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The design of a dynamically assembled foldarotaxane was envisioned with the aim of operating as a two cascading trigger‐based molecular shuttle. Under acidic conditions, both the macrocycle and helix were localized around their respective best molecular stations because they are far enough from each other not to alter the stability of complexes. The pH‐dependent localization of the macrocycle along the encircled axle allowed us to modulate the association between the helical foldamer and its sites of interaction on the axle. Under kinetic control—at low concentration and room temperature—when the foldarotaxane supramolecular architecture is kinetically stable, the pH‐responsive translation of the macrocycle along the thread triggered the gliding of the helix away from its initial best station. At higher concentration—when helix assembly/disassembly process is accelerated—the system reached the equilibrium state. A new foldarotaxane isomer then appeared through the change of the relative position of the helix and macrocycle along the thread. In this isomer, the helix segregated the macrocycle away from its best station. The fine control of the kinetic and thermodynamic processes, combined with the control of pH, allowed the reciprocal segregation of the helix or the ring away from their respective best sites of interaction. [ABSTRACT FROM AUTHOR]

Developing new methods to control the size and shape of the helical structures adopted by foldamers is highly important as the secondary structure displayed by these supramolecular scaffolds often dictates their activity and function. Herein, we report on a systematic study demonstrating that the helical pitch of ortho‐azobenzene/2,6‐pyridyldicarboxamide foldamers can be readily controlled through the nature of the terminal functionality. Remarkably, simply through varying the end group of the foldamer, and without modifying any other structural features of the scaffold, the helical pitch can be over doubled in magnitude (from 3.4 Å–7.3 Å). Additionally, crystallographic analysis of a library ten foldamers has identified general trends in the influence of a range of terminal functionalities, including carboxylbenzyl (Cbz), diphenylcarbamyl (N(Ph)2), ferrocene (Fc) and tert‐butyloxycarbonyl (Boc), in controlling the folding behaviour of these supramolecular scaffolds. These studies could prove useful in the future development of functional foldamers which adopt specific sizes and shapes. [ABSTRACT FROM AUTHOR]

In this study, we focus on the designability and controllability of the interaction interface between secondary structures, and discover an important interface interaction between helical secondary structures by non‐covalent synthesis along the helical axis. The formation of discrete heterochiral dimers consisting of left‐handed helix and right‐handed helix not only helps to discover nonclassical supramolecular chirality phenomena, but also enables controllable protein assembly. Highly ordered nanostructures were thus constructed using π‐stacking dimerization of helical foldamers to control tetrameric avidin proteins. The designable and modifiable primitives of artificial folded molecules enable the modification of secondary structure interfaces through non‐covalent interactions, leading to the generation of unique structures and functions. These findings are of fundamental importance to the understanding of the precise assembly process of helical foldamers and can provide insights to facilitate the rational design of abiotic protein‐like tertiary structures and further functionalization. [ABSTRACT FROM AUTHOR]

We report on dual, light‐responsive and redox‐active foldamers that demonstrate reversible and robust stimuli‐induced behaviour. Herein, UV/Vis, 1H NMR and circular dichroism (CD) spectroscopy and cyclic voltammetry have been used to establish the reversibility and highly robust nature of the light‐ and redox‐driven behaviour of these new foldamers with minimal levels of fatigue observed even upon multiple cyclic treatments with irradiative/non‐irradiative and oxidative/reductive conditions. This proof‐of‐concept work paves the way towards the creation of novel stimuli‐responsive foldamers of increasing sophistication capable of demonstrating reversible and robust responses to multiple distinct stimuli. [ABSTRACT FROM AUTHOR]

The folding of oligomeric strands is the method that nature has selected to generate ordered assemblies presenting spectacular functions. In the purpose to mimic these biomacromolecules and extend their properties and functions, chemists make important efforts to prepare artificial secondary, tertiary, and even quarternary structures based on folded abiotic backbones. A large variety of oligomers and polymers, encoded with chemical informations, were designed, synthesized and characterized, and the establishment of non‐covalent interactions lead to complex and functional supramolecular architectures resulting from a spontaneous self‐assembly process. The association of complementary molecular strands into double helical structures is a common structural pattern of nucleic acids and proteins, so the synthesis of bio‐inspired double helices has emerged as an important subject. In recent years, a number of synthetic oligomers have been reported to form stable double helices and it was shown that the equilibrium between single and double helices can be controlled via different stimuli like the modification of the solvent or the temperature. This kind of structure presents highly interesting functions, such as molecular recognition within the cavity of double helices, and some other potential applications will emerge in the future. [ABSTRACT FROM AUTHOR]

Synthetic duplexes with high stabilities have promising potential for mimicking biomolecular functions and developing supramolecular smart materials. Herein, we describe the synthesis and stimuli‐responsive properties of molecular duplexes derived from indolocarbazole–pyridine (I−P) oligomers. These duplexes adopt nonclassical helical structures, stabilized by I−P hydrogen‐bonding pairs in anhydrous chlorinated solvents. Notably, the longest duplex 62 (11‐mer)2 displays remarkable stability, forming twenty hydrogen bonds; its exchange energy barrier was determined to be ΔG≠=22.0 kcal ⋅ mol−1 at 75 °C in anhydrous (CDCl2)2. Upon the addition of water, a hydrated duplex 62 (11‐mer)2⊃10H2O was formed, with one water molecule inserted between each I−P hydrogen‐bonding pair. The Hill coefficient (n) for this process is 6.1, demonstrating extremely positive cooperativity. Conversely, the hydrated duplex 62 (11‐mer)2⊃10H2O was completely converted into the original anhydrous duplex 62 (11‐mer)2 when the temperature was increased. Interconversion between these two distinct duplexes can be repeatedly carried out by varying the temperature. Furthermore, reversible switching between hetero‐duplexes and homo‐duplexes was also demonstrated by controlling the temperature, with concomitant changes in the characteristic emission signals. [ABSTRACT FROM AUTHOR]

