Introduction to foldamers

Foldamers—synthetic oligomers and polymers that adopt well-defined folded structures—have emerged as a distinctive class of molecules at the interface of chemistry, biology, and materials science. Over the past two decades, their capacity to emulate the structural and functional features of natural biopolymers, such as proteins and nucleic acids, while providing enhanced stability, tunable conformations, and unique physicochemical properties, has stimulated extensive fundamental and applied investigations. These artificial folding architectures have been constructed from diverse backbones—including α-, β-, and γ-peptides, aromatic oligoamides, and their hybrid scaffolds—enabling precise control of molecular shape, surface presentation, and functional group arrangement. Foldamers thus represent a platform not only for the biomimicry of natural systems but also for the creation of entirely novel molecular entities. This themed issue highlights recent advances that demonstrate both the maturity and future potential of foldamer research. The studies presented here encompass molecular architectures, receptors, and bioactive scaffolds, all united by the principle that folding provides a general strategy to encode function.

Huc et al. investigate helical aromatic foldamers as protein-binding agents (https://doi.org/10.1039/d4ob01436g). A biotinylated foldamer, comparable to a 24-mer peptide, was synthesized and structurally characterized. Pull-down assays from yeast lysates identified multiple protein partners, and binding studies demonstrated affinities in the nanomolar to submicromolar range. These results indicate that even non-tailored foldamers can bind proteins strongly, suggesting potential applications in the modulation of protein function and complements to antibodies or aptamers.

Kirshenbaum et al. report the design of self-assembling peptide-based materials stabilized by aromatic interactions (https://doi.org/10.1039/d4ob01564a). Amphiphilic peptides are engineered to form defined nanostructures, such as fibers and sheets, in a sequence-dependent manner. Structural and biophysical analyses revealed that aromatic stacking and hydrogen bonding govern the assembly process and structural stability. The resulting materials display tunable mechanical and chemical properties, rendering them promising candidates for biomedical and nanotechnological applications, including scaffolds for tissue engineering, controlled drug delivery, and functional nanodevices.

Yokoo and Demizu et al. describe palindromic peptide foldamers to enhance peptide drug stability and cell permeability (https://doi.org/10.1039/d5ob00430f). These sequences adopt stable α-helical conformations, resist enzymatic degradation, and retain structure under denaturing conditions. Cellular uptake studies confirmed efficient intracellular delivery, largely independent of terminal stapling. The study highlights palindromic sequence design as a straightforward yet effective approach to improving peptide stability and delivery, offering promise for the development of next-generation therapeutic peptides.

The remaining contributions in this issue reflect the breadth of foldamer research. Several studies extend the scope of foldamer architecture, reporting new helices (https://doi.org/10.1039/D5OB00621J, https://doi.org/10.1039/D5OB00244C), hairpins, and layered motifs (https://doi.org/10.1039/D5OB00324E) that expand the repertoire of accessible structures (https://doi.org/10.1039/D5OB01226K). Others demonstrate the capacity of foldamers to function as receptors and adaptive frameworks (https://doi.org/10.1039/D5OB00228A), capable of binding carbohydrates (https://doi.org/10.1039/D5OB00908A, https://doi.org/10.1039/D4OB02061H), responding to solvent environments (https://doi.org/10.1039/D5OB00342C), or stabilizing otherwise unstable conformations (https://doi.org/10.1039/D5OB00355E). At the biology interface, foldamers provide insights into fundamental processes such as amyloid aggregation (https://doi.org/10.1039/D5OB00296F) and collagen stability (https://doi.org/10.1039/D5OB00176E), while also demonstrating activity as modulators of signaling pathways, including insulin receptor activation (https://doi.org/10.1039/D5OB00363F). At the translational level, foldamers are advancing as delivery vehicles, transporting DNA into cells with efficiencies comparable to established methodologies (https://doi.org/10.1039/D5OB00627A). Collectively, these contributions illustrate that foldamers have evolved from a niche curiosity into versatile molecular tools with broad applicability in chemistry, biology, and medicine.

Looking forward, several research directions appear particularly promising. The integration of foldamers with high-throughput selection and screening methodologies is expected to accelerate discovery. Synergy with materials science may enable the creation of adaptive frameworks and functional polymers for applications ranging from sensing to catalysis. In the biomedical domain, foldamers are positioned to progress beyond model systems towards genuine therapeutic modalities, functioning as protein binders, receptor modulators, or drug delivery platforms.

Ultimately, the field of foldamers exemplifies the creative application of folding as one of nature's most fundamental strategies. The contributions assembled in this issue underscore the significant progress achieved to date and point toward future opportunities. It is anticipated that these studies will stimulate further advances and inspire researchers across disciplines to explore how foldamers may be incorporated into their own scientific endeavors.

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