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Nanoparticle-mediated mRNA delivery has emerged as a promising therapeutic modality, but its growth is still limited by the discovery and optimization of effective and well-tolerated delivery strategies. Lipid nanoparticles containing charged or ionizable lipids are an emerging standard for in vivo mRNA delivery, so creating facile, tunable strategies to synthesize these key lipid-like molecules is essential to advance the field. Here, we generate a library of N-substituted glycine oligomers, peptoids, and undertake a multistage down-selection process to identify lead candidate peptoids as the ionizable component in our Nutshell nanoparticle platform. First, we identify a promising peptoid structural motif by clustering a library of >200 molecules based on predicted physical properties and evaluate members of each cluster for reporter gene expression in vivo. Then, the lead peptoid motif is optimized using design of experiments methodology to explore variations on the charged and lipophilic portions of the peptoid, facilitating the discovery of trends between structural elements and nanoparticle properties. We further demonstrate that peptoid-based Nutshells leads to expression of therapeutically relevant levels of an anti-respiratory syncytial virus antibody in mice with minimal tolerability concerns or induced immune responses compared to benchmark ionizable lipid, DLin-MC3-DMA. Through this work, we present peptoid-based nanoparticles as a tunable delivery platform that can be optimized toward a range of therapeutic programs.

This research evolves into a comparative study of three different phenolic composites as coatings for rigid contact lenses, with a particular emphasis on enhancing their antifouling properties and hydrophobicity. The primary layer, comprised of diverse phenolic compounds, serves as a sturdy foundation. An exclusive secondary layer, featuring synthetic peptoids, is introduced to further minimize biofouling. Validated through X-ray photoelectron spectroscopy, the surface analysis confirms the successful integration of the polyphenolic layers and the subsequent grafting of peptoids onto the lens surface. The efficacy of the proposed coatings is substantiated through protein adsorption tests, providing definitive evidence of their antifouling capabilities. This research employs a nuanced assessment of coating performance, utilizing the quantification of fluorescence intensity to gauge effectiveness. Additionally, contact angle measurements offer insights into wettability and surface characteristics, contributing to a comprehensive understanding of the coatings practicality.

Mineral-polymer composites found in nature exhibit exceptional structural properties essential to their function, and transferring these attributes to the synthetic design of functional materials holds promise across various sectors. Biomimetic fabrication of nanocomposites introduces new pathways for advanced material design and explores biomineralization strategies. This study presents a novel approach for producing single platelet nanocomposites composed of CaCO3 and biomimetic peptoid (N-substituted glycines) polymers, akin to the bricks found in the brick-and-mortar structure of nacre, the inner layer of certain mollusc shells. The significant aspect of the proposed strategy is the use of organic peptoid nanosheets as the scaffolds for brick formation, along with their controlled mineralization in solution. Here, we employ the B28 peptoid nanosheet as a scaffold, which readily forms free-floating zwitterionic bilayers in aqueous solution. The peptoid nanosheets were mineralized under consistent initial conditions (σcalcite = 1.2, pH 9.00), with variations in mixing conditions and supersaturation profiles over time aimed at controlling the final product. Nanosheets were mineralized in both feedback control experiments, where supersaturation was continuously replenished by titrant addition and in batch experiments without a feedback loop. Complete coverage of the nanosheet surface by amorphous calcium carbonate was achieved under specific conditions with feedback control mineralization, whereas vaterite was the primary CaCO3 phase observed after batch experiments. Thermodynamic calculations suggest that time-dependent supersaturation profiles as well as the spatial distribution of supersaturation are effective controls for tuning the mineralization extent and product. We anticipate that the control strategies outlined in this work can serve as a foundation for the advanced and scalable fabrication of nanocomposites as building blocks for nacre-mimetic and functional materials.

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study, TM9 was effective against three murine coronavirus strains, demonstrating that the therapeutic window is large enough to allow the use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber, and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from the liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain.

Cryogenic transmission electron microscopy (cryo‐TEM) combined with single particle analysis (SPA) is an emerging imaging approach for soft materials. However, the accuracy of SPA‐reconstructed nanostructures, particularly those formed by synthetic polymers, remains uncertain due to potential packing heterogeneity of the nanostructures. In this study, the combination of molecular dynamics (MD) simulations and image simulations is utilized to validate the accuracy of cryo‐TEM 3D reconstructions of self‐assembled polypeptoid fibril nanostructures. Using CryoSPARC software, image simulations, 2D classifications, ab initio reconstructions, and homogenous refinements are performed. By comparing the results with atomic models, the recovery of molecular details is assessed, heterogeneous structures are identified, and the influence of extraction location on the reconstructions is evaluated. These findings confirm the fidelity of single particle analysis in accurately resolving complex structural characteristics and heterogeneous structures, exhibiting its potential as a valuable tool for detailed structural analysis of synthetic polymers and soft materials. [ABSTRACT FROM AUTHOR]

The assembly of peptide and peptide‐inspired building blocks into functional, well‐defined, multi‐length scale materials represents an exciting, rapidly expanding research field that bridges the principles of polymer science and engineering with a tremendous breadth of biomolecular interactions. The advantageous features of peptides, including their biocompatibility, functional diversity, and high purity, are complemented by the breadth of potential applications that may arise from their resultant structures and assemblies. Applications in biology (tissue scaffolding and drug conjugation), electronics (electron and/or ion‐conduction), and membranes (ion capture and ultrafiltration) represent a few of many examples where such biologically rich materials hold potential for enabling new routes to enhanced materials performance. Achieving successful solution and interfacial assembly techniques for peptides and other peptidomimetic materials requires obtaining a deep understanding of their design principles and limitations, as well as their amenability to structure formation when subjected to a variety of environmental conditions, such as pH, solvent, and temperature, to which such assembly methods may be exquisitely sensitive. This review especially focuses on mechanisms and the product of oligo‐ and polypeptide assembly, often resulting in the formation of extended, wire‐like structures obtained by solution methods, with inclusion of peptoid‐based structures and the complementary roles of polymerizations and step‐by‐step synthetic methods. Moreover, we describe relationships between naturally occurring peptide‐based structures, such as Geobacter pili, that in turn inspire self‐assembly of peptide‐based structures, composites with polymer materials, and assemblies therefrom. [ABSTRACT FROM AUTHOR]