Whilst energetic and kinetic aspects of folding processes are meanwhile well understood for natural biomacromolecules, the folding dynamics in so far studied artificial foldamer counterparts remain largely unexplored. This is due to the low energy barriers between their conformational isomers that make the dynamic processes undetectable with conventional methods such as UV/Vis absorption, fluorescence, and NMR spectroscopy, making such processes ‘invisible’. Here we present an asymmetric perylene bisimide dimer (bis‐PBI 1) that possesses conformational chirality in its folded state. Owing to the large interconversion barrier (≥116 kJ mol−1), four stereoisomers could be separated and isolated. Since the interconversion between these stereoisomers requires the foldamer to first open and then to re‐fold, the transformation of one stereoisomer into others allowed us to ‘visualize’ the dynamics of folding with time and determine its lifetimes and the energetic barriers associated with the folding process. Supported by quantum chemical calculations, we identified the open structure to be only a fleetingly metastable state of higher energy. Our experimental observation of the kinetics associated with the molecular dynamics in the PBI foldamer advances the fundamental understanding of folding in synthetic foldamers and paves the way for the design of smart functional materials. [ABSTRACT FROM AUTHOR]

Helical foldamers have attracted much attention over the last decades given their resemblance to certain biomacromolecules and their potential in domains as different as pharmaceutics, catalysis and photonics. Various research groups have successfully controlled the right‐ or left‐ handedness of these oligomers by introducing stereogenic centers through covalent or non‐covalent chemistry. However, developing helical structures whose handedness can be reversibly switched remains a major challenge for chemists. To date, such an achievement has been reported with light‐responsive single‐stranded foldamers only. Herein, we demonstrate that grafting a unidirectional motor onto foldamer strands constitutes a relevant strategy to i) control the single or double helical state of a foldamer, ii) switch on the chiral induction process from the motor to the helical strands and iii) select the handedness of double helical structures through photochemical and thermal stimulations. [ABSTRACT FROM AUTHOR]

Constructing artificial ion channels is a challenging task. Herein, the de novo design of transmembrane ion channels made up of amphiphilic peptide–oligourea chimeric helices is described. They consist of an oligourea segment (7‐mer) attached to the C‐terminus of a short peptide (8‐mer). Mass spectrometry (MS) and transmission electron microscopy (TEM) analyses show that in an aqueous solution, two of these chimeras (HPU‐E and HPU‐N) independently form defined oligomeric structures. TEM also shows that they form fiber bundles. The third related chimera HPU‐F does not oligomerize (MS) but forms spherical nanostructures (TEM). HPU‐E and HPU‐N exhibit anion transport activity across lipid bilayers via antiport mechanism (HPU‐N > HPU‐E). The anion selectivity of HPU‐N is Cl−>NO3− > Br−>SCN− > I− > AcO−>F−, which can be due to anion binding within the channels rather than size exclusion. Patch‐clamp data support HPU‐N's Cl− selectivity (PCl−/PI− = 3.26). X‐ray crystal structure (1.77 Å) of HPU‐N reveals well‐packed α‐helices, and cryo‐electron microscopy data shows the formation of nanotubes (13.7 Å diameter pores) and transmembrane channels. The study shows that α‐peptide–oligourea‐based de novo design can yield unique bioactive molecules with defined structures and functions. [ABSTRACT FROM AUTHOR]

Natural membrane receptors are proteins that can report on changes in the concentration of external chemical messengers. Messenger binding to a receptor produces conformational changes that are relayed through the membrane into the cell; this information allows cells to adapt to changes in their environment. Artificial membrane receptors (R)‐1 and (S)‐1 are helical α‐aminoisobutyric acid (Aib) foldamers that replicate key parts of this information relay. Solution‐phase 19F NMR spectroscopy of zinc(II)‐capped receptor 1, either in organic solvent or in membrane‐mimetic micelles, showed messenger binding produced an enrichment of either left‐ or right‐handed screw‐sense; the chirality of the bound messenger was relayed to the other receptor terminus. Furthermore, in situ production of a chemical messenger in the external aqueous environment could be detected in real‐time by a racemic mixture of receptor 1 in micelles. The hydrolysis of insoluble anhydrides produced carboxylate in the aqueous phase, which bound to the receptors and gave a distinct 19F NMR output from inside the hydrophobic region of the micelles. [ABSTRACT FROM AUTHOR]

