Search

Fully synthetic peptoid membranes are known to mimic important features of biological membranes, with several advantages over other biomimetic membranes. A fundamental understanding of how the individual peptoid amphiphiles assemble in solution to form the bilayer membrane is key to unlocking their versatility for application in a broad range of processes. In this study, in situ X-ray scattering and molecular dynamics simulations are used to understand the early stages of assembly of three different peptoids that exhibit distinctly different crystallization kinetics. The in situ measurements reveal that the peptoids aggregate first into a nascent phase that is less crystalline than the assembled peptoid membrane. Anisotropic aromatic interactions are determined to be the dominant driving force in the early stages of membrane formation. These results provide key insights into how the peptoid assembly may be manipulated during the early stages of assembly and nucleation and growth.

The fabrication of ordered architectures that intimately integrate polymer, protein, and inorganic components remains difficult. Two promising building blocks to tackle this challenge are peptoids, peptide mimics capable of self-assembly into well-defined structures, and solid-binding peptides, which offer a biological path to controlled inorganic assembly. Here, we report on the synthesis of 3.3-nm-thick thiol-reactive peptoid nanosheets from equimolar mixtures of unmodified and maleimide-derivatized versions of the Nbpe6Nce6 oligomer, optimize the location of engineered cysteine residues in silica-binding derivatives of superfolder green fluorescent protein for maleimide conjugation, and react the two components to form protein-peptoid hybrids exhibiting partial or uniform protein coverage on both of their sides. Using 10 nm silica nanoparticles, we trigger the stacking of these 2D structures into a multilayered material composed of alternating peptoid, protein, and organic layers. This simple and modular approach to hierarchical hybrid synthesis should prove useful in bioimaging and photocatalysis applications.

The high information content of proteins drives their hierarchical assembly and complex function, including the organization of inorganic nanomaterials. Peptoids offer an organic scaffold very similar to proteins, but with a wider solubility range and easily tunable side chains and functional groups to create a variety of self-assembling architectures with atomic precision. If we could harness this paradigm and understand the factors that govern how they direct nucleation and assembly of inorganic materials to design order within such materials, new dimensions of function and fundamental science would emerge. In this work, peptoid tubes and sheets were explored as platforms to assemble colloidal quantum dots (QDs) and clusters. We have successfully synthesized CdSe QDs with difunctionalized capping ligands containing both carboxylic acid and thiol groups and mixed them with maleimide containing peptoids, to create an assembly of the QDs on the peptoid surface via a covalent linkage. This conjugation was seen to be successful with peptoid tubes, sheets and CdSe QDs and clusters. The particles were seen to have a high preference for the peptoid surface but non-specific interactions with carboxylic acid groups on the peptoids limited control over QD density via maleimide conjugation. Replacing the carboxylic acid groups with methoxy ethers, however, allowed for control over QD density as a function of maleimide concentration. 1H NMR analysis demonstrated that binding of QDs to peptoids involved a subset of surface ligands bound through the carboxylate functional group, allowing the distal thiol to engage in a covalent linkage to the maleimide. Overall, we have shown the compatibility and control of CdSe-peptoid interactions via a covalent linkage with varying peptoid structures and CdSe particles to create complex hybrid structures.

Imaging biological systems with simultaneous intrinsic chemical specificity and nanometer spatial resolution in their typical native liquid environment has remained a long-standing challenge. Here, we demonstrate a general approach of chemical nanoimaging in liquid based on infrared scattering scanning near-field optical microscopy (IR s-SNOM). It is enabled by combining AFM operation in a fluid cell with evanescent IR illumination via total internal reflection, which provides spatially confined excitation for minimized IR water absorption, reduced far-field background, and enhanced directional signal emission and sensitivity. We demonstrate in-liquid IR s-SNOM vibrational nanoimaging and conformational identification of catalase nanocrystals and spatio-spectral analysis of biomimetic peptoid sheets with monolayer sensitivity and chemical specificity at the few zeptomole level. This work establishes the principles of in-liquid and in situ IR s-SNOM spectroscopic chemical nanoimaging and its general applicability to biomolecular, cellular, catalytic, electrochemical, or other interfaces and nanosystems in liquids or solutions.