The detoxification of lethal organophosphate (OP) residues in the environment is crucial to prevent human exposure and protect modern society. Despite serving as excellent catalysts for OP degradation, natural enzymes require costly preparation and readily deactivate upon exposure to environmental conditions. Herein, we designed and prepared a series of phosphotriesterase mimics based on stable, self-assembled peptoid membranes to overcome these limitations of the enzymes and effectively catalyze the hydrolysis of dimethyl p-nitrophenyl phosphate (DMNP)─a nerve agent simulant. By covalently attaching metal-binding ligands to peptoid N-termini, we attained enzyme mimetics in the form of surface-functionalized crystalline nanomembranes. These nanomembranes display a precisely controlled arrangement of coordinated metal ions, which resemble the active sites found in phosphotriesterases to promote DMNP hydrolysis. Moreover, using these highly programmable peptoid nanomembranes allows for tuning the local chemical environment of the coordinated metal ion to achieve enhanced hydrolysis activity. Among the crystalline membranes that are active for DMNP degradation, those assembled from peptoids containing bis-quinoline ligands with an adjacent phenyl side chain showed the highest hydrolytic activity with a 219-fold rate acceleration over the background, demonstrating the important role of the hydrophobic environment in proximity to the active sites. Furthermore, these membranes exhibited remarkable stability and were able to retain their catalytic activity after heating to 60 °C and after multiple uses. This work provides insights into the principal features to construct a new class of biomimetic materials with high catalytic efficiency, cost-effectiveness, and reusability applied in nerve agent detoxification.

We report on the first peptoid‐based catalyst for visible light driven water oxidation, the complex TPT2Co. Peptoids are N‐substituted glycine oligomers, and TPT is a peptoid trimer incorporating terpyridine ligand, an ethanolic group as a proton acceptor and a non‐catalytic benzyl group. We explored the ability of TPT2Co to perform as a catalyst for water oxidation in phosphate buffer at pH 9.5, in the presence of the photosensitizer [Ru(bpy)3]2+ and the sacrificial electron acceptor Na2S2O8. We demonstrated that TPT2Co can catalyze water oxidation by a blue LED with an intensity of only 1.5 mW/cm2 towards oxygen production at pH 9.5 with a maximal TON of 28.1 in 45 min. The stability of TPT2Co during the light‐driven water oxidation as well as its ability to stabilize the photosensitizer were confirmed by a combination of UV‐Vis, IR and ESI‐MS analysis. [ABSTRACT FROM AUTHOR]

Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression. [ABSTRACT FROM AUTHOR]

The development of nontoxic and efficient antifreeze agents for organ cryopreservation is crucial. However, the research remains highly challenging. In this study, we designed and synthesized a series of peptoid oligomers using the solid-phase submonomer synthesis method by mimicking the amphiphilic structures of antifreeze proteins (AFPs). The obtained peptoid oligomers showed excellent antifreeze properties, reducing the ice crystal growth rate and inhibiting ice recrystallization. The effects of the hydrophobicity and sequence of the peptoid side chains were also studied to reveal the structure–property relationship. The prepared peptoid oligomers were detected as non-cytotoxic and considered to be useful in the biological field. We hope that the peptoid oligomers presented in this study can provide effective strategies for the design of biological cryoprotectants for organ preservation in the future. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is among the most neglected tropical diseases in the world. Drug cell permeability is essential for killing the intracellular residing parasites responsible for VL, making cell-permeating peptides a logical choice to address VL. Unfortunately, the limited biological stability of peptides restricts their usage. Sequence-specific oligo-N-substituted glycines ('peptoids') are a class of peptide mimics that offers an excellent alternative to peptides in terms of ease of synthesis and good biostability. We tested peptoids against the parasite Leishmania donovani in both forms, that is, intracellular amastigotes and promastigotes. N-alkyl hydrophobic chain addition (lipidation) and bromination of oligopeptoids yielded compounds with good antileishmanial activity against both forms, showing the promise of these antiparasitic peptoids as potential drug candidates to treat VL.

Storing solar energy is a key challenge in modern science. MOlecular Solar Thermal (MOST) systems, in particular those based on azobenzene switches, have received great interest in the last decades. The energy storage properties of azobenzene (t1/2<4 days; ΔH~270 kJ/kg) must be improved for future applications. Herein, we introduce peptoids as programmable supramolecular scaffolds to improve the energy storage properties of azobenzene‐based MOST systems. We demonstrate with 3‐unit peptoids bearing a single azobenzene chromophore that dynamics of the MOST systems can be tuned depending on the anchoring position of the photochromic unit on the macromolecular backbone. We measured a remarkable increase of the half‐life of the metastable form up to 14 days at 20 °C for a specific anchoring site, significantly higher than the isolated azobenzene moiety, thus opening new perspectives for MOST development. We also highlight that liquid chromatography coupled to mass spectrometry does not only enable to monitor the different stereoisomers during the photoisomerization process as traditionally done, but also allows to determine the thermal back‐isomerization kinetics. [ABSTRACT FROM AUTHOR]

