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A single amino acid in a peptide sequence can play an important role to tune the self‐assembly and hydrogelation behaviour. Here, a C‐terminal cysteine‐containing ultrashort peptide hydrogelator forms hydrogel through non‐covalent and covalent interactions. Interestingly, the hydrogel is insoluble in water and buffer solutions at different pH values (1‐13) and is thixotropic and injectable. In recent years, removing dyes from contaminated water has become a significant concern because of the shortage of freshwater resources. Therefore, the adsorption of dyes through a reliable, straightforward, nontoxic, cheap, and environmentally friendly adsorbent has become a popular topic. Hence, the hydrogelator was exploited to remove organic dyes from wastewater, harnessing its applicability in the gel phase and solid supports (filter paper and cotton). [ABSTRACT FROM AUTHOR]

Constructing synthetic materials to interact with cells offers significant promise for understanding natural cellular processes and manipulating cell behaviors beyond nature's capabilities. Peptide assemblies are particular promising in this regard, as they have demonstrated efficacy in promoting cell differentiation, repair, and regeneration as supportive scaffolds. However, distinct gaps persist between natural and synthetic assembly systems in various aspects. This Concept review explores representative studies focusing on developing chemical strategies to design peptide assemblies with precise control over displayed molecules, adjustable molecular dynamics to modulate cell behaviors, and responsiveness to biological stimuli. This paper would inspire more fundamental studies on molecular assemblies and foster inter‐disciplinary interests in material applications, advancing the interplay between natural cells and synthetic materials. [ABSTRACT FROM AUTHOR]

Biohybrid catalysts that operate in aqueous media are intriguing for systems chemistry. In this paper, we investigate whether control over the self‐assembly of biohybrid catalysts can tune their properties. As a model, we use the catalytic activity of functional hybrid molecules consisting of a catalytic H‐dPro‐Pro‐Glu tripeptide, derivatized with fatty acid and nucleobase moieties. This combination of simple biological components merged the catalytic properties of the peptide with the self‐assembly of the lipid, and the structural ordering of the nucleobases. The biomolecule hybrids self‐assemble in aqueous media into fibrillar assemblies and catalyze the reaction between butanal and nitrostyrene. The interactions between the nucleobases enhanced the order of the supramolecular structures and affected their catalytic activity and stereoselectivity. The results point to the significant control and ordering that nucleobases can provide in the self‐assembly of biologically inspired supramolecular catalysts. [ABSTRACT FROM AUTHOR]

Cyclisation of peptides by forming thioether (lanthionine), disulfide (cystine) or methylene thioacetal bridges between side chains is established as an important tool to stabilise a given structure, enhance metabolic stability and optimise both potency and selectivity. However, a systematic comparative study of the effects of differing bridging modalities on peptide conformation has not previously been carried out. In this paper, we have used the NMR deconvolution algorithm, NAMFIS, to determine the conformational ensembles, in aqueous solution, of three cyclic analogues of angiotensin(1–7), incorporating either disulfide, or non‐reducible thioether or methylene thioacetal bridges. We demonstrate that the major solution conformations are conserved between the different bridged peptides, but the distribution of conformations differs appreciably. This suggests that subtle differences in ring size and bridging structure can be exploited to fine‐tune the conformational properties of cyclic peptides, which may modulate their bioactivities. [ABSTRACT FROM AUTHOR]

A relaxin‐like gonad‐stimulating peptide (RGP), Aso‐RGP, featuring six cysteine residues, was identified in the Crown‐of‐Thorns Starfish (COTS, Acanthaster cf. solaris) and initially produced through recombinant yeast expression. This method yielded a single‐chain peptide with an uncleaved C‐peptide (His Tag) and suboptimal purity. Our objective was to chemically synthesize Aso‐RGP in its mature form, comprising two chains (A and B) and three disulfide bridges, omitting the C‐peptide. Furthermore, we aimed to synthesize a newly identified relaxin‐like peptide, Aso‐RLP2, from COTS, which had not been previously synthesized. This paper reports the first total chemical synthesis of Aso‐RGP and Aso‐RLP2. Aso‐RGP synthesis proceeded without major issues, whereas the A‐chain of Aso‐RLP2, in its reduced and unfolded state with two free thiols, presented considerable challenges. These were initially marked by "messy" RP‐HPLC profiles, typically indicative of synthesis failure. Surprisingly, oxidizing the A‐chain significantly improved the RP‐HPLC profile, revealing the main issue was not synthesis failure but the peptide's aggregation tendency, which initially obscured analysis. This discovery highlights the critical need to account for aggregation in peptide synthesis and analysis. Ultimately, our efforts led to the successful synthesis of both peptides with purities exceeding 95 %. [ABSTRACT FROM AUTHOR]