Injecting fluids into deep underground geologic structures is a critical component to development of long-term strategies for managing greenhouse gas emissions and facilitating energy extraction operations. Recently, we reported that metal-organic frameworks are low-frequency absorptive acoustic metamaterial that may be injected into the subsurface enhancing geophysical monitoring tools used to track fluids and map complex structures. A key requirement for this nanotechnology deployment is transportability through porous geologic media without being retained by mineral-fluid interfaces. Flow-through column studies were used to estimate transport and retention properties of five different polymer-coated MIL-101(Cr) nanoparticles in siliceous porous media. Nanoparticle transport experiments revealed that nanoparticle surface characteristics play a critical role in nanoparticle colloidal stability and as well the transport.

Developing tunable and stable peroxidase mimetics with high catalytic efficiency provides a promising opportunity to improve and expand enzymatic catalysis in lignin depolymerization. A class of peptoid-based peroxidase mimetics with tunable catalytic activity and high stability is developed by constructing peptoids and hemins into self-assembled crystalline nanomaterials. By varying peptoid side chain chemistry to tailor the microenvironment of active sites, these self-assembled peptoid/hemin nanomaterials (Pep/hemin) exhibit highly modulable catalytic activities toward two lignin model substrates 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and 3,3’,5,5’-tetramethylbenzidine. Among them, a Pep/hemin complex containing the pyridyl side chain showed the best catalytic efficiency (Vmax/Km = 5.81 × 10−3 s−1). These Pep/hemin catalysts are highly stable; kinetics studies suggest that they follow a peroxidase-like mechanism. Moreover, they exhibit a high efficacy on depolymerization of a biorefinery lignin. Because Pep/hemin catalysts are highly robust and tunable, we expect that they offer tremendous opportunities for lignin valorization to high value products.

COVID-19 remains an ongoing issue across the globe, highlighting the need for a rapid, selective, and accurate sensor for SARS-CoV-2 and its emerging variants. The chemical specificity and signal amplification of surface-enhanced Raman spectroscopy (SERS) could be advantageous for developing a quantitative assay for SARS-CoV-2 with improved speed and accuracy over current testing methods. Here, we have tackled the challenges associated with SERS detection of viruses. As viruses are large, multicomponent species, they can yield different SERS signals, but also other abundant biomolecules present in the sample can generate undesired signals. To improve selectivity in complex biological environments, we have employed peptides as capture probes for viral proteins and developed an angiotensin-converting enzyme 2 (ACE2) mimetic peptide-based SERS sensor for SARS-CoV-2. The unique vibrational signature of the spike protein bound to the peptide-modified surface is identified and used to construct a multivariate calibration model for quantification. The sensor demonstrates a 300 nM limit of detection and high selectivity in the presence of excess bovine serum albumin. This work provides the basis for designing a SERS-based assay for the detection of SARS-CoV-2 as well as engineering SERS biosensors for other viruses in the future.

Near-infrared (NIR) laser-induced phototherapy through NIR agents has demonstrated the great potential for cancer therapy. However, insufficient tumor killing due to the nonuniform heat or cytotoxic singlet oxygen ( 1 O 2 ) distribution over tumors from phototherapy results in tumor recurrence and inferior outcomes. To achieve high tumor killing efficacy, one of the solutions is to employ the combinational treatment of phototherapy with other modalities, especially with chemotherapeutic agents. In this paper, a simple and effective multimodal therapeutic system was designed via combining chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) to achieve the polytherapy of malignant glioma which is one of the most aggressive tumors in the brain. IR-780 (IR780) dye-labeled tube-forming peptoids (PepIR) were synthesized and self-assembled into crystalline nanotubes (PepIR nanotubes). These PepIR nanotubes showed an excellent efficacy for PDT/PTT because the IR780 photosensitizers were effectively packed and separated from each other within crystalline nanotubes by tuning IR780 density; thus, a self-quenching of these IR780 molecules was significantly reduced. Moreover, the efficient DOX loading achieved due to the nanotube large surface area contributed to an efficient and synergistic chemotherapy against glioma cells. Given the unique properties of peptoids and peptoid nanotubes, we believe that the developed multimodal DOX-loaded PepIR nanotubes in this work offer great promises for future glioma therapy in clinic.

