Variety Of Side Chains Research Articles

Poly(2-ethyl-2-oxazoline) bottlebrushes: How nanomaterial dimensions can influence biological interactions

Biocompatible polymers are crucial components of successful nano-sized carriers, which enable the delivery of otherwise largely ineffective therapeutics. Poly(2-ethyl-2-oxazoline) (PEtOx) is one polymer that has shown potential for this application due to its demonstrated low fouling nature and biocompatibility comparable to the current gold standard carrier, poly(ethylene glycol). PEtOx based bottlebrushes, in particular, are promising therapeutic carriers due to their anisotropic nature, which can be easily fine-tuned. Despite this potential, little is known about the interaction of PEtOx bottlebrushes with biological systems. The present study provides a detailed insight into the cellular interactions and biodistribution of PEtOx bottlebrushes in a mouse model. Three PEtOx bottlebrushes of varied side-chain and backbone lengths were designed to highlight the effect that the degree of polymerisation (DP) of each aspect may have on both cellular interaction and biodistribution. Herein we show that PEtOx bottlebrushes display no adverse effects to either cells or mice over 48 h at doses that would be relevant to drug delivery applications. Furthermore, increasing either the backbone or side-chain length of PEtOx bottlebrushes leads to a reduction in cellular association in vitro and an increase in blood circulation times in vivo. The fact that small changes to the dimensions of the PEtOx bottlebrushes have a marked effect on biodistribution and blood circulation times may prove to be a highly beneficial insight for the design of next-generation PEtOx bottlebrushes nanocarriers with tailor-made profiles dependent on the application required.

Design of Thioether Cyclic Peptide Scaffolds with Passive Permeability and Oral Exposure.

Advances in the design of permeable peptides and in the synthesis of large arrays of macrocyclic peptides with diverse amino acids have evolved on parallel but independent tracks. Less precedent combines their respective attributes, thereby limiting the potential to identify permeable peptide ligands for key targets. Herein, we present novel 6-, 7-, and 8-mer cyclic peptides (MW 774-1076 g·mol-1) with passive permeability and oral exposure that feature the amino acids and thioether ring-closing common to large array formats, including DNA- and RNA-templated synthesis. Each oral peptide herein, selected from virtual libraries of partially N-methylated peptides using in silico methods, reflects the subset consistent with low energy conformations, low desolvation penalties, and passive permeability. We envision that, by retaining the backbone N-methylation pattern and consequent bias toward permeability, one can generate large peptide arrays with sufficient side chain diversity to identify permeability-biased ligands to a variety of protein targets.

Side-chain manipulation of poly (phenylene oxide) based anion exchange membrane: Alkoxyl extender integrated with flexible spacer

Anion exchange membranes (AEMs) are an important component in anion exchange membrane fuel cells, and their side chain structures have a significant impact on membrane performance. Here, we construct a series of poly(phenylene oxide) (PPO)-based AEMs with varied side chain structures and investigate the effects of alkyl or alkoxyl extenders (or “tail” of the cation) and spacers (or the link between backbone and cation head group) on AEM performance. Our investigations demonstrate that the simultaneous introduction of alkoxyl extender and spacer can significantly improve water absorption and ion conductivity of membrane; this is attributed to the good hydrophilicity of alkoxyl group and flexibility of spacer that benefit the formation hydrophilic domains. At an IEC (ion exchange capacity) of 1.13 mmol/g, the AEM containing both spacer and alkoxyl extender exhibits a hydroxide conductivity of 87.3 mS/cm (80 °C), which is much higher than that of other spacer-containing membranes at similar IECs. The H2/O2 single cell constructed with this membrane exhibits a good peak power density of 292 mW/cm2 at 60 °C. In addition, the steric hindrance of the extender gives rise to higher alkali stability of the AEM than that of the membrane which does not have the extender. Our work provides a meaningful direction of side chain design which can effectively improve conductivity and alkaline stability of AEMs.

Synthesis and Evaluation of 2-Hydroxy-1,4-naphthoquinone Derivatives as Potent Antimalarial Agents.