Potassium ion transport across myocardial cell membrane is essential for type 2 long QT syndrome (LQT2). However, the dysfunction of potassium ion transport due to genetic mutations limits the therapeutic effect in treating LQT2. Biomimetic ion channels that selectively and efficiently transport potassium ions across the cellular membranes are promising for the treatment of LQT2. To corroborate this, we synthesized a series of foldamer-based ion channels with different side chains, and found a biomimetic ion channel of K+ (BIC K) with the highest transport activity among them. The selected BIC K can restore potassium ion transport and increase transmembrane potassium ion current, thus shortening phase 3 of action potential (AP) repolarization and QT interval in LQT2. Moreover, BIC K does not affect heart rate and cardiac rhythm in treating LQT2 model induced by E4031 in isolated heart as well as in guinea pigs. By restoring ion transmembrane transport tactic, biomimetic ion channels, such as BIC K , will show great potential in treating diseases related to ion transport blockade. Type 2 long QT syndrome (LQT2) is a disease caused by K+ transport disorder, which can cause malignant arrhythmia and even death. There is currently no radical cure, so it is critical to explore ways to improve K+ transmembrane transport. In this study, we report that a small-molecule biomimetic ion channel BIC K can efficiently simulate natural K+ channel proteins on the cardiomyocyte and cure E4031-induced LQT2 in guinea pig by restoring K+ transport function for the first time. This study found that the potassium transmembrane transport by BIC K significantly reduced the QT interval, which provides a conceptually new strategy for the treatment of LQT2 disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Oligomers of the achiral α‐aminoisobutyric acid (Aib) adopt a 310 helical conformation in which the screw‐sense preference can be controlled by a single chiral residue. The use of the fluorinated residue α‐Trifluoromethylalanine (α‐TfmAla) revealed a unique way to both induce and measure the screw‐sense preference of such oligomers acting as 19F NMR probe. This work proposes a systematic study of the effect of this fluorinated chiral inducer on the helical screw‐sense preference of poly‐Aib oligomers. The impact of the position of the fluorinated residue into pentamers (N‐terminal, central or C‐terminal) as well as the nature of the C‐terminal capping of the peptides was thoroughly studied in light of complete structural analysis. A deeper understanding of the fluorine effect was achieved confirming the unique ability of α‐TfmAla as a helical screw‐sense controller. [ABSTRACT FROM AUTHOR]

Supramolecular polymers offer tremendous potential to produce new "smart" materials, however, there remains a need to develop systems that are responsive to external stimuli. In this work, visible‐light responsive hydrogen‐bonded supramolecular polymers comprising photoresponsive supramolecular synthons (I–III) consisting of two hydrogen bonding motifs (HBMs) connected by a central ortho‐tetrafluorinated azobenzene have been characterized by DOSY NMR and viscometry. Comparison of different hydrogen‐bonding motifs reveals that assembly in the low and high concentration regimes is strongly influenced by the strength of association between the HBMs. I, Incorporating a triply hydrogen‐bonded heterodimer, was found to exhibit concentration dependent switching between a monomeric pseudo‐cycle and supramolecular oligomer through intermolecular hydrogen bonding interactions between the HBMs. II, Based on the same photoresponsive scaffold, and incorporating a quadruply hydrogen‐bonded homodimer was found to form a supramolecular polymer which was dependent upon the ring‐chain equilibrium and thus dependent upon both concentration and photochemical stimulus. Finally, III, incorporating a quadruply hydrogen‐bonded heterodimer represents the first photoswitchable AB type hydrogen‐bonded supramolecular polymer. Depending on the concentration and photostationary state, four different assemblies dominate for both monomers II and III, demonstrating the ability to control supramolecular assembly and physical properties triggered by light. [ABSTRACT FROM AUTHOR]

Artificial molecular muscles are highly attractive in the field of molecular machinery due to their unique properties of contraction and stretching motion. However, the synthesis of molecular muscles poses formidable challenges as it is hindered by undesirable yields and poor selectivity. Herein, we present a procedure for the dynamic assembly of foldaxane‐based [c2]daisy chains, wherein the hermaphroditic sequences consisting of aromatic helices and peptide rods are interlocked through inter‐strand hydrogen‐bonding interactions. The binding complementarity facilitates a selective and efficient assembly of [c2]daisy chain structures, inhibiting the creation of by‐products. Introducing multiple recognition sites confers the system with contraction and stretching motion actuated by chemical stimuli. The rate of this muscle‐like motion is calculated to be 0.8 s−1, which is 107 times faster than that of complex dissociation. [ABSTRACT FROM AUTHOR]

Constructing artificial ion channels is a challenging task. Herein, the de novo design of transmembrane ion channels made up of amphiphilic peptide–oligourea chimeric helices is described. They consist of an oligourea segment (7‐mer) attached to the C‐terminus of a short peptide (8‐mer). Mass spectrometry (MS) and transmission electron microscopy (TEM) analyses show that in an aqueous solution, two of these chimeras (HPU‐E and HPU‐N) independently form defined oligomeric structures. TEM also shows that they form fiber bundles. The third related chimera HPU‐F does not oligomerize (MS) but forms spherical nanostructures (TEM). HPU‐E and HPU‐N exhibit anion transport activity across lipid bilayers via antiport mechanism (HPU‐N > HPU‐E). The anion selectivity of HPU‐N is Cl−>NO3− > Br−>SCN− > I− > AcO−>F−, which can be due to anion binding within the channels rather than size exclusion. Patch‐clamp data support HPU‐N's Cl− selectivity (PCl−/PI− = 3.26). X‐ray crystal structure (1.77 Å) of HPU‐N reveals well‐packed α‐helices, and cryo‐electron microscopy data shows the formation of nanotubes (13.7 Å diameter pores) and transmembrane channels. The study shows that α‐peptide–oligourea‐based de novo design can yield unique bioactive molecules with defined structures and functions.