It is reported herein the synthesis of a novel amphiphilic diblock peptoid bearing a terminal conjugated oligoaniline and its self-assembly into small-diameter (D ≈ 35 nm) crystalline nanotubes with high aspect ratios (30). It is shown that both tetraaniline (TANI)-peptoid and bianiline (BANI)-peptoid triblock molecules self-assemble in solution to form rugged highly crystalline nanotubes that are very stable to protonic acid doping and de-doping processes. The similarity of the crystalline tubular structure of the nanotube assemblies revealed by electron microscopy imaging, and X-ray diffraction analysis of the nanotube assemblies of TANI-functionalized peptoids and nonfunctionalized peptoids showed that the peptoid is an efficient ordered structure directing motif for conjugated oligomers. Films of doped TANI-peptoid nanotubes has a dc conductivity of ca. 95 mS cm

The mechanisms of interface biochemistry are often obscured through ensemble averaging of complex networks of proteins that exhibit varying degrees of structural heterogeneity. Here, we perform nanometer spatially resolved chemical spectroscopy using infrared vibrational scattering-scanning near-field optical microscopy (IR s-SNOM) to image protein–protein interactions and conformational heterogeneity of (i) a two-dimensional lipid-like peptoid membrane and (ii) a three-dimensional catalase crystal. In the peptoid membrane, which consists of stacked ∼4 nm high peptoid layers, spatio-spectral line width analyses reveal heterogeneity of the vibrational dynamics due to peptoid–substrate and peptoid–peptoid interactions. In s-SNOM imaging of catalase crystals, our results revealed complex secondary structures that vary over nanometer length scales. Broadening of vibrational resonances, as observed from the dehydrated catalase crystals, indicates a higher degree of heterogeneity as compared to the synthetic pe...

The ability of antibodies to bind a wide variety of analytes with high specificity and high affinity makes them ideal candidates for therapeutic and diagnostic applications. However, the poor stability and high production cost of antibodies have prompted exploration of a variety of synthetic materials capable of specific molecular recognition. Unfortunately, it remains a fundamental challenge to create a chemically diverse population of protein-like, folded synthetic nanostructures with defined molecular conformations in water. Here we report the synthesis and screening of combinatorial libraries of sequence-defined peptoid polymers engineered to fold into ordered, supramolecular nanosheets displaying a high spatial density of diverse, conformationally constrained peptoid loops on their surface. These polyvalent, loop-functionalized nanosheets were screened using a homogeneous Forster resonance energy transfer (FRET) assay for binding to a variety of protein targets. Peptoid sequences were identified that bound to the heptameric protein, anthrax protective antigen, with high avidity and selectivity. These nanosheets were shown to be resistant to proteolytic degradation, and the binding was shown to be dependent on the loop display density. This work demonstrates that key aspects of antibody structure and function-the creation of multivalent, combinatorial chemical diversity within a well-defined folded structure-can be realized with completely synthetic materials. This approach enables the rapid discovery of biomimetic affinity reagents that combine the durability of synthetic materials with the specificity of biomolecular materials.

Herein we show that by appending bulky β-cyclodextrin (CD) groups onto sheet-forming peptoids, we obtain cylindrical micelles that further assembly into membranes and intertwined ribbons on substrates in aqueous solution, depending on the choice of solution and substrate conditions. In situ atomic force microscopy (AFM) shows that micelle assembly occurs in two steps, starting with "precursor" particles that transform into worm-like micelles, which extend and coalesce to form the higher order structures with a rate and a degree of cooperativity dependent on pH and Ca2+ concentration. After co-assembly with hydrophobic 4-(2-hydroxyethylamino)-7-nitro-2,1,3-benzoxadiazole (NBD) donors that occupy the hydrophobic core, followed by exposure to hydrophilic Rhodamine B as acceptors that insert into cyclodextrin, the micelles exhibit highly efficient Forster resonance energy transfer efficiency in aqueous solution, thereby mimicking natural light harvesting systems.