Since the global peptide drug market demand has been predicted to increase, highly efficient and inexpensive mass scale peptides are required. However, the production process raises questions about the cost of energy input, scale‐up production, raw materials, and solvents treatment. This paper introduces 2 methods for the 2–4 mer oligopeptides bond formation for batch reaction utilizing 50–100 mol% of a mild Brønsted acid under the mild condition. One of the methods has been capably adapted to flow synthesis at room temperature using organic solvents with boiling points below 100 °C. The method applies the tert‐butoxycarbonyl amino methoxy group, forming the desired dipeptide without solvent at mild temperatures. Furthermore, the conversion of the carboxylic acid leaving the group to phenyl ester promotes peptide bond formation, and the reaction were applied to di, tri, and tetrapeptide bond formation in excellent yield without notable racemization at ambient temperature (up to >99 % yield and 99 : 1 dr). Finally, this study proposes this new production method to overcome the limited scale‐up production by reaction device scale: liquid phase biomimetic catalytic peptide flow synthesis utilizing a mild Brønsted acid. [ABSTRACT FROM AUTHOR]

This paper describes a method that combines a microfluidic device and self‐assembled monolayers for matrix‐assisted laser desorption/ionization mass spectrometry (SAMDI) mass spectrometry to calculate the cooperativity in binding of calcium ions to peptidylarginine deiminase type 2 (PAD2). This example uses only 120 μL of enzyme solution and three fluidic inputs. This microfluidic device incorporates a self‐assembled monolayer that is functionalized with a peptide substrate for PAD2. The enzyme and different concentrations of calcium ions are flowed through each of eight channels, where the position along the channel corresponds to reaction time and position across the channel corresponds to the concentration of Ca2+. Imaging SAMDI (iSAMDI) is then used to determine the yield for the enzyme reaction at each 200 μm pixel on the monolayer, providing a time course for the reactions. Analysis of the peptide conversion as a function of position and time gives the degree of cooperativity (n) and the concentration of ligand required for half maximal activity (K0.5) for the Ca2+ – dependent activation of PAD2. This work establishes a high‐throughput and label‐free method for studying enzyme‐ligand binding interactions and widens the applicability of microfluidics and matrix‐assisted laser desorption/ionization mass spectrometry (MALDI) imaging mass spectrometry. [ABSTRACT FROM AUTHOR]

Recently, we presented a strategy for packaging peptides as side‐chains in high‐density brush polymers. For this globular protein‐like polymer (PLP) formulation, therapeutic peptides were shown to resist proteolytic degradation, enter cells efficiently and maintain biological function. In this paper, we establish the role charge plays in dictating the cellular uptake of these peptide formulations, finding that peptides with a net positive charge will enter cells when polymerized, while those formed from anionic or neutral peptides remain outside of cells. Given these findings, we explored whether cellular uptake could be selectively induced by a stimulus. In our design, a cationic peptide is appended to a sequence of charge‐neutralizing anionic amino acids through stimuli‐responsive cleavable linkers. As a proof‐of‐concept study, we tested this strategy with two different classes of stimuli, exogenous UV light and an enzyme (a matrix metalloproteinase) associated with the inflammatory response. The key finding is that these materials enter cells only when acted upon by the stimulus. This approach makes it possible to achieve delivery of the polymers, therapeutic peptides or an appended cargo into cells in response to an appropriate stimulus. [ABSTRACT FROM AUTHOR]

Polydopamine (PD) and melanin species are chemically complex systems, the formation and properties of which are incompletely understood. Inspired by the role of functional amyloids in melanin biosynthesis, this paper examines the influences of the supramolecular structure of amyloids on oxidative polymerization of dopamine. Kinetic analyses on the formation of PD species in the presence of hen egg white lysozyme (HEWL) fibers or soluble HEWL revealed that both forms gave rise to the total quantity of PD species, but the rate of their formation could be accelerated only by the amyloid form. PD species formed with HEWL fibers showed a morphology of bundled fibers, whereas those with soluble HEWL had a mesh‐like structure. Amyloid fibers of recombinant Pmel17 had properties similar to those of HEWL fibers in modulating PD formation. The results presented here suggest how nature designs functionality with an amyloid structure and can help understand and engineer chemistries of other functional amyloids. [ABSTRACT FROM AUTHOR]

Abstract: The reaction mechanism in an active site is of the utmost importance when trying to understand the role that an enzyme plays in biological processes. In a recently published paper [Theor. Chem. Acc. 2017, 136, 86], we formalised the Relative Energy Gradient (REG) method for automating an Interacting Quantum Atoms (IQA) analysis. Here, the REG method is utilised to determine the mechanism of peptide hydrolysis in the aspartic active site of the enzyme HIV‐1 Protease. Using the REG method along with the IQA approach we determine the mechanism of peptide hydrolysis without employing any arbitrary parameters and with remarkable ease (albeit at large computational cost: the system contains 133 atoms, which means that there are 17 689 individual IQA terms to be calculated). When REG and IQA work together it is possible to determine a reaction mechanism at atomistic resolution from data directly derived from quantum calculations, without arbitrary parameters. Moreover, the mechanism determined by this novel method gives concrete insight into how the active site residues catalyse peptide hydrolysis. [ABSTRACT FROM AUTHOR]