DNA mimic foldamers based on aromatic oligoamide helices bearing anionic phosphonate side chains have been shown to bind to DNA‐binding proteins sometimes orders of magnitude better than DNA itself. Here, we introduce new features in the DNA mimic foldamers to facilitate structural investigations of their interactions with proteins. Thirteen new foldamer sequences have been synthesized and characterized using NMR, circular dichroism, molecular modeling, and X‐ray crystallography. The results show that foldamer helix handedness can be quantitatively biased by means of a single stereogenic center, that the foldamer structure can be made C2‐symmetrical as in palindromic B‐DNA sequences, and that associations between foldamer helices can be promoted utilizing dedicated C‐terminal residues that act as sticky ends in B‐DNA structures. [ABSTRACT FROM AUTHOR]

Chirality is ubiquitous in nature, and homochirality is manifested in many biomolecules. Although β‐double helices are rare in peptides and proteins, they consist of alternating L‐ and D‐amino acids. No peptide double helices with homochiral amino acids have been observed. Here, we report chiral β‐double helices constructed from γ‐peptides consisting of alternating achiral (E)‐α,β‐unsaturated 4,4‐dimethyl γ‐amino acids and chiral (E)‐α,β‐unsaturated γ‐amino acids in both single crystals and in solution. The two independent strands of the same peptide intertwine to form a β‐double helix structure, and it is stabilized by inter‐strand hydrogen bonds. The peptides with chiral (E)‐α,β‐unsaturated γ‐amino acids derived from α‐L‐amino acids adopt a (P)‐β‐double helix, whereas peptides consisting of (E)‐α,β‐unsaturated γ‐amino acids derived from α‐D‐amino acids adopt an (M)‐β‐double helix conformation. The circular dichroism (CD) signature of the (P) and (M)‐β‐double helices and the stability of these peptides at higher temperatures were examined. Furthermore, ion transport studies suggested that these peptides transport ions across membranes. Even though the structural analogy suggests that these new β‐double helices are structurally different from those of the α‐peptide β‐double helices, they retain ion transport activity. The results reported here may open new avenues in the design of functional foldamers. [ABSTRACT FROM AUTHOR]

Metals play an important role in the structure and functions of various proteins. The combination of metal ions and peptides have been emerging as an attractive field to create advanced structures and biomaterials. Here, we are reporting the anion‐influenced, silver ion coordinated diverse networks of designed short tripeptide 310‐helices with terminal pyridyl groups. The short peptides adopted classical right‐handed, left‐handed and 310EL‐helical conformations in the presence of different silver salts. The peptides have displayed conformational flexibility to accommodate different sizes and interactions of anions to yield a variety of metal‐coordinated networks. The complexes of metal ions and peptides have shown different porous networks, right‐ and left‐handed helical polymers, transformation of helix into superhelix and 2 : 2 metal‐peptide macrocycles. Further, the metal‐peptide crystals with inherent dipoles of helical peptides gave striking second harmonic generation response. The optical energy upconversion from NIR to red and green light is demonstrated. Overall, we have shown the utilization of short 310‐helices for the construction of diverse metal‐coordinated helical networks and notable non‐linear optical effects. [ABSTRACT FROM AUTHOR]

The entry of the SARS-CoV-2 virus into a human host cell begins with the interaction between the viral spike protein (S protein) and human angiotensin-converting enzyme 2 (hACE2). Therefore, a possible strategy for the treatment of this infection is based on inhibiting the interaction of the two abovementioned proteins. Compounds that bind to the SARS-CoV-2 S protein at the interface with the alpha-1/alpha-2 helices of ACE2 PD Subdomain I are of particular interest. We present a stepwise optimisation of helical peptide foldamers containing trans-2-aminocylopentanecarboxylic acid residues as the folding-inducing unit. Four rounds of optimisation led to the discovery of an 18-amino-acid peptide with high affinity for the SARS-CoV-2 S protein (Kd = 650 nM) that inhibits this protein–protein interaction with IC50 = 1.3 µM. Circular dichroism and nuclear magnetic resonance studies indicated the helical conformation of this peptide in solution. [ABSTRACT FROM AUTHOR]

Expanding the chemical diversity of peptide macrocycle libraries for display selection is desirable to improve their potential to bind biomolecular targets. We now have implemented a considerable expansion through a large aromatic helical foldamer inclusion. A foldamer was first identified that undergoes flexizyme‐mediated tRNA acylation and that is capable of initiating ribosomal translation with yields sufficiently high to perform an mRNA display selection of macrocyclic foldamer–peptide hybrids. A hybrid macrocyclic nanomolar binder to the C‐lobe of the E6AP HECT domain was selected that showed a highly converged peptide sequence. A crystal structure and molecular dynamics simulations revealed that both the peptide and foldamer are helical in an intriguing reciprocal stapling fashion. The strong residue convergence could be rationalized based on their involvement in specific interactions with the target protein. The foldamer stabilizes the peptide helix through stapling and through contacts with key residues. These results altogether represent a significant extension of the chemical space amenable to display selection and highlight possible benefits of inserting an aromatic foldamer into a peptide macrocycle for the purpose of protein recognition. [ABSTRACT FROM AUTHOR]

The entry of the SARS-CoV-2 virus into a human host cell begins with the interaction between the viral spike protein (S protein) and human angiotensin-converting enzyme 2 (hACE2). Therefore, a possible strategy for the treatment of this infection is based on inhibiting the interaction of the two abovementioned proteins. Compounds that bind to the SARS-CoV-2 S protein at the interface with the alpha-1/alpha-2 helices of ACE2 PD Subdomain I are of particular interest. We present a stepwise optimisation of helical peptide foldamers containing trans-2-aminocylopentanecarboxylic acid residues as the folding-inducing unit. Four rounds of optimisation led to the discovery of an 18-amino-acid peptide with high affinity for the SARS-CoV-2 S protein (Kd = 650 nM) that inhibits this protein–protein interaction with IC50 = 1.3 µM. Circular dichroism and nuclear magnetic resonance studies indicated the helical conformation of this peptide in solution.