A series of 3-substituted-2-hydroxy-1,4-naphthoquinone derivatives with a variety of side chains were successfully synthesized by Mannich reaction of 2-hydroxy-1,4-naphthoquinone (lawsone) with selected amines and aldehydes. All substances (1-16) were evaluated for in-vitro antimalarial activity against strains of Plasmodium falciparum by microculture radioisotope technique. Bioassay data revealed that ten derivatives (1-8, 11 and 13) displayed significantly good activity with values of IC50 ranging from 0.77 to 4.05 µg/mL. The best biological profile (IC50 = 0.77 µg/mL) was observed in compound 1, possessing a n-butyl substituted aminomethyl group. Experimental results support the potential use of our active Mannich components as promising antimalarial agents in the fight against malaria infections and multidrug resistance problems.

Submonomer synthesis of sequence defined peptoids with diverse side-chains.

Peptoids are a diverse family of sequence-defined oligomers of N-substituted glycine monomers, that can be readily accessed by the solid-phase submonomer synthesis method. Due to the versatility and efficiency of this chemistry, and the easy access to hundreds of potential monomers, there is an enormous potential sequence space that can be explored. This has enabled researchers from many different fields to custom-design peptoid sequences tailored to a wide variety of problems in biomedicine, nanoscience and polymer science. Here we provide detailed protocols for the synthesis of peptoids, using optimized protocols that can be performed by non-chemists. The submonomer method is fully compatible with Fmoc-peptide synthesis conditions, so the method is readily automated on existing automated peptide synthesizers using protocols provided here. Although the submonomer synthesis for peptoids is well established, there are special considerations required in order to access many of the most useful and desirable sidechains. Here we provide methods to include most of the amino-acid-like side chains, some of the most important non-natural monomer classes, as well as the creation of peptoid conjugates and peptide-peptoid hybrids.

Phase transitions of poly(oligo(ethylene glycol) methyl ether methacrylate)-water systems

The phase diagrams for poly (oligo (ethylene glycol) methyl ether methacrylate) (POEGMA) hydrogels with varying side chain lengths over broad temperature and composition ranges are shown for the first time. It is also shown that the ability of water to crystallize is strictly correlated with the occurrence of a volume phase transition in hydrogels, as both phenomena require the continuous water pathways in the system. A discontinuity in the water phase appears above wp = 0.83 for PMEO2MA and wp = 0.56 for other POEGMAs. In contrast to PMEO2MA, POEGMA hydrogels with longer oligoether chains are characterized by two distinct regimes for the glass transition as a function of polymer content. It was also confirmed that crystallization of the polymer network can be observed for POEGMA networks with suitably long oligoether chain lengths, namely, n ≥ 7. Moreover, the range of the polymer crystalline phase occurrence was found to increase with the length of the oligoether chain.

Effect of chemical structure on dispersity of polycarboxylate superplasticiser in cement paste

This study examines the mechanism of adsorption–dispersion by superplasticisers with varying side chain density in cement paste. Acrylic acid was used to copolymerise with 2-methylprop-2-ene polyethylene glycol, using chain transfer agent to synthesise polycarboxylate ether superplasticisers (PCEs) with comparable main chain lengths and different side chain densities. Gel permeation chromatography, zeta potential, total organic carbon and fluidity tests were used to investigate the adsorption–dispersion of PCE samples in cement pastes with different amounts of tricalcium aluminate (C3A) additive. The results indicate: products with higher side chain densities also have correspondingly shorter main chains, which allows them to form conformations with comparable initial adsorption performance; with C3A added, samples with denser side chains performed better, and their resistance to adsorption became more prominent at higher C3A content.

Amino Acid and Peptide-Based Liquid Crystals: An Overview.