In this paper, a new disulfide-forming agent based on the finding that alkoxy 3-nitro-2-pyridinesulfenates (Npys-OR) can oxidize thiol groups is reported. Methyl 3-nitro-2-pyridinesulfenate (Npys-OMe), which is easily prepared from 3-nitro-2-pyridinesulfenyl chloride in a one-step reaction and has a reduction peak potential ( Epc) of −0.541 V versus Ag/AgCl, produces the cyclic nonapeptide oxytocin from its linear form in good yield (92 %) with minimal oligomer formation. Npys-OMe in the solid phase also demonstrated excellent results in oxytocin synthesis. Other disulfide-containing peptides, such as α-human atrial natriuretic peptide and α-conotoxin ImI, were also successfully synthesized. During these syntheses, no side reactions of methionine (Met) and tryptophan (Trp) residues or the S-acetamidomethyl (Acm) protecting group were detected. These results suggested that Npys-OMe or its solid-phase analog provides a new strategy for regioselective disulfide bond formation to assist the synthesis of complex disulfide-rich peptides. [ABSTRACT FROM AUTHOR]

We report the synthesis, gelation abilities and aggregation‐induced, blue‐shifted emission (AIBSE) properties of two minimalistic diketopiperazine‐based gelators. Despite containing a highly insoluble luminophore that makes up more than half of their respective molecular masses, efficient hydrogelation by multiple stimuli for one and efficient organogelation for the other compound are reported. Insights into the aggregation and gelation properties were gained through examination of the photophysical and material properties of selected gels, which are representative of the different modes of gelation. The synthesis of the gelators is highly modular and based on readily available amino acid building blocks, allowing the efficient and rapid diversification of these core structures and fine‐tuning of gel properties. [ABSTRACT FROM AUTHOR]

One approach to protein assembly involves water‐soluble supramolecular receptors that act like glues. Bionanoarchitectures directed by these scaffolds are often system‐specific, with few studies investigating their customization. Herein, the modulation of cucurbituril‐mediated protein assemblies through the inclusion of peptide tectons is described. Three peptides of varying length and structural order were N‐terminally appended to RSL, a β‐propeller building block. Each fusion protein was incorporated into crystalline architectures mediated by cucurbit[7]uril (Q7). A trimeric coiled‐coil served as a spacer within a Q7‐directed sheet assembly of RSL, giving rise to a layered material of varying porosity. Within the spacer layers, the coiled‐coils were dynamic. This result prompted consideration of intrinsically disordered peptides (IDPs) as modulatory tectons. Similar to the coiled‐coil, a mussel adhesion peptide (Mefp) also acted as a spacer between protein–Q7 sheets. In contrast, the fusion of a nucleoporin peptide (Nup) to RSL did not recapitulate the sheet assembly. Instead, a Q7‐directed cage was adopted, within which disordered Nup peptides were partially "captured" by Q7 receptors. IDP capture occurred by macrocycle recognition of an intrapeptide Phe‐Gly motif in which the benzyl group was encapsulated by Q7. The modularity of these protein–cucurbituril architectures adds a new dimension to macrocycle‐mediated protein assembly. Segregated protein crystals, with alternating layers of high and low porosity, could provide a basis for new types of materials. [ABSTRACT FROM AUTHOR]

Pseudo-complementary peptide nucleic acid (pcPNA), as one of the most widely used synthetic DNA analogues, invades double-stranded DNA according to Watson-Crick rules to form invasion complexes. This unique mode of DNA recognition induces structural changes at the invasion site and can be used for a range of applications. In this paper, pcPNA is conjugated with a nuclear localization signal (NLS) peptide, and its invading activity is notably promoted both thermodynamically and kinetically. Thus, the double-duplex invasion complex is formed promptly at low pcPNA concentrations under high salt conditions, where the invasion otherwise never occurs. Furthermore, NLS-modified pcPNA is successfully employed for site-selective DNA scission, and the targeted DNA is selectively cleaved under conditions that are not conducive for DNA cutters using unmodified pcPNAs. This strategy of pcPNA modification is expected to be advantageous and promising for a range of in vitro and in vivo applications. [ABSTRACT FROM AUTHOR]

A novel peptide stapling method effected by a double thiol‐ene reaction between two cysteine residues and a divinyl diester to access stapled peptides with enhanced cell permeability is reported. This diverse chemical tool kit provides facile access to stapled peptides with varying bridge lengths. Stapled Axin mimetics were synthesised by using this stapling method resulting in improved α‐helicity relative to the unstapled peptide. Cell penetrating stapled analogues of the SIGK peptide that targets the protein–protein interaction hotspot of Gβγ proteins were also synthesised that exhibited a moderate increase in α‐helicity and were cell permeable. This chemoselective peptide stapling method is highly amenable as a facile method to easily modify synthetic α‐helical peptides to target intracellular proteins. [ABSTRACT FROM AUTHOR]