Unlike many other biologically relevant ions (Na+, K+, Ca2+, Cl−, etc) and protons, whose cellular concentrations are closely regulated by highly selective channel proteins, Li+ ion is unusual in that its concentration is well tolerated over many orders of magnitude and that no lithium‐specific channel proteins have so far been identified. While one naturally evolved primary pathway for Li+ ions to traverse across the cell membrane is through sodium channels by competing with Na+ ions, highly sought‐after artificial lithium‐transporting channels remain a major challenge to develop. Here we show that sulfur‐containing organic nanotubes derived from intramolecularly H‐bonded helically folded aromatic foldamers of 3.6 Å in hollow cavity diameter could facilitate highly selective and efficient transmembrane transport of Li+ ions, with high transport selectivity factors of 15.3 and 19.9 over Na+ and K+ ions, respectively. [ABSTRACT FROM AUTHOR]

We introduce a novel cyclic β‐amino acid, trans‐(3S,4R)‐4‐aminotetrahydrothiophene‐3‐carboxylic acid (ATTC), as a versatile building block for designing peptide foldamers with controlled secondary structures. We synthesized and characterized a series of β‐peptide hexamers containing ATTC using various techniques, including X‐ray crystallography, circular dichroism, and NMR spectroscopy. Our findings reveal that ATTC‐containing foldamers can adopt 12‐helical conformations similar to their isosteres and offer the possibility of fine‐tuning their properties via post‐synthetic modifications. In particular, chemoselective conjugation strategies demonstrate that ATTC provides unique post‐synthetic modification opportunities, which expand their potential applications across diverse research areas. Collectively, our study highlights the versatility and utility of ATTC as an alternative to previously reported cyclic β‐amino acid building blocks in both structural and functional aspects, paving the way for future research in the realm of peptide foldamers and beyond. [ABSTRACT FROM AUTHOR]

To reach their potential as mimics of the dynamic molecules present in biological systems, foldamers must be designed to display stimulus‐responsive behavior. Here we report such a foldamer architecture based on alternating pyridine‐diketopiperazine linkers. Epimerization is conveniently prevented through a copper‐catalyzed coupling protocol. The compounds' native unswitched conformation is first discovered in the solid and solution state. The foldamers can be solubilized in DMSO and pH 9.5 buffer, retaining conformational control to a large degree. Lastly, dynamic switching is demonstrated through treatment with acid, leading to behaviour we describe as stimulus‐responsive sidechain reconfiguration. [ABSTRACT FROM AUTHOR]

Development of miniaturized lab‐on‐chip devices for the detection of rapid and specific small molecule‐protein binding interactions at very low concentrations holds significant importance in drug discovery and biomedical applications. Here, the label‐free detection of small molecule‐protein interactions is reported on the surface functionalizable nanotubes of α,γ‐hybrid peptide helical foldamers using nanoscale capacitance and impedance spectroscopy. The 12‐helix conformation of the α,γ‐hybrid peptide observed in the single crystals, self‐assembled into nanotubes in an aqueous environment with exposed cysteine thiols for small molecule conjugation. The binding of streptavidin to the covalently linked biotin on the surface of nanotubes was detected at the picomolar concentrations. No change in the capacitance and impedance were observed in the absence of either immobilized biotin or protein streptavidin. The functionalizable hybrid peptide nanotubes reported here pave the way for the label‐free detection of various small molecule protein interactions at very low concentrations. [ABSTRACT FROM AUTHOR]

ortho‐Phenylenes are one of the simplest classes of aromatic foldamers, adopting helical geometries because of aromatic stacking interactions. The folding and misfolding of ortho‐phenylenes are slow on the NMR timescale at or below room temperature, allowing detection of folding states using 1H NMR spectroscopy. Herein, an ortho‐phenylene hexamer is coupled with a RAFT chain transfer agent (CTA) on each repeat unit. A variety of acrylic monomers are polymerized onto the CTA‐functionalized ortho‐phenylene using PET‐RAFT to yield functionalized star polymers with ortho‐phenylene cores. The steric bulk of the acrylate monomer units as well as the chain length of each arm of the star polymer is varied. 1H NMR spectroscopy shows that the folding of the ortho‐phenylenes do not vary, providing a robust helical core for star polymer systems. [ABSTRACT FROM AUTHOR]

Oligomers designed to form a helix‐turn‐helix super‐secondary structure have been prepared by covalently bridging aliphatic oligourea foldamer helices with either rigid aromatic or more flexible aliphatic spacers. The relative helix orientation in these dimers was investigated at high resolution using X‐ray diffraction analysis. In several cases, racemic crystallography was used to facilitate crystallization and structure determination. All structures were solved by direct methods. Well‐defined parallel helical hairpin motifs were observed in all cases when 4,4′‐methylene diphenyl diisocyanate was employed as a dimerizing agent, irrespective of primary sequence and chain length. [ABSTRACT FROM AUTHOR]

