Introduction to the themed issue on Foldamer Chemistry

Since the advent of foldamer science as a concept less than 20 years ago, the discipline has taken root in the chemist's repertoire. Specialist scientific meetings have been organized periodically to successfully promote foldamer themes and, equally importantly, the principles are now considered to be relevant to a wide portfolio of inter-disciplinary applications, ranging from the search for biologically active molecules to new materials.

This themed issue presents a collection of 3 review articles and 14 research papers, which provide a representative state-of-the-art coverage of the high level research being carried out in a selection of the main areas of foldamer research. It is appropriate that these contributions come from research groups spanning four continents, underlining the extent to which foldamers have had an impact on the scientific community.

Timely perspectives are presented on emerging areas within the foldamer field. An instructive assessment is made of the role played by single or multiple γ-turn features in peptide oligomers, leading to the unusual γ-helix architecture (Formaggio et al., DOI: 10.1039/C4NJ01564A). Recent developments in the procedures used for the identification of biologically active macrocyclic peptides are reviewed, and their relevance to future foldamer design is discussed (Suga et al., DOI: 10.1039/C4NJ01633E). In the area of abiotic foldamers, recent progress involving aromatic oligoureas and oligoguanidines is surveyed, showing how these materials can provide both multi-layered and helical foldamers (Kudo & Tanatani et al., DOI: 10.1039/C4NJ01885K).

Peptides constructed from non-canonical amino acids have been a cornerstone of foldamer chemistry since its inception, and they remain the focus of a large proportion of contemporary research. These endeavors continue to bring their rewards, providing new insight and revealing novel design features for programmed biotic foldamer design. In this regard, new syntheses of cyclic β-amino acids in enantiomerically pure form provide ever-welcome additions to the foldamer building block toolbox (Cativiela et al., DOI: 10.1039/C4NJ01894J; Choi et al., DOI: 10.1039/C4NJ02056A).

New discernment emerges from detailed assessments of both folded and extended regular conformational preferences displayed by novel homo- or hetero-oligomer peptide sequences, which diversely incorporate α-, β-, γ- and/or δ-amino acids. The built-in design features of these peptides lead to a deeper understanding of the subtle and often interconnected factors which control folding preferences (Aitken et al., DOI: 10.1039/C4NJ01929F; Balaram et al., DOI: 10.1039/C5NJ00132C; Sharma, Kunwar et al., DOI: 10.1039/C4NJ02031F). In a different approach to the control of oligopeptide secondary structure, the solid-state analysis of Aib-rich foldamers shows the important relationship between a fold-inducing feature present at the N-terminus and the global screw-sense of the oligomers (Clayden et al., DOI: 10.1039/C4NJ01547A). Shrewd tactics are revealed for the construction of superstructure morphologies through the self-assembly of 14-helix β³-peptides (Mechler et al., DOI: 10.1039/C4NJ01926A). Theoretical studies continue to provide a valuable complement to experimental work, and a number of helical foldamer structures are predicted for oligomers of a γ-amino acid incorporating a cyclopentane ring restriction (Kang & Lee, DOI: 10.1039/C4NJ01202J), which can be expected to provide inspiration for future foldamer design.

Folded motifs other than helices are of increasing interest, notably in mimetics of β-sheet structures. A promising model for this type of foldamer manifold incorporates an aryl hydrazide, judiciously juxtaposed with the α-peptide strand via a β-hairpin mimetic (Piarulli, Ongeri et al., DOI: 10.1039/C4NJ01437E).

Moving away from bio-inspired foldamers, an intriguing cooperative inter-play is observed in mixed oligomers of proline and anthranilic acid, leading to zipper-like architectures (Sanjayan et al., DOI: 10.1039/C4NJ02151G). Functionalized aromatic building blocks occupy center stage in the area of abiotic foldamers, and an in-depth molecular dynamics study provides a valuable tool for the prediction of secondary structure preferences and solution-state dynamics of aryl amide families (Pophristic et al., DOI: 10.1039/C4NJ01925C). New studies show how aromatic oligoamides with greater backbone flexibility can be prepared with improved efficiency and lend themselves to cooperative conformational transitions (Gong et al., DOI: 10.1039/C4NJ01820F).

The development of stimulus-sensitive foldamers is a step towards their application as smart materials and is one of the current challenges for foldamer chemistry. Two successful demonstrations thereof complete the line-up of papers in this collection. The organized self-assembly of coumarin-functionalized lysine dipeptides in aqueous medium leads to the formation of hydrogels, which can subsequently be photo-crosslinked to provide stabilized nanofibers (Parquette et al., DOI: 10.1039/C5NJ00038F). In a break from amide-based manifolds, a new design strategy for the development of novel photo-responsive spiroborate helicates is described, providing a tool for controlling expansion and contraction motions associated in turn with metal ion complexation or expulsion (Yashima et al., DOI: 10.1039/C4NJ01669F).

I would like to thank all of the contributors and reviewers, and I hope that readers will enjoy this themed issue and find the collection of articles both instructive and inspirational.

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