Peptide DNA interactions are involved in gene expression. In this work, photoswitchable azobenzene moieties were implemented in the peptide backbone of a DNA minor‐ and a major‐groove binder. DNA binding affinity was affected by photochemical isomerization, which provides promising tools for DNA modulation. The cover art is inspired by light‐induced motion, here symbolized as dancing, in photoswitchable small peptides and their dynamic interaction with metal ions and DNA. Jana Volarić is thanked for her contribution to the design. More information on the research can be found in the Full Paper by W. Szymanski, B. L. Feringa, et al. on page 4965. [ABSTRACT FROM AUTHOR]

A pulsed electron paramagnetic resonance (EPR) spectroscopic ruler is reported for the measurement of distances and distance distributions based on a novel spin ‐ labelling strategy. The ruler consists of a series of α ‐ helical peptides, labelled at the N ‐ terminal end with a porphyrin moiety that can be excited to the triplet state, and with a nitroxide at various sequence positions, spanning distances in the range between 1.8 – 8 nm. The new labelling approach has a high potential for measuring nanometer distances in biological macromolecules due to the distinctive properties of the porphyrin triplet state. More information can be found in the Full Paper by M. Di Valentin et al. on page 17204 ff. [ABSTRACT FROM AUTHOR]

Bacterial colonization and biofilm formation on abiotic surfaces are initiated by the adhesion of peptides and proteins. Understanding the adhesion of such peptides and proteins at a molecular level thus represents an important step toward controlling and suppressing biofilm formation on technological and medical materials. This study investigates the molecular adhesion of a pilus‐derived peptide that facilitates biofilm formation of Pseudomonas aeruginosa, a multidrug‐resistant opportunistic pathogen frequently encountered in healthcare settings. Single‐molecule force spectroscopy (SMFS) was performed on chemically etched ZnO112‾0 ${\left(11\bar{2}0\right)}$ surfaces to gather insights about peptide adsorption force and its kinetics. Metal‐free click chemistry for the fabrication of peptide‐terminated SMFS cantilevers was performed on amine‐terminated gold cantilevers and verified by X‐ray photoelectron spectroscopy (XPS) and polarization‐modulated infrared reflection absorption spectroscopy (PM‐IRRAS). Atomic force microscopy (AFM) and XPS analyses reveal stable topographies and surface chemistries of the substrates that are not affected by SMFS. Rupture events described by the worm‐like chain model (WLC) up to 600 pN were detected for the non‐polar ZnO surfaces. The dissociation barrier energy at zero force ΔG(0), the transition state distance xb and bound‐unbound dissociation rate at zero force koff(0) for the single crystalline substrate indicate that coordination and hydrogen bonds dominate the peptide/surface interaction. [ABSTRACT FROM AUTHOR]

The increasing prevalence of neurodegenerative diseases has spurred researchers to develop advanced 3D models that accurately mimic neural tissues. Hydrogels stand out as ideal candidates as their properties closely resemble those of the extracellular matrix. A critical challenge in this regard is to comprehend the influence of the scaffold's mechanical properties on cell growth and differentiation, thus enabling targeted modifications. In light of this, a synthesis and comprehensive analysis of acrylamide‐based hydrogels incorporating a peptide has been conducted. Adequate cell adhesion and development is achieved due to their bioactive nature and specific interactions with cellular receptors. The integration of a precisely controlled physicochemical hydrogel matrix and inclusion of the arginine‐glycine‐aspartic acid peptide sequence has endowed this system with an optimal structure, thus providing a unique ability to interact effectively with biomolecules. The analysis fully examined essential properties governing cell behavior, including pore size, mechanical characteristics, and swelling ability. Cell‐viability experiments were performed to assess the hydrogel's biocompatibility, while the incorporation of grow factors aimed to promote the differentiation of neuroblastoma cells. The results underscore the hydrogel's ability to stimulate cell viability and differentiation in the presence of the peptide within the matrix. [ABSTRACT FROM AUTHOR]

Peptide and protein bioconjugation sees ever‐growing applications in the pharmaceutical sector. Novel strategies and reagents that can address the chemo‐ and regioselectivity issues inherent to these biomolecules, while delivering stable and functionalizable conjugates, are therefore needed. Herein, we introduce the crosslinking ethynylbenziodazolone (EBZ) reagent JW‐AM‐005 for the conjugation of peptides and proteins through the selective linkage of cysteine residues. This easily accessed compound gives access to peptide dimers or stapled peptides under mild and tuneable conditions. Applied to the antibody fragment of antigen binding (Fab) species, JW‐AM‐005 delivered rebridged proteins in a one‐pot three‐reaction process with high regioselectivity, outperforming the standard reagents commonly used for this transformation. [ABSTRACT FROM AUTHOR]