Helically folded oligoamides of 8‐amino‐2‐quinolinecarboxylic acid composed of up to 41 units were prepared using optimized manual solid‐phase synthesis (SPS). The high yield and purity of the final products places these SPS protocols among the most efficient known to date. Furthermore, analytical methods allowing for the clear identification and purity assessment of the products were validated, including 1H NMR, a seldom used method for such large molecules. Adaption of the SPS protocols, in particular using in situ acid chloride activation under Appel's conditions, made it possible to efficiently implement SPS on a commercial peptide synthesizer, leading to a dramatic reduction of the laboratory work required to produce long sequences. Automation constitutes a breakthrough for the development of helical aromatic oligoamide foldamers. [ABSTRACT FROM AUTHOR]

This review provides a fresh overview of non-canonical amino acids and their applications in the design of peptidomimetics. Non-canonical amino acids appear widely distributed in nature and are known to enhance the stability of specific secondary structures and/or biological function. Contrary to the ubiquitous DNA-encoded amino acids, the structure and function of these residues are not fully understood. Here, results from experimental and molecular modelling approaches are gathered to classify several classes of non-canonical amino acids according to their ability to induce specific secondary structures yielding different biological functions and improved stability. Regarding side-chain modifications, symmetrical and asymmetrical α,α-dialkyl glycines, Cα to Cα cyclized amino acids, proline analogues, β-substituted amino acids, and α,β-dehydro amino acids are some of the non-canonical representatives addressed. Backbone modifications were also examined, especially those that result in retro-inverso peptidomimetics and depsipeptides. All this knowledge has an important application in the field of peptidomimetics, which is in continuous progress and promises to deliver new biologically active molecules and new materials in the near future. [ABSTRACT FROM AUTHOR]

A de novo designed class of peptide‐based fluoropolymers composed of fluorinated aliphatic amino acids as main components is reported. Structural characterization provided insights into fluorine‐induced alterations on β‐strand to α‐helix transition upon an increase in SDS content and revealed the unique formation of PPII structures for trifluorinated fluoropeptides. A combination of circular dichroism, fluorescence‐based leaking assays and surface enhanced infrared absorption spectroscopy served to examine the insertion and folding processes into unilamellar vesicles. While partitioning into lipid bilayers, the degree of fluorination conducts a decrease in α‐helical content. Furthermore, this study comprises a report on the proteolytic stability of peptides exclusively built up by fluorinated amino acids and proved all sequences to be enzymatically degradable despite the degree of fluorination. Herein presented fluoropeptides as well as the distinctive properties of these artificial and polyfluorinated foldamers with enzyme‐degradable features will play a crucial role in the future development of fluorinated peptide‐based biomaterials. [ABSTRACT FROM AUTHOR]

Hybrids of short oligourea foldamers with residues of α, β and γ-amino acids esters at the C-terminus were obtained and subjected to a reaction with LiOH. There are two possible transformations under such conditions, one of which is ester hydrolysis and the formation of a carboxylic group and the other is the cyclization reaction after abstraction of a proton from urea by a base. We have investigated this reaction with difference C-terminal residue structures, as well as under different work-up conditions, especially for oligourea hybrids with α-amino acid esters. For these compounds, an oligourea–hydantoin combination is the product of cyclization. The stability of the hydantoin ring under alkaline conditions has been alsotested. Furthermore, this work reports data related to the structure of C-terminal-modified oligourea foldamers in solution and, for one compound, in the solid state. Helical folding is preserved both for cyclized and linear modifications, with oligourea–acid hybrids appearing to be more conformationally stable, as they are stabilized by an additional intramolecular hydrogen bond in comparison to cyclic derivatives. [ABSTRACT FROM AUTHOR]

The construction of protein‐sized synthetic chains that blend natural amino acids with artificial monomers to create so‐called heterogeneous‐backbones is a powerful approach to generate complex folds and functions from bio‐inspired agents. A variety of techniques from structural biology commonly used to study natural proteins have been adapted to investigate folding in these entities. In NMR characterization of proteins, proton chemical shift is straightforward to acquire and an information‐rich metric that bears directly on a variety of properties related to folding. Leveraging chemical shift to gain insight into folding requires a set of reference chemical shift values corresponding to each building block type (i.e., the 20 canonical amino acids in the case of natural proteins) in a random coil state and knowledge of systematic changes in chemical shift associated with particular folded conformations. Although well documented for natural proteins, these issues remain unexplored in the context of protein mimetics. Here, we report random coil chemical shift values for a library of artificial amino acid monomers frequently used to construct heterogeneous‐backbone protein analogues as well as a spectroscopic signature associated with one monomer class, β3‐residues bearing proteinogenic side chains, adopting a helical folded conformation. Collectively, these results will facilitate the continued utilization of NMR for the study of structure and dynamics in protein‐like artificial backbones. [ABSTRACT FROM AUTHOR]