Human nonreceptor tyrosine kinase (TK) Fyn is implicated in various cellular processes and has been exploited as a sophisticated druggable target of pediatric T-cell lymphoma by blocking its kinase domain with small-molecule inhibitors or disrupting its regulatory SH2 and SH3 domains with peptidic inhibitors. In this study, the proline-heavy 9P1Y-peptide was found as a good binder of Fyn SH3 domain, of which the chemical diversity space was extended by replacing its proline residues with a variety of N-substituted amino acids, since N-substitution can mimic the side-chain location and shape of proline. A systematic single-point N-substituting perturbation profile (SSNPP) for 9P1Y-peptide was created theoretically, from which a systematic combinatorial peptoid library (SCPL) was then generated by introducing favorable N-substituted to different proline residue positions of the peptide. The computational design was further substantiated by fluorescence spectroscopy assays to identify five promising peptoid hits in the SCPL as potential Fyn SH3 binders. In particular, the designed peptoid Ptoid2 exhibited a good affinity to Fyn SH3 domain ( K d = 0. 7 6 μ M) and a moderate selectivity for Fyn over Lyn (3.8-fold), which are improved substantially from the natural 9P1Y-peptide. Molecular mechanism underlying the N-substituting perturbation effect was also examined in detail. The chemical diversity space of a Fyn SH3 binder is exploited by replacing its proline residues with a variety of N-substituted amino acids. A systematic single-point N-substituting perturbation profile is created and a systematic combinatorial peptoid library is generated by introducing favorable N-substituted to different proline residues. [ABSTRACT FROM AUTHOR]

Cationic antimicrobial peptides (CAMPs) are powerful molecules with antimicrobial, antibiofilm and endotoxin-scavenging activities. These properties make CAMPs very attractive drugs in the face of the rapid increase in multidrug-resistant (MDR) pathogens, but they are limited by their susceptibility to proteolytic degradation. An intriguing solution to this issue could be the development of functional mimics of CAMPs with structures that enable the evasion of proteases. Peptoids (N-substituted glycine oligomers) are an important class of peptidomimetics with interesting benefits: easy synthetic access, intrinsic proteolytic stability and promising bioactivities. Here, we report the characterization of P13#1, a 13-residue peptoid specifically designed to mimic cathelicidins, the best-known and most widespread family of CAMPs. P13#1 showed all the biological activities typically associated with cathelicidins: bactericidal activity over a wide spectrum of strains, including several ESKAPE pathogens; the ability to act in combination with different classes of conventional antibiotics; antibiofilm activity against preformed biofilms of Pseudomonas aeruginosa, comparable to that of human cathelicidin LL-37; limited toxicity; and an ability to inhibit LPS-induced proinflammatory effects which is comparable to that of "the last resource" antibiotic colistin. We further studied the interaction of P13#1 with SDS, LPSs and bacterial cells by using a fluorescent version of P13#1. Finally, in a subcutaneous infection mouse model, it showed antimicrobial and anti-inflammatory activities comparable to ampicillin and gentamicin without apparent toxicity. The collected data indicate that P13#1 is an excellent candidate for the formulation of new antimicrobial therapies. [ABSTRACT FROM AUTHOR]

This research evolves into a comparative study of three different phenolic composites as coatings for rigid contact lenses, with a particular emphasis on enhancing their antifouling properties and hydrophobicity. The primary layer, comprised of diverse phenolic compounds, serves as a sturdy foundation. An exclusive secondary layer, featuring synthetic peptoids, is introduced to further minimize biofouling. Validated through X-ray photoelectron spectroscopy, the surface analysis confirms the successful integration of the polyphenolic layers and the subsequent grafting of peptoids onto the lens surface. The efficacy of the proposed coatings is substantiated through protein adsorption tests, providing definitive evidence of their antifouling capabilities. This research employs a nuanced assessment of coating performance, utilizing the quantification of fluorescence intensity to gauge effectiveness. Additionally, contact angle measurements offer insights into wettability and surface characteristics, contributing to a comprehensive understanding of the coating’s practicality.

Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression.

The development of nontoxic and efficient antifreeze agents for organ cryopreservation is crucial. However, the research remains highly challenging. In this study, we designed and synthesized a series of peptoid oligomers using the solid-phase submonomer synthesis method by mimicking the amphiphilic structures of antifreeze proteins (AFPs). The obtained peptoid oligomers showed excellent antifreeze properties, reducing the ice crystal growth rate and inhibiting ice recrystallization. The effects of the hydrophobicity and sequence of the peptoid side chains were also studied to reveal the structure–property relationship. The prepared peptoid oligomers were detected as non-cytotoxic and considered to be useful in the biological field. We hope that the peptoid oligomers presented in this study can provide effective strategies for the design of biological cryoprotectants for organ preservation in the future.

Water oxidation (WO) is the first step in the water-splitting process aiming at the production of hydrogen as a green renewable fuel. To successfully perform WO, potent strategies for overcoming the high energetic barrier and slow kinetics of this reaction are urgently required. One such strategy is the use of molecular catalysis. Specifically, Cu-based catalysts have been highlighted over the last decade due to their stability and fast kinetics. Among them, Cu-peptoids, where peptoids are peptidomimetics akin to peptides and are N-substituted glycine oligomers, can act as stable and active catalysts for oxidation transformations including electrocatalytic WO. Previously, we suggested that a benzyl group incorporated as a side chain near the catalytic site within a Cu-peptoid electrocatalyst for WO has a structural role in the activity of the electrocatalyst in phosphate buffer (PBS). Herein, we aimed to test this hypothesis and understand how an incorporated structural element side chain affects WO. To this aim, we prepared a set of peptoid trimers each with a different structural element replacing the benzyl group by either naphthyl, cyclohexyl, benzyl, propyl chloride, or propyl side chains as well as a peptoid lacking a structural element. We studied the structure of their Cu complexes and tested these complexes as electrocatalysts for WO. We discovered that while all the peptoids self-assemble to form dinuclear Cu-peptoid complexes, the duplex that has no structural side chain, Cu2(BE)2, is structurally different from the others in the solid state. Moreover, Cu2(BE)2 remains dinuclear in a PBS at pH 11, while all the other duplexes are mononuclear in the PBS. Finally, though most of the complexes showed low electrocatalytic activity for WO, the dinuclear complex Cu2(BE)2 performed with the highest turnover frequency of 484 s−1. Nevertheless, this dinuclear complex slowly decomposes to the corresponding mononuclear complex as a more stable species during WO, while the other mononuclear complexes retain their structure in solution but display much slower kinetics (ca. 5 to 8 s−1) under the same conditions. Overall, our results demonstrate that bulkier side chains hamper the stability of dinuclear Cu-peptoids in a PBS, and hence, their efficiency as WO electrocatalysts is also hampered. [ABSTRACT FROM AUTHOR]