The first contact of polyphenols (tannins) with the human body occurs in the mouth, where they are known to interact with proline‐rich proteins (PRPs). These interactions are important at a sensory level, especially for the development of astringency, but affect also various other biochemical processes. Employing thermodynamic measurements, fluorescence and CD spectroscopy, we investigated the binding process of the prototypical polyphenol ellagic acid (EA) to different IB‐PRPs and BSA, also in the presence of ethanol, which is known to influence tannin–protein interactions. Binding of EA to BSA and the small peptide IB7‐14 is weak, but very strong to IB9‐37. The differences in binding strength and stoichiometry are due to differences in the binding motifs, which also lead to differences in the thermodynamic signatures of the binding process. EA binding to BSA is enthalpy‐driven, whereas binding to both IB7‐14 and IB9‐37 is entropy‐driven. The presence of 10 vol.% EtOH, as present in wines, increases the binding constant of EA with BSA and IB7‐14 drastically, but not that with IB9‐37; however, it changes the binding stoichiometry. These differences can be attributed to the effect of EtOH on the conformation dynamics of the proteins and to changes in hydration properties in alcoholic solution. [ABSTRACT FROM AUTHOR]

Nanofabrication based on biological templates has attracted considerable interest because of its applications in materials science and biomedicine. Herein, a facile method is reported for the synthesis of well‐defined TiO2 nanofibers by using a simple N‐(9‐fluorenylmethoxycarbonyl)‐protected phenylalanine–phenylalanine–aspartic acid tripeptide (Fmoc‐Phe–Phe–Asp‐OH, Fmoc‐FFD) as the template. Compared with other synthetic methods of inorganic nanomaterials, these self‐assembling peptides could control the structure and the catalytic activity of the synthesized nanomaterials produced under mild synthetic conditions. The as‐synthesized peptide‐TiO2 hybrid nanofibers and the calcined TiO2 nanofibers were characterized by using transmission electron microscopy (TEM), scanning electron microscopy (SEM), circular dichroism (CD) spectroscopy, and X‐ray diffraction (XRD). The results show that well‐defined TiO2 nanofibers could form when the pH of the peptide solution was 5–7, whereas nanoparticles formed when the pH was 8. Moreover, the peptide‐templated TiO2 nanofibers showed improved photocatalytic activity for the degradation of methyl orange (MO). Finally, the photocatalytic activity of the TiO2 could be controlled by adjusting the pH of the peptide solution during the synthetic process. Peptide template: TiO2 nanomaterials with tunable photocatalytic activity were prepared by using N‐(9‐fluorenylmethoxycarbonyl)‐protected phenylalanine—aspartic acid tripeptide (Fmoc‐FFD) as the template. By incorporating titanium diisopropoxide bis(acetyl‐acetonate) into the peptide solutions, the TiO2 precursors could mineralize and condense with the peptide assemblages. After removing the peptide templates by calcination, a series of TiO2 nanostructures with enhanced photocatalytic activity were formed. [ABSTRACT FROM AUTHOR]

Oligomers based on an aromatic ether derived ϵ‐amino acid peptides folded into herringbone helical structures, induced by successive NH−O−NH & O−NH−O bifurcated hydrogen bonding interactions and reinforced by π‐π stacking between aryls from adjacent layers. The diaryl ether bonds −O− worked both as structural units to provide turn motifs for changing the amplitude of the slope along the axis of helix for herringbone formation, and also as acceptors for hydrogen bonding. Attachment of a single chiral carbon to the C‐termini of the peptides induced excess of single‐handed screw sense and amplification through the chain propagation as exemplified by chain length dependent circular dichroism (CD) investigations. [ABSTRACT FROM AUTHOR]

Multiblock copolymers: A new method to synthesize functional multiblock copolymers composed of alternately aligned sequential peptides and vinyl polymers is described. Cyclic oligopeptides containing an alkoxyamine bond in the framework have been developed as an initiator for NMP. Radical polymerization by this type of initiator enables multiple peptide blocks to be directly inserted into the vinyl polymer backbone during the polymerization. Folding behavior of the resultant multiblock peptide–polymer hybrid is also demonstrated. For more information see the Full Paper by N. Higashi, T. Koga, et al. on page 15050 ff. [ABSTRACT FROM AUTHOR]

Reactions of rare‐earth‐metal methylidene complexes with imines, azobenzenes, or amines result in the access to a wide variety of imido rare‐earth‐metal complexes, providing three new routes to such rare‐earth‐metal imido complexes. L. Zhang, X. Zhou et al. present an example of trivalent rare‐earth‐metal‐promoted activation of azobenzene and imines to form the corresponding imido complexes in their Full Paper on page 7865 ff. The cover picture shows three different transportation ways from Shanghai to Rome, representing three synthetic pathways to objective complexes. As the saying goes, all roads lead to Rome; similarly imido rare‐earth‐metal complexes can be obtained by various protocols. [ABSTRACT FROM AUTHOR]