Flexible and biocompatible metal peptide frameworks (MPFs) derived from short and ultra‐short peptides have been explored for the storage of greenhouse gases, molecular recognition, and chiral transformations. In addition to short flexible peptides, peptides with specifically folded conformations have recently been utilized to fabricate a variety of metal helix frameworks (MHFs). The secondary structures of the peptides govern the structure‐assembly relationship and thereby control the formation of three‐dimensional (3D)‐MHFs. Particularly, the hierarchical structural organization of peptide‐based MHFs has not yet been discussed in detail. Here, we describe the recent progress of metal‐driven folded peptide assembly to construct 3D porous structures for use in future energy storage, chiral recognition, and biomedical applications, which could be envisioned as an alternative to the conventional metal‐organic frameworks (MOFs). [ABSTRACT FROM AUTHOR]

Protein, as the main cause of cell interactions, can be the key to solving the riddle of cancer and many other diseases. Disorders in protein–protein interactions (PPIs) are often the main cause of several diseases, making them attractive as drug targets. The Hdm2-p53 interaction is an attractive therapeutic target in oncology. In normal cells, p53 activity levels are controlled by negative regulators such as Human double minute 2 (Hdm2). Overexpression of Hdm2 in cancer cells prevents p53 from exerting its normal function. Disruption of the Hdm2-p53 interaction to maintain p53 function is considered a therapeutic approach to cancer treatment. Peptidomimetics have emerged as promising candidates for the treatment of various diseases by modulating PPIs. Herein, an investigation of three classes of unnatural backbone units in the folding behavior of peptides based on the p53 sequence has been reported. Among the unnatural oligomers in the molecular dynamics (MD) simulation study, helix mimetics containing the Cα-Me-Leu residue and α-amino isobutyric acid (Aib) have a higher helical content than the natural p53 peptide. Therefore, they can be suitable inhibitors for Hdm2-P53 interaction. [ABSTRACT FROM AUTHOR]

Metadynamics simulation has been used to determine the conformational energy landscapes of several helical quinoline oligoamides bearing β‐pinene‐derived pyridine at either the C or N‐terminus. Based on the experimental results, the helix‐sense preference for four types of foldamers with the chiral terminal group has been verified. To compare to the key factors inducing handedness to helix‐sense preference, a terminal group with three hydrogen bond sites is designed and corresponding foldamers are built. The calculated results show that the delocalization effect and steric hindrance are mainly responsible for a particular helix‐sense preference for the investigated foldamers. The more hydrogen bonds between the terminal group and oligoamide units are formed, the more stable foldamers are. [ABSTRACT FROM AUTHOR]

Oligourea foldamers fold into 2.5‐helices. Most of the known modifications of the backbone, such as NH or CO group substitutions or incorporations of non‐canonical residues, do not change the conformational properties of the resulting oligourea oligomers. In this study, we examined the structural influence of the methyl group, substituting NH protons in one or two residues at the N‐terminus of the foldamer. Such N‐methylated oligoureas appear to be helically folded with helix parameters determined from the crystal structure being almost the same as for non‐methylated oligomers. Solution studies (CD, NMR) reveal that the backbone with N‐Me urea groups is more flexible, but the urea group is still predominantly in trans,trans conformation. N‐Methylation does not change the structural properties of oligourea foldamers, and thus may be a useful modification for modulating the strength of hydrogen bonds and intermolecular interactions. [ABSTRACT FROM AUTHOR]

Currently, completely abiotic channel systems that concurrently reproduce the high selectivity and high permeation rate of natural protein channels are rare. Here, we provide one such biomimetic channel system, i.e., a novel family of helically folded hybrid amide foldamers that can serve as powerful artificial proton channels to mimic key transport features of the exceptionally selective Matrix‐2 (M2) proton channels. Possessing an angstrom‐scale tubular pore 3 Å in diameter, these low water permeability artificial channels transport protons at a rate 1.22 and 11 times as fast as gramicidin A and M2 channels, respectively, with exceptionally high selectivity factors of 167.6, 122.7, and 81.5 over Cl−, Na+, and K+ ions. Based on the experimental and computational findings, we propose a novel proton transport mechanism where a proton may create a channel‐spanning water chain from two or more short water chains to facilitate its own transmembrane flux via the Grotthuss mechanism. [ABSTRACT FROM AUTHOR]

This review provides a fresh overview of non-canonical amino acids and their applications in the design of peptidomimetics. Non-canonical amino acids appear widely distributed in nature and are known to enhance the stability of specific secondary structures and/or biological function. Contrary to the ubiquitous DNA-encoded amino acids, the structure and function of these residues are not fully understood. Here, results from experimental and molecular modelling approaches are gathered to classify several classes of non-canonical amino acids according to their ability to induce specific secondary structures yielding different biological functions and improved stability. Regarding side-chain modifications, symmetrical and asymmetrical α,α-dialkyl glycines, Cα to Cα cyclized amino acids, proline analogues, β-substituted amino acids, and α,β-dehydro amino acids are some of the non-canonical representatives addressed. Backbone modifications were also examined, especially those that result in retro-inverso peptidomimetics and depsipeptides. All this knowledge has an important application in the field of peptidomimetics, which is in continuous progress and promises to deliver new biologically active molecules and new materials in the near future.