Over the past half-decade, scientists and clinicians have witnessed remarkable success of therapeutic peptides in both the diagnosis and the treatment of various diseases. Although peptide drugs have major advantages over other therapeutic modalities, poor physicochemical and proteolytic stability profiles are major setbacks that undercut their clinical application. An assortment of different chemical modifications coupled with suitable delivery technologies could potentially generate greatly improved peptide drugs that can be translated to the clinic. FDA approval of oral semaglutide (Rybelsus®) in 2019 for the management of type 2 diabetes marked a key milestone in the advancement of peptide therapeutics. Peptides have unique characteristics that make them highly desirable as therapeutic agents. The physicochemical and proteolytic stability profiles determine the therapeutic potential of peptides. Multiple strategies to enhance the therapeutic profile of peptides have emerged. They include chemical modifications, such as cyclization, substitution with d -amino acids, peptoid formation, N -methylation, and side-chain halogenation, and incorporation in delivery systems. There have been recent advances in approaches to discover peptides having these modifications to attain desirable therapeutic properties. We critically review these recent advancements in therapeutic peptide development. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is among the most neglected tropical diseases in the world. Drug cell permeability is essential for killing the intracellular residing parasites responsible for VL, making cell‐permeating peptides a logical choice to address VL. Unfortunately, the limited biological stability of peptides restricts their usage. Sequence‐specific oligo‐N‐substituted glycines (‘peptoids’) are a class of peptide mimics that offers an excellent alternative to peptides in terms of ease of synthesis and good biostability. We tested peptoids against the parasite Leishmania donovani in both forms, that is, intracellular amastigotes and promastigotes. N‐alkyl hydrophobic chain addition (lipidation) and bromination of oligopeptoids yielded compounds with good antileishmanial activity against both forms, showing the promise of these antiparasitic peptoids as potential drug candidates to treat VL.

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study, TM9 was effective against three murine coronavirus strains, demonstrating that the therapeutic window is large enough to allow the use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber, and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from the liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain.

Cis‐trans isomerization of amide bonds impedes de novo design of folded peptoids (poly‐N‐substituted glycines) with precise secondary structures and affects peptoid‐biomolecule binding affinity. Herein, from X‐ray, NMR and DFT studies of azapeptoids, we have discovered a tetrel bonding interaction that stabilizes trans‐peptoids. We show that peptoids having α‐heteroatoms and N‐aryl groups in the sidechain adopt trans‐amide geometries due to the presence of a nX/πAr→σ*Cα−N tetrel bonding interaction between the sidechain α‐heteroatom lone pair (nX) or π‐electrons (πAr) and the σ* orbital of the backbone Cα−N bond. Further, CD spectroscopic studies of oligo‐proline host–guest model peptides showed that azapeptoid residues stabilize polyproline II helical conformation. These data indicate that the sidechain‐backbone tetrel bonding could be leveraged to design peptoids with precise secondary structures for a wide range of biological and material applications. [ABSTRACT FROM AUTHOR]

The field of cell‐penetrating peptides is dominated by the use of oligomers of arginine residues. Octanol–water partitioning in the presence of an anionic lipid is a validated proxy for cell‐penetrative efficacy. Here, we add one, two, or three N‐methyl groups to Ac‐Arg‐NH2 and examine the effects on octanol–water partitioning. In the absence of an anionic lipid, none of these arginine derivatives can be detected in the octanol layer. In the presence of sodium dodecanoate, however, increasing N‐methylation correlates with increasing partitioning into octanol, which is predictive of higher cell‐penetrative ability. We then evaluated fully Nα‐methylated oligoarginine peptides and observed an increase in their cellular penetration compared with canonical oligoarginine peptides in some contexts. These findings indicate that a simple modification, Nα‐methylation, can enhance the performance of cell‐penetrating peptides. [ABSTRACT FROM AUTHOR]

DNA nanotechnology has established approaches for designing programmable and precisely controlled nanoscale architectures through specific Watson-Crick base-pairing, molecular plasticity, and intermolecular connectivity. In particular, superior control over DNA origami structures could be beneficial for biomedical applications, including biosensing, in vivo imaging, and drug and gene delivery. However, protecting DNA origami structures in complex biological fluids while preserving their structural characteristics remains a major challenge for enabling these applications. Here, we developed a class of structurally well-defined peptoids to protect DNA origamis in ionic and bioactive conditions and systematically explored the effects of peptoid architecture and sequence dependency on DNA origami stability. The applicability of this approach for drug delivery, bioimaging, and cell targeting was also demonstrated. A series of peptoids (PE1-9) with two types of architectures, termed as "brush" and "block," were built from positively charged monomers and neutral oligo-ethyleneoxy monomers, where certain designs were found to greatly enhance the stability of DNA origami. Through experimental and molecular dynamics studies, we demonstrated the role of sequence-dependent electrostatic interactions of peptoids with the DNA backbone. We showed that octahedral DNA origamis coated with peptoid (PE2) can be used as carriers for anticancer drug and protein, where the peptoid modulated the rate of drug release and prolonged protein stability against proteolytic hydrolysis. Finally, we synthesized two alkyne-modified peptoids (PE8 and PE9), conjugated with fluorophore and antibody, to make stable DNA origamis with imaging and cell-targeting capabilities. Our results demonstrate an approach toward functional and physiologically stable DNA origami for biomedical applications.