According to their restricted conformational freedom, heterocyclic γ-amino acids are usually considered to be related to Z-vinylogous γ-amino acids. In this context, oligomers alternating α-amino acids and thiazole-based γ-amino acids (ATCs) were expected to fold into a canonical 12-helical shape as described for α/γ-hybrid peptides composed of cis-α/β-unsaturated γ-amino acids. However, through a combination of X-ray crystallography, NMR spectroscopy, FTIR experiments, and DFT calculations, it was determined that the folding behavior of ATC-containing hybrid peptides is much more complex. The homochiral α/( S)-ATC sequences were unable to adopt a stable conformation, whereas the heterochiral α/( R)-ATC peptides displayed novel ribbon structures stabilized by unusual C9/12-bifurcated hydrogen bonds. These ribbon structures could be considered as a succession of pre-organized γ/α dipeptides and may provide the basis for designing original α-helix mimics. [ABSTRACT FROM AUTHOR]

This work reports two new peptide-based fluorescence probes ( 1 and 2) for the detection of ds-DNA at physiological pH. Probes 1 and 2 contain a fluorophore, either amino-naphthalimide or diethyl-aminocoumarin, respectively, and two identical peptide arms each equipped with a guanidiniocarbonylpyrrole (GCP) anion-binding motif. These probes show 'switch-on' fluorescence response upon binding to ds-DNA, whereby they can differentiate between various types of polynucleotides. For instance, they exhibit more pronounced fluorescence response for AT-rich polynucleotides than GC-rich polynucleotides, and both give only negligible response to ds-RNA. The fluorimetric response of 1 is proportional to the AT-basepair content in DNA, whereas the fluorescence of 2 is sensitive to the secondary structure of the polynucleotide. Fluorescence experiments, thermal melting experiments and circular dichroism studies suggest that 1 interacts with ds-DNA in a combined intercalation and minor groove binding, whereas 2 interacts mainly with the outer surface of DNA/RNA. As 1 and 2 have a very low cytotoxicity, 1 can be applied for the imaging of nuclear DNA in cells. [ABSTRACT FROM AUTHOR]

The pseudopeptide L, derived from a nitrilotriacetic acid scaffold and functionalized with three histidine moieties, is reminiscent of the amino acid side chains encountered in the Alzheimer's peptide (Aβ). Its synthesis and coordination properties for CuΙ and CuΙΙ are described. L efficiently complex CuΙΙ in a square-planar geometry involving three imidazole nitrogen atoms and an amidate-Cu bond. By contrast, CuΙ is coordinated in a tetrahedral environment. The redox behavior is irreversible and follows an ECEC mechanism in accordance with the very different environments of the two redox states of the Cu center. This is in line with the observed resistance of the CuΙ complex to oxidation by oxygen and the CuΙΙ complex reduction by ascorbate. The affinities of L for CuΙΙ and CuΙ at physiological pH are larger than that reported for the Aβ peptide. Therefore, due to its peculiar Cu coordination properties, the ligand L is able to target both redox states of Cu, redox silence them and prevent reactive oxygen species production by the CuAβ complex. Because reactive oxygen species contribute to the oxidative stress, a key issue in Alzheimer's disease, this ligand thus represents a new strategy in the long route of finding molecular concepts for fighting Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Precisely incorporating a wide range of structural and functional multiblocks along a polymer backbone is a significant challenge in polymer chemistry and offers promising opportunities to design highly ordered materials, including controlled polymer folding. Herein, a facile and versatile strategy for preparing functional multiblock copolymers composed of sequential peptides and well-defined vinyl polymers with a narrow polydispersity is reported. Cyclic oligopeptides have been developed that contain an alkoxyamine bond in the framework. By using this type of cyclic initiator, peptide-containing multiblock copolymers are successfully synthesized by nitroxide-mediated polymerization of styrene. To demonstrate the versatility of this method, radical (co)polymerizations were carried out for different monomers ( p-chlorostyrene, 4-vinylpyridine, and styrene/acrylonitrile) and by three different cyclic peptide initiators with specific amino acid sequences. The resultant multiblock copolymer is foldable through intramolecular interactions between peptide blocks. It is believed that this approach will significantly advance the field of controlled polymer synthesis for complex structures and single-chain folding. [ABSTRACT FROM AUTHOR]

The rational design of a well-defined protein-like tertiary structure formed by small peptide building blocks is still a formidable challenge. By using peptide-oligonucleotide conjugates (POC) as building blocks, we present the self-assembly of miniature coiled-coil α-helical peptides guided by oligonucleotide duplex and triplex formation. POC synthesis was achieved by copper-free alkyne-azide cycloaddition between three oligonucleotides and a 23-mer peptide, which by itself exhibited multiple oligomeric states in solution. The oligonucleotide domain was designed to furnish a stable parallel triplex under physiological pH, and to be capable of templating the three peptide sequences to constitute a small coiled-coil motif displaying remarkable α-helicity. The formed trimeric complex was characterized by ultraviolet thermal denaturation, gel electrophoresis, circular dichroism (CD) spectroscopy, small-angle X-ray scattering (SAXS), and molecular modeling. Stabilizing cooperativity was observed between the trimeric peptide and the oligonucleotide triplex domains, and the overall molecular size (ca. 12 nm) in solution was revealed to be independent of concentration. The topological folding of the peptide moiety differed strongly from those of the individual POC strands and the unconjugated peptide, exclusively adopting the designed triple helical structure. [ABSTRACT FROM AUTHOR]