Metal-dependent enzymes are abundant and vital catalytic agents in nature. The functional versatility of metalloenzymes has made them common targets for improvement by protein engineering as well as mimicry by de novo designed sequences. In both strategies, the incorporation of non-canonical cofactors and/or non-canonical side chains has proved a useful tool. Less explored—but similarly powerful—is the utilization of non-canonical covalent modifications to the polypeptide backbone itself. Such efforts can entail either introduction of limited artificial monomers in natural chains to produce heterogeneous backbones or construction of completely abiotic oligomers that adopt defined folds. Herein, we review recent research applying artificial protein-like backbones in the construction of metalloenzyme mimics, highlighting progress as well as open questions in this emerging field. [Display omitted] [ABSTRACT FROM AUTHOR]

A series of aromatic oligoamide foldamer sequences containing different proportions of three δ‐amino acids derived from quinoline, pyridine, and benzene and possessing varying flexibility, for example due to methylene bridges, were synthesized. Crystallographic structures of two key sequences and 1H NMR data in water concur to show that a canonical aromatic helix fold prevails in almost all cases and that helix stability critically depends on the ratio between rigid and flexible units. Notwithstanding subtle variations of curvature, i. e. the numbers of units per turn, the aromatic δ‐peptide helix is therefore shown to be general and tolerant of a great number of sp3 centers. We also demonstrate canonical helical folding upon alternating two monomers that do not promote folding when taken separately: folding occurs with two methylenes between every other unit, not with one methylene between every unit. These findings highlight that a fine‐tuning of helix handedness inversion kinetics, curvature, and side chain positioning in aromatic δ‐peptidic foldamers can be realized by systematically combining different yet compatible δ‐amino acids. [ABSTRACT FROM AUTHOR]

The incorporation of dehydroamino acid or fragments of oxazole into peptide chain is accompanied by a distorted three-dimensional structure and additionally enables the introduction of non-typical side-chain substituents. Thus, such compounds could be building blocks for obtaining novel foldamers and/or artificial enzymes (artzymes). In this paper, effective synthetic procedures leading to such building blocks—tetrapeptides containing glycyldehydroalanine, glycyldehydrophenylalanine, and glycyloxazole subunits—are described. Peptides containing serine were used as substrates for their conversion into peptides containing dehydroalanine and aminomethyloxazole-4-carboxylic acid while considering possible requirements for the introduction of these fragments into long-chain peptides at the last steps of synthesis. [ABSTRACT FROM AUTHOR]

The 11/9‐helix is one of nontraditional helices available to α/β‐peptides with alternating residue types. Several β‐amino acid residues are known to promote 11/9‐helical folding with two types of intramolecular hydrogen bonds. Both β2‐amino acids and β3‐amino acids are common acyclic β‐amino acids that can be regarded as homologs of α‐amino acids with the same side chain group. However, β2‐amimo acids have not been widely used as much as β3‐amino acids partly because β2‐residue is believed to be not as strong as β3‐residue in promoting a distinct conformation. Here we report 11/9‐helical folding of α/β‐peptides that consist of L‐α‐alanine and (S)‐β2‐homoalanine with residue alternation. In addition, circular dichroism study reveals that β2‐homoalanine promotes 11/9‐helical folding more strongly than β3‐homoalanine in polar protic solvent conditions. [ABSTRACT FROM AUTHOR]

A "foldamer" is an artificial oligomeric molecule with a regular secondary or tertiary structure consisting of various building blocks. A "stapled peptide" is a peptide with stabilized secondary structures, in particular, helical structures by intramolecular covalent side-chain cross-linking. Helical foldamers and stapled peptides are potential drug candidates that can target protein-protein interactions because they enable multipoint molecular recognition, which is difficult to achieve with low-molecular-weight compounds. This mini-review describes a variety of peptide-based foldamers and stapled peptides with a view to their applications in drug discovery, including our recent progress. [ABSTRACT FROM AUTHOR]

The synthesis and structural characterization of the ferrocene imide derivatives Fc−CO−NH−CO−Me (4), Fc−CO−NH−CO−Fc (7) and Fc−CO−NH−CO−Fn−CO−NH−CO−Fc (8) have been reported. The mononuclear, dinuclear and trinuclear ferrocene imides were prepared by the reaction of ferrocenecarboxamide (3), with acetyl chloride, ferrocenecarbonyl chloride (2) and ferrocene-1,1’-(dicarbonyl chloride) (6), respectively. IR spectroscopic analysis revealed the absence of intramolecular hydrogen bonds in solutions of imides 4, 7 and 8. The crystal packing of N-acetylferrocenecarboxamide (4) is characterized by N−H⋯O hydrogen bonds forming centrosymmetric dimers, while the molecules of its homologue N-methylferrocenecarboxamide (5) are self-assembled by intermolecular N−H⋯O bonds into infinite chains. A detailed conformational analysis (DFT study) suggests the cis-trans configuration of ferrocene imide derivative 7 in solution. The effect of different substituents attached to bridged imide nitrogen on conformational properties of bis-ferrocenyl imides was further investigated and results compared to the existing experimental data.

Tight binding was observed between the C‐terminal cross section of aromatic oligoamide helices in aqueous solution, leading to the formation of discrete head‐to‐head dimers in slow exchange on the NMR timescale with the corresponding monomers. The nature and structure of the dimers was evidenced by 2D NOESY and DOSY spectroscopy, mass spectrometry and X‐ray crystallography. The binding interface involves a large hydrophobic aromatic surface and hydrogen bonding. Dimerization requires that helices have the same handedness and the presence of a C‐terminal carboxy function. The protonation state of the carboxy group plays a crucial role, resulting in pH dependence of the association. Dimerization is also influenced by neighboring side chains and can be programmed to selectively produce heteromeric aggregates. [ABSTRACT FROM AUTHOR]