Heterogeneous Foldamers from Aliphatic–Aromatic Amino Acid Building Blocks: Current Trends and Future Prospects

Abstract

Chemists' constant pursuit of understanding of the underlying principles of nature's most intricate phenomenon such as protein folding has led to the development of the field of “foldamers”. The emergence of diverse classes of unnatural amino acid building blocks has unleashed countless opportunities to design, develop and explore the structural and functional aspects of synthetic peptides. One current trend in foldamer chemistry is the heterofoldamer approach, which involves systematic stoichiometric variation of various natural/unnatural amino acid residues, leading to conformational ordering with intriguing structural architectures. In this regard, the incorporation of aromatic amino acids provides efficient structural rigidification and tunability to the molecular scaffolds, which can exhibit a range of secondary structural features. Recent times have witnessed an upsurge of foldamers featuring aliphatic‐aromatic residues with diverse structural propensities. This review is an effort to cover this rapidly developing field of foldamer science and also to envisage its future perspectives.

Parallel Homochiral and Anti‐Parallel Heterochiral Hydrogen‐Bonding Interfaces in Multi‐Helical Abiotic Foldamers

“…as isolated helices or b-strands,o ccur in ag reat variety of synthetic backbones. [1] In contrast, the design of tertiary folds is ac onsiderable challenge.T his challenge is worth pursuing because tertiary folding is the level at which sophisticated functions emerge in proteins and the same may be expected for foldamers.The way is being paved by impressive progress in protein design [2] and increasing mastery in programming binding interfaces between peptidic structures,i np articular within peptide helix bundles. [2b,c,3] Forinstance,helix bundles have been reported in peptidomimetics,s uch as b-peptides [4] and b-ureas.…”

Oligomers of α‐ABpeptoid/β3‐peptide hybrid

“…In addition to foldamers with homogeneous backbones, peptidomimetics possessing heterogeneous backbone structures are of considerable interest . The use of heterogeneous backbones could not only expand the structural complexity and functional repertoire of peptidomimetic foldamers but also exhibit various biological activities.…”

Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure

“…The bulk of research on this class of molecules, termed “foldamers,” 1 has focused on secondary structures (helices, sheets, and turns) that are either inspired by motifs found in nature or completely abiotic in origin. 2 More recent work has sought to create unnatural backbones mimic target folds with increased intricacy, such as multi-helix quaternary assemblies, 3 multi-stranded sheets, 4 and unimolecular tertiary structures. 5 The design of such molecules remains a significant challenge, the magnitude of which scales with the complexity of the desired fold.…”