The synthesis and conformational analysis of the first series of peptoid oligomers composed of consecutive N-(alkylamino)glycine units is investigated. We demonstrate that N-(methylamino)glycine homooligomers can be readily synthesized in solution using N-Boc-N-methylhydrazine as a peptoid submonomer and stepwise or segment coupling methodologies. Their structures were analyzed in solution by 1D and 2D NMR, in the solid state by X-ray crystallography (dimer 2), and implicit solvent QM geometry optimizations. N-(Methylamino)peptoids were found to preferentially adopt trans amide bonds with the side chain N–H bonds oriented approximately perpendicular to the amide plane. This orientation is conducive to local backbone stabilization through intra-residue hydrogen bonds but also to intermolecular associations. The high capacity of N-(methylamino)peptoids to establish intermolecular hydrogen bonds was notably deduced from pronounced concentration-dependent N–H chemical shift variation in 1H NMR and the antiparallel arrangement of mirror image molecules held together via two hydrogen bonds in the crystal lattice of dimer 2.

Cationic amphipathic structures are often utilized in natural membrane-active host-defense peptides. Negatively charged surface membranes of rapidly proliferating bacterial and cancer cells have been targeted by various synthetic peptides and peptidomimetics adopting the structural motif. Herein, we synthesized a set of conjugates composed of cationic amphipathic peptoids (i.e., oligo-N-substituted glycines) and a chlorin photosensitizer, named chlorin e6 (Ce6)-peptoid conjugates (CPCs). Among the nine CPCs, CPC 7, composed of Ce6, a PEG linker, and guanidine-rich helical amphipathic peptoids, exhibited a distinct photoresponsive inactivation of Gram-positive and Gram-negative bacteria. Subsequent studies showed that CPC 7 effectively killed various cancer cells after irradiation with red light (655 nm), suggesting the potential of CPC 7 as a dual antimicrobial and anticancer agent. Confocal laser scanning microscopy and flow cytometry data suggested that CPC 7 could induce apoptotic cell death. Our results show the potential of peptoid-based photosensitizer conjugates as a versatile platform for antimicrobial and anticancer photodynamic therapy agents and peptoid therapeutics. [ABSTRACT FROM AUTHOR]

Natural metalloenzymes stabilize metal centers by utilizing multiple imidazole moieties. Inspired by nature's design principles, the introduction of multiple azoles into ligands has been an effective method for constructing transition metal complexes. Herein, we describe a post‐synthetic modification of peptoids to incorporate multiple azoles on side chains. A simple substitution reaction between an azole (imidazole, pyrazole, 1,2,3‐triazole, and tetrazole) and a chloroalkyl‐containing peptoid provided access to a variety of azole‐containing peptoids. Ten azole‐containing peptoids were synthesized from a single chloroalkyl‐containing peptoid, and the efficiency of each azole for the substitution reaction was evaluated. We have identified that several of the azole‐containing peptoids are capable of binding with Cu(II) and Fe(III). Our synthetic approach can contribute to the expansion of peptoids' chemical diversity and the development of novel peptoids for metal recognition and catalysis. [ABSTRACT FROM AUTHOR]

Artificial vesicles for mimicking the unique structures and functions of natural organelles represent a promising scientific object in biomimicry. However, the development of the stimuli-responsive and ultrathin vesicles assembled from sequence-defined biomimetic polymers for controllable applications is still a significant challenge. Herein, we report the self-assembly of azobenzene-based amphiphilic alternating peptoids to generate photo-responsive and ultrathin peptoid vesicle (pepsomes) with an average diameter of ∼180 nm. Both cryo-transmission electron microscopy (TEM) and dissipative particle dynamics simulation proved that the vesicular membrane was the ultrathin bilayer structure around ∼1.6 nm. The photo-responsive ability of pepsomes was demonstrated by the reversible size changes upon the alternative irradiation with ultraviolet (UV) and visible lights, which was attributable to the photoisomerization virtue of azobenzene moiety. As a proof-of-concept, the photo-controllable catalytic action of gold nanoparticles-decorated pepsomes was evaluated toward the borohydride-mediated reduction from 4-nitrophenol to 4-aminophenol. Photo-controllable reversible and recyclable catalytic activity was effectively modulated using the alternative irradiation with UV and visible lights for five cycles. Our work provides a simple strategy to prepare stimuli-responsive and ultrathin vesicles for potential application on nanocatalysis. [ABSTRACT FROM AUTHOR]

Objective: To discover a novel peptoid antagonist that targets the interleukin‐15 (IL‐15) receptor and to evaluate its therapeutic efficacy in the treatment of inflammation and arthritis. Methods: A new compound (IFRA3, interleukin‐15 receptor antagonist 3) was discovered using a unique on‐bead two‐colour combinatorial cell screening of a peptoid library. The interaction of IFRA3 with IL‐15 receptor was assessed by in vitro pull‐down and thermal shift assays. The efficacy of IFRA3 in treating inflammation and arthritis was evaluated in mouse models. Results: IFRA3Q1 (a tetrameric derivative of IFRA3) inhibited the activity of IL‐15 and suppressed CTLL‐2 cell proliferation (which depends on IL‐15 activity). IFRA3Q1 exhibited strong in vivo anti‐inflammatory activity in carrageenan‐induced inflammation in mice. Furthermore, IFRA3Q1 inhibited collagen‐induced arthritis in DBA/1J mice. Conclusion: By binding to and inhibiting the function of IL‐15 receptor, IFRA3Q1 exhibited significant anti‐arthritis activity. Our findings suggest that IFRA3Q1 represents a new paradigm for arthritis therapy by targeting IL‐15 signalling. [ABSTRACT FROM AUTHOR]