The role of amino acids and peptides has found remarkable usage in both living systems and nonliving materials, which have enabled its utility by virtue of crafting molecular architectures through covalent bonds and non-covalent interactions. In material chemistry, the role of peptides in Liquid Crystals (LCs) is profound, especially in the rapid construction of supramolecular hierarchical networks. The importance of LCs for a variety of societal needs leads to the synthesis of innumerable LCs by conventional mesogenic strategy and nonconventional molecular design principles. For example, electronic appliances, including flat panel TV displays, electronic notebooks, digital cameras, domestic devices, use LCs as an integral component for such applications. In addition, LCs are useful in biological systems, including stem cell research, sensors for bacteria, virus, and proteins. These accomplishments are possible mostly due to the non-conventional molecular design principles for crafting LCs using smaller molecular motifs. The usage of amino acids and peptides in LCs facilitates many intrinsic characteristics, including side-chain diversity, chirality, directionality, reversibility, electro-optical, columnar axis, stimuli-responsive complex molecular architectures. The next essential criteria for any LCs design for useful applications are room temperature LC (RT-LC); therefore, the quest for such LCs system remains highly significant. Evidently, there are around half a million liquid crystalline molecules; only a handful of RTLCs has been found, as there is no simple, precise strategy or molecular design principles to obtain RT-LC systems. The smaller molecular motifs of amino acids and linear peptides as a structural part of mesogenic molecules led to many LC phases with properties, including lyotropic, thermotropic, and its applications in different realms. Therefore, this review serves as a compilation of Small Peptide-based LCs (SPLCs) exhibiting lyotropic and thermotropic phases with applications in the recent advancements.

Synthesis and Characterization of Heterodimers and Fluorescent Nisin Species by Incorporation of Methionine Analogues and Subsequent Click Chemistry.

Noncanonical amino acids form a highly diverse pool of building blocks that can render unique physicochemical properties to peptides and proteins. Here, four methionine analogues with unsaturated and varying side chain lengths were successfully incorporated at four different positions in nisin in Lactococcus lactis through force feeding. This approach allows for residue-specific incorporation of methionine analogues into nisin to expand their structural diversity and alter their activity profiles. Moreover, the insertion of methionine analogues with biorthogonal chemical reactivity, e.g., azidohomoalanine and homopropargylglycine, provides the opportunity for chemical coupling to functional moieties and fluorescent probes as well as for intermolecular coupling of nisin variants. All resulting nisin conjugates retained antimicrobial activity, which substantiates the potential of this method as a tool to further study its localization and mode of action.

Engineering the atomic structure of sequence-defined peptoid polymers and their assemblies

Peptoids are a family of sequence-defined, non-natural biomimetic polymers which show excellent properties including good chemical and enzymatic stability and high structural tunability. The solid-phase submonomer synthesis method allows precise control over the identity and sequence of chemically diverse side chains, enabling the atomic engineering of their chemical structures for a variety of applications. This unprecedented level of structural control enables access to atomically defined three-dimensional chain conformations and assemblies, facilitating the design and optimization of a variety of nanoscale architectures that can function in biology and materials science. In order to approach the rational design of peptoid materials in a more predictive and precise manner, it is crucial to fully understand how chemical information, in the form of the monomer sequence, encodes their folding and assembly into structurally defined, functional 3D shapes. This perspective focuses on recent studies into the atomic engineering of peptoid nanostructures by examining the impact of sequence variations on their secondary and three-dimensional structures, as well as their functional properties.

Design, synthesis, and molecular docking study of new monastrol analogues as kinesin spindle protein inhibitors.

Lung, colorectal, and breast cancers are the top three types of cancer by incidence and are responsible for one-third of the cancer incidence and mortality. A series of 18 3,4-dihydropyrimidine analogues bearing a 1,2-methylenedioxybenzene component at position 4 with diverse side chains at positions 5 and 6 was designed and synthesized as inhibitors of the Eg5 kinesin enzyme. Target compounds were screened for their anticancer activity according to the NCI-USA protocol toward a panel of 60 cancer cell lines. Compounds 12a and 12b displayed the best antiproliferation activity against many cell lines. Interestingly, compound 12a displayed lethal effects against non-small-cell lung cancer NCI-H522 cells (-42.26%) and MDA-MB-468 breast cancer cells (-1.10%) at a single-dose assay concentration of 10-5 M. Compounds 11c, 11d, 11g, 12a-d, 13, 15, and 18a were assayed against the kinesin enzyme, with IC50 values ranging from 1.2 to 18.71 μM, which were more potent compared with monastrol (IC50 = 20 μM). Cell cycle analysis of NCI-H522 cells treated with compound 12a showed cell cycle arrest at the G2/M phase. Furthermore, the expression levels of active caspase-3 and -9 were measured. A molecular docking study was performed for some demonstrative compounds as well as monastrol docked into the allosteric binding site of the kinesin spindle protein.

Poly(carboxypyrrole)s That Depolymerize from Head to Tail in the Solid State in Response to Specific Applied Signals.