Triplex-forming peptide nucleic acids (TFPNAs) were targeted to double-helical regions of 19F-labeled RNA hairpin models (a UA-rich duplex with a hexaethylene glycol (heg) loop and a microRNA model, miR-215). In addition to conventional UV- and circular dichroism (CD)-based detection, binding was monitored by 19F NMR spectroscopy. Detailed information on the stoichiometry and transition between the triple-helical peptide nucleic acid (PNA)/RNA and (PNA)2/RNA binding modes could be obtained. γ-( R)-Hydroxymethyl-modified thymine-1-yl- and 2-aminopyridin-3-yl-acetyl derivatives of TFPNAs were additionally synthesized, which were targeted to the same RNA models, and the effect of the γ-( R)-hydroxymethyl group on binding was studied. An appropriate pattern of γ-( R)-hydroxymethyl modifications reduced the stability of the ternary complex and preferred stoichiometric binding to the miR-215 model. [ABSTRACT FROM AUTHOR]

The application of thiol-yne/thiol-ene reactions to synthesize mono- and bicyclic-stapled peptides and proteins is reported. First, a thiol-ene-based peptide-stapling method in aqueous conditions was developed. This method enabled the efficient stapling of recombinantly expressed coil-coiled proteins. The resulting stapled protein demonstrated higher stability in its secondary structure than the unstapled version. Furthermore, a thiol-yne coupling was performed by using an α,ω-diyne to react with two cysteine residues to synthesize a stapled peptide with two vinyl sulfide groups. The stapled peptide could further react with another biscysteine peptide to yield a bicyclic stapled peptide with enhanced properties. For example, the cell permeability of a stapled peptide was further increased by appending an oligoarginine cell-penetrating peptide. The robustness and versatility of thiol-yne/thiol-ene reactions that can be applied to both synthetic and expressed peptides and proteins were demonstrated. [ABSTRACT FROM AUTHOR]

The introduction of macrocyclic constraints in peptides (peptide stapling) is an important tool within peptide medicinal chemistry for stabilising and pre-organising peptides in a desired conformation. In recent years, the copper-catalysed azide-alkyne cycloaddition (CuAAC) has emerged as a powerful method for peptide stapling. However, to date CuAAC stapling has not provided a simple method for obtaining peptides that are easily diversified further. In the present study, we report a new diversity-oriented peptide stapling (DOPS) methodology based on CuAAC chemistry. Stapling of peptides incorporating two azide-modified amino acids with 1,3,5-triethynylbenzene efficiently provides ( i, i+7)- and ( i, i+9)-stapled peptides with a single free alkyne positioned on the staple, which can be further conjugated or dimerised. A unique feature of the present method is that it provides easy access to radiolabelled stapled peptides by catalytic tritiation of the alkyne positioned on the staple. [ABSTRACT FROM AUTHOR]

Detailed conformational analyses of our previously reported cyclopropane-based peptidomimetics and conformational analysis-driven ligand optimization are described. Computational calculations and X-ray crystallography showed that the characteristic features of cyclopropane function effectively to constrain the molecular conformation in a three-dimensionally diverse manner. Subsequent principal component analysis revealed that the diversity covers the broad chemical space filled by peptide secondary structures in terms of both main-chain and side-chain conformations. Based on these analyses, a lead stereoisomer targeting melanocortin receptors was identified, and its potency and subtype selectivity were improved by further derivatization. The presented strategy is effective not only for designing non-peptidic ligands from a peptide ligand but also for the rational optimization of these ligands based on the plausible target-binding conformation without requiring the three- dimensional structural information of the target and its peptide ligands. [ABSTRACT FROM AUTHOR]

Single molecules that co‐transport cations as well as anions across lipid membranes are few despite their high biological utility. The elegant yet simple lipidomimmetic peptide design herein enables efficient HCl transport without the use of any external additives for proton transport. The carboxylic acids in the dipeptide scaffold provide a handle to append two long hydrophobic tails and also provide a polar hydrophilic carboxylate group. The peptide central unit also provides NH sites for anion binding. Protonation of the carboxylate group coupled with the weak halide binding of the terminal NH group results in HCl transport with transport rates of H+>Cl−. The lipid‐like structure also facilitates seamless membrane integration and flipping of the molecule. The biocompatibility, design simplicity, and potential pH regulation of these molecules open up several avenues for their therapeutic use. [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]