Cationic antimicrobial peptides (CAMPs) are powerful molecules with antimicrobial, antibiofilm and endotoxin-scavenging activities. These properties make CAMPs very attractive drugs in the face of the rapid increase in multidrug-resistant (MDR) pathogens, but they are limited by their susceptibility to proteolytic degradation. An intriguing solution to this issue could be the development of functional mimics of CAMPs with structures that enable the evasion of proteases. Peptoids (N-substituted glycine oligomers) are an important class of peptidomimetics with interesting benefits: easy synthetic access, intrinsic proteolytic stability and promising bioactivities. Here, we report the characterization of P13#1, a 13-residue peptoid specifically designed to mimic cathelicidins, the best-known and most widespread family of CAMPs. P13#1 showed all the biological activities typically associated with cathelicidins: bactericidal activity over a wide spectrum of strains, including several ESKAPE pathogens; the ability to act in combination with different classes of conventional antibiotics; antibiofilm activity against preformed biofilms of Pseudomonas aeruginosa, comparable to that of human cathelicidin LL-37; limited toxicity; and an ability to inhibit LPS-induced proinflammatory effects which is comparable to that of “the last resource” antibiotic colistin. We further studied the interaction of P13#1 with SDS, LPSs and bacterial cells by using a fluorescent version of P13#1. Finally, in a subcutaneous infection mouse model, it showed antimicrobial and anti-inflammatory activities comparable to ampicillin and gentamicin without apparent toxicity. The collected data indicate that P13#1 is an excellent candidate for the formulation of new antimicrobial therapies.

Water oxidation (WO) is the first step in the water-splitting process aiming at the production of hydrogen as a green renewable fuel. To successfully perform WO, potent strategies for overcoming the high energetic barrier and slow kinetics of this reaction are urgently required. One such strategy is the use of molecular catalysis. Specifically, Cu-based catalysts have been highlighted over the last decade due to their stability and fast kinetics. Among them, Cu-peptoids, where peptoids are peptidomimetics akin to peptides and are N-substituted glycine oligomers, can act as stable and active catalysts for oxidation transformations including electrocatalytic WO. Previously, we suggested that a benzyl group incorporated as a side chain near the catalytic site within a Cu-peptoid electrocatalyst for WO has a structural role in the activity of the electrocatalyst in phosphate buffer (PBS). Herein, we aimed to test this hypothesis and understand how an incorporated structural element side chain affects WO. To this aim, we prepared a set of peptoid trimers each with a different structural element replacing the benzyl group by either naphthyl, cyclohexyl, benzyl, propyl chloride, or propyl side chains as well as a peptoid lacking a structural element. We studied the structure of their Cu complexes and tested these complexes as electrocatalysts for WO. We discovered that while all the peptoids self-assemble to form dinuclear Cu-peptoid complexes, the duplex that has no structural side chain, Cu2(BE)2, is structurally different from the others in the solid state. Moreover, Cu2(BE)2 remains dinuclear in a PBS at pH 11, while all the other duplexes are mononuclear in the PBS. Finally, though most of the complexes showed low electrocatalytic activity for WO, the dinuclear complex Cu2(BE)2 performed with the highest turnover frequency of 484 s−1. Nevertheless, this dinuclear complex slowly decomposes to the corresponding mononuclear complex as a more stable species during WO, while the other mononuclear complexes retain their structure in solution but display much slower kinetics (ca. 5 to 8 s−1) under the same conditions. Overall, our results demonstrate that bulkier side chains hamper the stability of dinuclear Cu-peptoids in a PBS, and hence, their efficiency as WO electrocatalysts is also hampered.

Bacterial infections have been a serious threat to mankind throughout history. Natural antimicrobial peptides (AMPs) and their membrane disruption mechanism have generated immense interest in the design and development of synthetic mimetics that could overcome the intrinsic drawbacks of AMPs, such as their susceptibility to proteolytic degradation and low bioavailability. Herein, by exploiting the self-assembly and pore-forming capabilities of sequence-defined peptoids, we discovered a family of low-molecular weight peptoid antibiotics that exhibit excellent broad-spectrum activity and high selectivity toward a panel of clinically significant Gram-positive and Gram-negative bacterial strains, including vancomycin-resistant Enterococcus faecalis (VREF), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), Escherichia coli , Pseudomonas aeruginosa , and Klebsiella pneumoniae . Tuning the peptoid side chain chemistry and structure enabled us to tune the efficacy of antimicrobial activity. Mechanistic studies using transmission electron microscopy (TEM), bacterial membrane depolarization and lysis, and time-kill kinetics assays along with molecular dynamics simulations reveal that these peptoids kill both Gram-positive and Gram-negative bacteria through a membrane disruption mechanism. These robust and biocompatible peptoid-based antibiotics can provide a valuable tool for combating emerging drug resistance.

While plaques comprised of fibrillar Aβ aggregates are hallmarks of Alzheimer's disease, soluble Aβ oligomers present higher neurotoxicity. Thus, one therapeutic approach is to prevent the formation of Aβ oligomers and reduce their associated harmful effects. We have proposed a peptoid mimic of the Aβ hydrophobic KLVFF core as an ideal candidate aggregation inhibitor due to its ability to evade proteolytic degradation via repositioning of the side chain from the α-carbon to the amide nitrogen. This peptoid, JPT1, utilizes chiral sidechains to achieve a helical structure, while C-terminal addition of two phenylalanine residues places aromatic groups on two sides of the helix with spacing designed to facilitate interaction with amyloid β-sheet structure. We have previously shown that JPT1 modulates Aβ fibril formation. Here, we demonstrate that JPT1 also modulates Aβ oligomerization, and we explore the role of the charge on the linker between the KLVFF mimic and the extended aromatic residues. Additionally, we demonstrate that peptoid-induced changes in Aβ oligomerization correlate with attenuation of oligomer-induced nuclear factor-κB activation in SH-SY5Y human neuroblastoma cells. These findings support the therapeutic potential of peptoids to target early stages of Aβ aggregation and impact the associated Aβ-induced cellular response., (© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Peptoids are oligomers of N‐substituted glycine units. They structurally resemble peptides but, unlike natural peptides, the side chains of peptoids are present on the amide nitrogen atoms instead of the α‐carbons. The N‐substitution improves cell‐permeability of peptoids and enhance their proteolytic stability over natural peptides. Therefore, peptoids are ideal peptidomimetic candidates for drug discovery, especially for intracellular targets. Unfortunately, most peptoid ligands discovered so far possess moderate affinity towards their biological targets. The moderate affinity of peptoids for biomacromolecules is linked to their conformational flexibility, which causes substantial entropic loss during the peptoid‐biomacromolecule binding process. The conformational flexibility of peptoids is caused by the lack of backbone chirality, absence of hydrogen bond donors (NH) in their backbone to form CO⋅⋅⋅HN hydrogen bonds and the facile cis‐trans isomerization of their tertiary amide bonds. In recent years, many investigators have shown that the incorporation of specific side chains with unique steric and stereoelectronic features can favourably shift the cis‐trans equilibria of peptoids towards one of the two isomeric forms. Such strategies are helpful to design homogenous peptoid oligomers having well defined secondary structures. Herein, we discuss the strategies developed over the years to control the cis‐trans isomerization of peptoid amide bonds. [ABSTRACT FROM AUTHOR]