Due to the branched structure feature and unique properties, a variety of star-shaped polymers have been designed and synthesized. Despite those advances, solid-phase synthesis of star-shaped sequence-defined synthetic polymers that exhibit hierarchical self-assembly remains a significant challenge. Hence, we present an effective strategy for the solid-phase synthesis of three-armed star-shaped peptoids, in which ethylenediamine was used as the centric star pivot. Based on the sequence of monomer addition, a series of AA'A''-type and ABB'-type peptoids were synthesized and characterized by UPLC-MS (ultrahigh performance liquid chromatography-mass spectrometry). By taking advantage of the easy-synthesis and large side-chain diversity, we synthesized star-shaped peptoids with tunable functions. We further demonstrated the aqueous self-assembly of some representative peptoids into biomimetic nanomaterials with well-defined hierarchical structures, such as nanofibers and nanotubes. These results indicate that star-shaped peptoids offer the potential in self-assembly of biomimetic nanomaterials with tunable chemistries and functions.

American trypanosomiasis, commonly known as Chagas disease, is a neglected tropical disease caused by the protozoan parasiteTrypanosoma cruzi. The chronic form of the infection often causes debilitating morbidity and mortality. However, the current treatment for the disease is typically inadequate owing to drug toxicity and poor efficacy, necessitating a continual effort to discover and develop new antiparasitic therapeutic agents. The structure ofT. cruzihistidyl-tRNA synthetase (HisRS), a validated drug target, has previously been reported. Based on this structure and those of human cytosolic HisRS, opportunities for the development of specific inhibitors were identified. Here, efforts are reported to identify small molecules that bind toT. cruziHisRS through fragment-based crystallographic screening in order to arrive at chemical starting points for the development of specific inhibitors.T. cruziHisRS was soaked into 68 different cocktails from the Medical Structural Genomics of Pathogenic Protozoa (MSGPP) fragment library and diffraction data were collected to identify bound fragments after soaking. A total of 15 fragments were identified, all bound to the same site on the protein, revealing a fragment-binding hotspot adjacent to the ATP-binding pocket. On the basis of the initial hits, the design of reactive fragments targeting the hotspot which would be simultaneously covalently linked to a cysteine residue present only in trypanosomatid HisRS was initiated. Inhibition ofT. cruziHisRS was observed with the resultant reactive fragments and the anticipated binding mode was confirmed crystallographically. These results form a platform for the development of future generations of selective inhibitors for trypanosomatid HisRS.

A highly photostable, ultra-bright, biocompatible and NIR emissive semiconducting polymer dot (Pdot) based pH sensor was achieved by dendronizing the squaraine probe molecule., One constraint of semiconducting polymer dots (Pdots), especially those with near-IR emission, is their low effective emitter ratio (∼1.5 mole percent), which limits their pH sensing performance. The other critical issue of existing Pdot-based pH sensors is their poor photostability. To address these issues, we developed a series of Pdots by dendronizing the squaraine-based pH responsive near-IR emitter, which is covalently incorporated into the polyfluorene (PFO) backbone. The fluorescence self-quenching of the NIR squaraine emitter was effectively suppressed at a high emitter concentration of 5 mole percent. Through controlling the individually incomplete energy transfer from the amorphous PFO donor to the blue β-phase PFO and NIR squaraine emitter, we obtained a ratiometric pH sensor with simultaneously improved pH sensitivity, brightness, and photostability. The Pdots showed a fast and reversible pH response over the whole biological pH range of 4.7 to 8.5. Intracellular pH mapping was successfully demonstrated using this ultra-bright and photostable Pdot-based pH indicator.

Despite recent advances in the assembly of organic nanotubes, conferral of sequence-defined engineering and dynamic response characteristics to the tubules remains a challenge. Here we report a new family of highly designable and dynamic nanotubes assembled from sequence-defined peptoids through a unique “rolling-up and closure of nanosheet” mechanism. During the assembly process, amorphous spherical particles of amphiphilic peptoid oligomers crystallize to form well-defined nanosheets before folding to form single-walled nanotubes. These nanotubes undergo a pH-triggered, reversible contraction–expansion motion. By varying the number of hydrophobic residues of peptoids, we demonstrate tuning of nanotube wall thickness, diameter, and mechanical properties. Atomic force microscopy-based mechanical measurements show peptoid nanotubes are highly stiff (Young’s Modulus ~13–17 GPa). We further demonstrate the precise incorporation of functional groups within nanotubes and their applications in water decontamination and cellular adhesion and uptake. These nanotubes provide a robust platform for developing biomimetic materials tailored to specific applications., The application potential of organic nanotubes is currently limited by their lack of designable or dynamic properties. Here, Chen et al. use sequence-defined peptoids to assemble a new family of pH-responsive stiff nanotubes whose dimensions, components and functions can be easily tailored.

