities highlight the potential of heterogeneous backbone foldamers for use in biomedical applications and provide guidelines for future studies into new target functions.