Dynamics of epigenetic modifications such as acetylation and deacetylation of histone proteins have been shown to be crucial for the life cycle development and survival of Plasmodium falciparum , the deadliest malaria parasite. In this study, we present a novel series of peptoid-based histone deacetylase (HDAC) inhibitors incorporating nitrogen-containing bicyclic heteroaryl residues as a new generation of antiplasmodial peptoid-based HDAC inhibitors. We synthesized the HDAC inhibitors by an efficient multicomponent protocol based on the Ugi four-component reaction. The subsequent screening of 16 compounds from our mini-library identified 6i as the most promising candidate, demonstrating potent activity against asexual blood-stage parasites (IC 50 Pf 3D7 = 30 nM; IC 50 Pf Dd2 = 98 nM), low submicromolar activity against liver-stage parasites (IC 50 Pb EEF = 0.25 μM), excellent microsomal stability (t 1/2 > 60 min), and low cytotoxicity to HEK293 cells (IC 50 = 136 μM). [Display omitted] • Synthesis of heteroaryl-decorated HDAC inhibitors 6a-6p via a multicomponent protocol. • Several compounds displayed high potency against asexual blood-stage parasites. • 6i and 6j showed additional submicromolar activity against liver stage parasites. • Most compounds exhibited low cytotoxicity. • Several compounds demonstrated metabolic stability in human liver microsomes. [ABSTRACT FROM AUTHOR]

Abstract Objective To discover a novel peptoid antagonist that targets the interleukin‐15 (IL‐15) receptor and to evaluate its therapeutic efficacy in the treatment of inflammation and arthritis. Methods A new compound (IFRA3, interleukin‐15 receptor antagonist 3) was discovered using a unique on‐bead two‐colour combinatorial cell screening of a peptoid library. The interaction of IFRA3 with IL‐15 receptor was assessed by in vitro pull‐down and thermal shift assays. The efficacy of IFRA3 in treating inflammation and arthritis was evaluated in mouse models. Results IFRA3Q1 (a tetrameric derivative of IFRA3) inhibited the activity of IL‐15 and suppressed CTLL‐2 cell proliferation (which depends on IL‐15 activity). IFRA3Q1 exhibited strong in vivo anti‐inflammatory activity in carrageenan‐induced inflammation in mice. Furthermore, IFRA3Q1 inhibited collagen‐induced arthritis in DBA/1J mice. Conclusion By binding to and inhibiting the function of IL‐15 receptor, IFRA3Q1 exhibited significant anti‐arthritis activity. Our findings suggest that IFRA3Q1 represents a new paradigm for arthritis therapy by targeting IL‐15 signalling.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases with irreversible damage of the brain and a continuous pathophysiological process. Early detection and accurate diagnosis are essential for the early intervention of AD. Precise detection of blood biomarkers related to AD could provide a shortcut to identifying early-stage patients before symptoms. In recent years, targeting peptides or peptoids have been chosen as recognition elements in nano-sensors or fluorescence detection to increase the targeting specificity, while peptide-based probes were also developed considering their specific advantages. Peptide-based sensors and probes have been developed according to different strategies, such as natural receptors, high-throughput screening, or artificial design for AD detection. This review will briefly summarize the recent developments and trends of AD diagnosis platforms based on peptide and peptoid as recognition elements and provide insights into the application of peptide and peptoid with different sources and characteristics in the diagnosis of AD biomarkers. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases with irreversible damage of the brain and a continuous pathophysiological process. Early detection and accurate diagnosis are essential for the early intervention of AD. Precise detection of blood biomarkers related to AD could provide a shortcut to identifying early-stage patients before symptoms. In recent years, targeting peptides or peptoids have been chosen as recognition elements in nano-sensors or fluorescence detection to increase the targeting specificity, while peptide-based probes were also developed considering their specific advantages. Peptide-based sensors and probes have been developed according to different strategies, such as natural receptors, high-throughput screening, or artificial design for AD detection. This review will briefly summarize the recent developments and trends of AD diagnosis platforms based on peptide and peptoid as recognition elements and provide insights into the application of peptide and peptoid with different sources and characteristics in the diagnosis of AD biomarkers.

Polypeptoids (poly‐N‐substituent glycines) are a class of highly tailorable peptidomimetic polymers. Polypeptoids have identical backbones as polypeptides (poly‐C‐substituent glycines), but sidechains of polypeptoids are appended to backbone nitrogen rather than α‐carbon of polypeptides. As a result, peptoid backbone lacks of chirality and hydrogen bond donors. This unique structure gives polypeptoids a combined merit of both high stability as synthetic polymers and biocompatibility as biopolymers. In addition, peptoid sequences can be engineered precisely to assemble specific crystalline patterns such as spheres, fibers, ribbons, tubes, and sheets, which shows promising potentials of polypeptoids for different applications such as antimicrobials, catalysts, drug delivery, and templating inorganic materials. In this review, we summarize recent investigations into hierarchical self‐assembly pathways and molecular structures of peptoid crystals that are of interest as templates for fabricating functional materials for potential biomedical, biochemical, and bioengineering applications. This review provides a summary of recent experimental and computational studies of polypeptoid assembly in solution and solid‐liquid interfaces, current achievements in the field, and discusses future challenges and opportunities for the rational design of self‐assembled polypeptoid nanomaterials. [ABSTRACT FROM AUTHOR]