We report the discovery of a straightforward protocol to convert phenols into the corresponding aryl triflates using 1‐methyl‐3‐((trifluoromethyl)sulfonyl)‐1,3‐dihydro‐2H‐benzo[d]imidazol‐2‐one in the presence of a fluoride source. This novel reagent can be handled without any precautions to exclude air or moisture making this method highly convenient. The reactions generally show very clean conversions within only a few minutes at room temperature. The mild conditions allow the so far unprecedented O‐triflation of tyrosine in peptides bearing challenging side chains present for example in arginine and histidine including the late‐stage triflation of complex bioactive peptides. We show how aryl triflates – an interesting but so far underutilized group – can be used to optimize physicochemical and in vitro properties of compound series in medicinal chemistry. We believe that this method is highly attractive for applications in peptide functionalization as well as automated and medicinal chemistry. [ABSTRACT FROM AUTHOR]

Finding an ideal bioorthogonal reaction that responds to a wide range of biological queries and applications is of great interest in biomedical applications. Rapid diazaborine (DAB) formation in water by the reactions of ortho‐carbonyl phenylboronic acid with α‐nucleophiles is an attractive conjugation module. Nevertheless, these conjugation reactions demand to satisfy stringent criteria for bioorthogonal applications. Here we show that widely used sulfonyl hydrazide (SHz) offers a stable DAB conjugate by combining with ortho‐carbonyl phenylboronic acid at physiological pH, competent for an optimal biorthogonal reaction. Remarkably, the reaction conversion is quantitative and rapid (k2>103 M−1 s−1) at low micromolar concentrations, and it preserves comparable efficacy in a complex biological milieu. DFT calculations support that SHz facilitates DAB formation via the most stable hydrazone intermediate and the lowest energy transition state compared to other biocompatible α‐nucleophiles. This conjugation is extremely efficient on living cell surfaces, enabling compelling pretargeted imaging and peptide delivery. We anticipate this work will permit addressing a wide range of cell biology queries and drug discovery platforms exploiting commercially available sulfonyl hydrazide fluorophores and derivatives. [ABSTRACT FROM AUTHOR]

The co‐evolution of peptide formation and membrane self‐assembly is considered an essential step in the origin of life. However, more research is required on both processes, particularly on the interaction between prebiotic simple fatty‐acid membranes and peptide synthesis. In this study, the sodium trimetaphosphate (P3m)‐activated peptide formation reaction of phenylalanine (Phe) in an alkaline decanoic acid‐decanol vesicle system was systematically investigated. The experimental results showed that peptide formation could competitively occur with N‐acyl amino acid (NAA) formation. NAA formation did not follow the traditional P3m‐activated peptide formation reaction involving the intermediate cyclic acylphosphoramidate (CAPA). Decanoic acid was activated by P3m to form a mixed anhydride, which then reacted with an amino acid to form the amide NAA. As a kind of membrane‐forming amphiphile, NAA can form vesicles independently and reduce the critical vesicle concentration of the fatty‐acid vesicles. Moreover, 11 other representative amino acids, namely alanine (Ala), aspartic acid (Asp), glutamic acid (Glu), glycine (Gly), isoleucine (Ile), leucine (Leu), proline (Pro), serine (Ser), threonine (Thr), valine (Val), and arginine (Arg), were selected for investigation. All of them reacted with decanoic acid to form NAA via the activation effect of P3m. The abovementioned mechanism involving P3m‐activated carboxylic acid has not been reported in the literature. Our experimental results indicate that the participation of decanoic acid in the P3m activation‐based peptide formation reaction system plays a significant role in the emergence of functionalized protocells. The P3m activation effect can provide diversified raw membrane materials to form and stabilize protocell membranes; moreover, the small peptides, such as Phe‐Leu, formed in the same reaction system can induce the amplification of primitive cells. This implies that synergistic symbiosis between membrane and peptide can be realized via the P3m activation effect. [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]

The direct amide bond formation between a carboxylic acid and an amine still constitutes a challenging reaction for both academia and industry. We demonstrate herein that several pairs of amines (halogen bond acceptors) and organohalogen sources may be used for the photochemical amidation reaction under either UVA or sunlight irradiation. Our studies led to the identification of pyridine‐CBr4 as an efficient agent to perform amide synthesis under LED 370 nm irradiation, avoiding super‐stoichiometric quantities. An extended substrate scope was demonstrated, showing that the widely used amino and carboxyl protecting groups are compatible with this photochemical protocol, while a number of industrially interesting products and bioactive compounds were synthesized. Direct infusion‐high resolution mass spectrometry studies suggest an unprecedented type of carboxylic acid activation mode upon irradiation, involving the generation of a symmetric anhydride, an active ester with pyridine N‐oxide and a mixed anhydride with hypobromous acid. [ABSTRACT FROM AUTHOR]

Front Cover: Concentration-Dependent Interactions of Amphiphilic PiB Derivative Metal Complexes with Amyloid Peptides A and Amylin (Chem. Eur. J. 6/2021) Keywords: amylin; amyloid peptide; A ; metal complex; micellar aggregation EN amylin amyloid peptide A metal complex micellar aggregation 1860 1860 1 01/29/21 20210126 NES 210126 B Metal chelates targeted to amyloid peptides b are widely explored as diagnostic tools or therapeutic agents. Amylin, amyloid peptide, A , metal complex, micellar aggregation. [Extracted from the article]