Substantial progress has been made in applying nanotubes in biomedical applications such as bioimaging and drug delivery due to their unique architecture, characterized by very large internal surface areas and high aspect ratios. However, the biomedical applications of organic nanotubes, especially for those assembled from sequence-defined molecules, are very uncommon. In this paper, the synthesis of two new peptoid nanotubes (PepTs1 and PepTs2) is reported by using sequence-defined and ligand-tagged peptoids as building blocks. These nanotubes are highly robust due to sharing a similar structure to those of nontagged ones, and offer great potential to hold guest molecules for biomedical applications. The findings indicate that peptoid nanotubes loaded with doxorubicin drugs are promising candidates for targeted tumor cell imaging and chemo-photodynamic therapy.

The N-heterocyclic carbene-catalyzed [4 + 2] cyclization of ketenes and 3-aroylcoumarins has been developed to give the corresponding dihydrocoumarin-fused multisubstituted dihydropyranones in high yield with good diastereoselectivity and high enantioselectivity.

Cyclic phosphoric acid catalyzed one-pot, four component reactions of benzil, aldehydes, primary amines and ammonium acetate in refluxing ethanol were developed, giving highly substituted imidazoles in excellent yield.

The use of PGT and IOT as chiral catalysts allows the highly enantioselective synthesis of both enantiomers (III).

Optically active highly functionalized 3,4-dihydropyridin-2-ones were synthesized by N-heterocyclic carbene-catalyzed [4+2] enantioselective cycloaddition of ketenes and 1-azadienes.

N-Heterocyclic carbenes (NHCs) prove to be efficient catalysts for the aza-Morita-Baylis-Hillman (aza-MBH) reaction of cyclopent-2-en-1-one or cyclohex-2-en-1-one with a variety of N-tosylarylimines to give the aza-MBH adduct in high yields. Crossover experiments show NHC can add to N-tosylarylimines in a reversible manner, which allows the addition of NHC to cyclic enones and thus catalyzes the aza-Mortia-Baylis-Hillman reaction.

The N-heterocyclic carbene-catalyzed [4 + 2] cyclization of ketenes and 3-aroylcoumarins has been developed to give the corresponding dihydrocoumarin-fused multisubstituted dihydropyranones in high yield with good diastereoselectivity and high enantioselectivity.

The carbene precursor (Ia) is suitable for the transformation of azadienes bearing a terminal aryl group.

Highly functionalized dihydropyridinones were synthesized via the N-heterocyclic carbene-catalyzed enantioselective [4 + 2] annulation of α-chloroaldehydes and azadienes. Hydrogenation of the resulted dihydropyridinones afforded the corresponding piperidinones with high enantiopurity.

Cyclic phosphoric acid catalyzed one-pot, four component reactions of benzil, aldehydes, primary amines and ammonium acetate in refluxing ethanol were developed, giving highly substituted imidazoles in excellent yield.

The use of PGT and IOT as chiral catalysts allows the highly enantioselective synthesis of both enantiomers (III).

An enantioselective synthesis of highly substituted dihydropyridin-2-ones is realized using an unprecedented NHC-catalyzed cycloaddition of 1-azadienes and ketenes.

N-Heterocyclic carbenes (NHCs) prove to be efficient catalysts for the aza-Morita-Baylis-Hillman (aza-MBH) reaction of cyclopent-2-en-1-one or cyclohex-2-en-1-one with a variety of N-tosylarylimines to give the aza-MBH adduct in high yields. Crossover experiments show NHC can add to N-tosylarylimines in a reversible manner, which allows the addition of NHC to cyclic enones and thus catalyzes the aza-Mortia-Baylis-Hillman reaction.