Membranes for use in high gas exchange lung applications are riddled with fouling. The goal of this research is to create a membrane that can function in an artificial lung until the actual lung becomes available for the patient. The design of the artificial lung is based on new hollow fiber membranes (HFMs), due to which the current devices have short and limited periods of low fouling. By successfully modifying membranes with attached peptoids, low fouling can be achieved for longer periods of time. Hydrophilic modification of porous polysulfone (PSF) membranes can be achieved gradually by polydopamine (PSU-PDA) and peptoid (PSU-PDA-NMEG5). Polysulfone (PSU-BSA-35Mg), polysulfone polydopamine (PSUPDA-BSA-35Mg) and polysulfone polydopamine peptoid (PSU-PDA-NMEG5-BSA35Mg) were tested by potting into the new design of gas exchange modules. Both surfaces of the modified membranes were found to be highly resistant to protein fouling permanently. The use of different peptoids can facilitate optimization of the low fouling on the membrane surface, thereby allowing membranes to be run for significantly longer time periods than has been currently achieved. [ABSTRACT FROM AUTHOR]

Enzyme-linked immunosorbent assay (ELISA) microarray performance is limited by low assay sensitivity and dynamic range. Increasing the surface area for reagent binding can help to improve performance, but standard techniques such as roughening the surface or adding a polymer coating lead to increased non-specific fluorescence and do not have reproducibly improved performance. Another approach to increase surface area is adding a microsphere coating on the surface. Poly-N-substituted glycine (peptoid) microspheres are ideal for this application due to low immunogenicity, protease-resistance, and biocompatibility. Peptoids are polymers with a backbone similar to peptides, but with the side chains appended to nitrogen rather than the alpha carbon. A variety of side chain chemistries can be incorporated into peptoids through a solid-phase, sequence-specific synthesis protocol. Here we report the development of sandwich ELISA microarray on peptoid microsphere coated glass slides. Coating morphology was evaluated via SEM and efficacy was assessed by ELISA microarray performance. Peptoid microsphere coated glass slides exhibit an increase in signal intensity and dynamic range as compared to commercially available microarray slides. These studies show the potential for peptoid microspheres as coatings for ELISA microarray slides, as well as for use in other biosensor applications.

Addressing intracellular targets is a challenging task that requires potent molecular transporters capable to deliver various cargos. Herein, we report the synthesis of hydrophobic macrocycles composed of both amino acids and peptoid monomers. The cyclic tetramers and hexamers were assembled in a modular approach using solid as well as solution phase techniques. To monitor their intracellular localization, the macrocycles were attached to the fluorophore Rhodamine B. Most molecular transporters were efficiently internalized by HeLa cells and revealed a specific accumulation in mitochondria without the need for cationic charges. The data will serve as a starting point for the design of further cyclic peptoid-peptide hybrids presenting a new class of highly efficient, versatile molecular transporters.

Bioactive compounds, such as antimicrobial peptides (AMPs), have increasingly been used recently to counteract the rapidly increasing incidence of bacterial resistance to usual antibiotics and chemotherapeutics. In humans, endogenous AMPs are part of the immune system and act against pathogens. Defensins compose a class of AMPs that have activity against gram-positive and -negative bacteria, viruses, and fungi. For some, antitumour activity has also been reported. Such characteristics indicate that they represent a potential new class of therapeutic agents against microorganisms, including multidrug resistant pathogens. However, pH and enzymatic degradation and variable tissue distribution of these compounds limit their clinical application. New technologies and different methods have been developed to overcome these limitations and increase their half-life, such as cyclization, lipidation, design of peptidomimetics, synthesis of hybrid peptides, and use of nanocarriers. The objective of this review was to analyse current applications of defensins as antimicrobial agents and their mechanism of action. Moreover, new technologies and methods for stabilizing defensins are discussed.

Overall, the reaction time of the liquid-phase synthesis is similar to that of the solid-phase synthesis in a microwave reactor. Keywords: Peptoid; Peptide; Tag; Liquid-phase synthesis; Large-scale synthesis EN Peptoid Peptide Tag Liquid-phase synthesis Large-scale synthesis 376 379 4 03/22/21 20210301 NES 210301 GLO:1CJF/01mar21:bkcs12223-toc-0001.jpg PHOTO (COLOR): . gl Optimized reaction conditions for the tag-assisted liquid-phase synthesis of peptoids are reported. Although peptoids have been mainly synthesized via the solid-phase submonomer method because of the advantages of these methods in discovery research, where increased chemical diversity is important, alternative synthetic methods will offer more options to peptoid researchers, especially those studying on peptoids entering the development phase. One of the most frequently used peptoid monomers is ( I S i )- I N i -(1-phenylethyl)glycine ( I N i spe or ( I S i )-(-)-1-phenylethylamine), which contains a bulky -chiral aromatic side chain and induces helical secondary structure.24,32 Therefore, we attempted the synthesis of a heptameric peptoid composed of I N i spe using the tag-assisted liquid-phase synthesis. [Extracted from the article]

Natural antifreeze proteins are known for their excellent control of ice formation and growth, while synthetic molecules seldom have the similar effects. Here we report a series of protein mimetic peptoids with different side chains exhibiting significant ice recrystallization inhibition activity, and their structure–property relationships are also studied. The presence of peptoid can clearly slow down ice growth and decrease ice crystal grain size, but shows no thermal hysteresis, which make peptoids great antifreeze agent candidates in cryopreservation. Peptoids with methyl, ethyl and amino groups on side chains can modulate ice crystal shape, while peptoids bearing hydroxyl and ethyl groups decrease ice growth rate the most. All peptoids can reduce ice crystal grain size and the one with hydroxyl groups give the smallest grain size. This study reveals peptoid structure effects on ice growth and points to the design rules for biomimetic antifreeze agents. [ABSTRACT FROM AUTHOR]