This Article describes the design, synthesis, and analysis of a new class of polymer that is capable of depolymerizing continuously, completely, and cleanly from head to tail when a detection unit on the head of the polymer is exposed to a specific applied signal. The backbone of this polymer consists of 1,3-disubstituted pyrroles and carboxy linkages similar to polyurethanes. Diverse side chains or reactive end-groups can be introduced readily, which provides modular design of polymer structure. The designed depolymerization mechanism proceeds through spontaneous release of carbon dioxide and azafulvene in response to a single triggering reaction with the detection unit. These poly(carboxypyrrole)s depolymerize readily in nonpolar environments, and even in the bulk as solid-state plastics.

Peptoid-based hierarchically-structured biomimetic nanomaterials: Synthesis, characterization and applications

Peptoids (or poly- N -substituted glycines) are a promising class of bioinspired sequence-defined polymers due to their highly efficient synthesis, high chemical stability, enzyme hydrolysis resistance, and biocompatibility. By tuning the side chain chemistry of peptoids, it allows for precise control over sequences and achieving a large side-chain diversity. Due to these unique features, in the last several years, many amphiphilic peptoids were designed as highly tunable building blocks for the preparation of biomimetic nanomaterials with well-defined hierarchical structures and desired functionalities. Herein, we provide an overview of the recent achievements in this area by dividing them into the following three aspects. First, mica- and silica-templated peptoid self-assembly are summarized. The presence of inorganic substrates provides the guarantee of investigating their self-assembly mechanisms and interactions between peptoids and substrates using nanoscale characterization techniques, particularly in situ atomic force microscopy (AFM) and AFM-based dynamic force spectroscopy (AFM-DFS). Second, solution-phase self-assembly of peptoids into nanotubes and nanosheets is presented, as well as their self-repair properties. Third, the applications of peptoid-based nanomaterials are outlined, including the construction of catalytic nanomaterials as a template and cytosolic delivery as cargoes.

Hydrophobicity-Modulated Small Antibacterial Molecule Eradicates Biofilm with Potent Efficacy against Skin Infections.

The role of molecular arrangement of hydrophobic and hydrophilic groups for designing membrane-active molecules remains largely ambiguous. To explore this aspect, herein we report a series of membrane-active small molecules by varying the spatial distribution of hydrophobic groups. The two terminal amino groups of linear triamines such as diethylene triamine, bis(trimethylene)triamine, and bis(hexamethylene)triamine were conjugated with cationic amino acids bearing variable side chain hydrophobicity (such as diaminobutyric acid, ornithine, and lysine). The hydrophobicity was also modulated through conjugation of different long chain fatty acids with the central secondary amino group of the triamine. Molecules with constant backbone hydrophobicity displayed an enhanced antibacterial activity and decreased hemolytic activity upon increasing the side chain hydrophobicity of amino acids. On the other hand, increased hydrophobicity in the backbone introduced a slight hemolytic activity but a higher increment in antibacterial activity, resulting in better selective antibacterial compounds. The optimized lead compound derived from structure-activity-relationship (SAR) studies was the dodecanoyl analogue of a lysine series of compounds consisting of bis(hexamethylene)triamine as the backbone. This compound was active against various Gram-positive and Gram-negative bacteria at a low concentration (MIC ranged between 3.1 and 6.3 μg/mL) and displayed low toxicity toward mammalian cells (HC50 = 890 μg/mL and EC50 against HEK = 85 μg/mL). Additionally, it was able to kill metabolically inactive bacterial cells and eradicate preformed biofilms of MRSA. This compound showed excellent activity in a mouse model of skin infection with reduction of ∼4 log MRSA burden at 40 mg/kg dose without any sign of skin toxicity even at 200 mg/kg. More importantly, it revealed potent efficacy in an ex vivo model of human skin infection (with reduction of 85% MRSA burden at 50 μg/mL), which indicates great potential of the compound as an antibacterial agent to treat skin infections.

Relation between Surface Area and Surface Potential Change during (co)Polyesters Degradation as Langmuir Monolayer

ABSTRACTPolyhydroxyalkanoates (PHAs) are degradable (co)polyesters synthesized by microorganisms with a variety of side-chains and co-monomer ratios. PHAs can be efficiently hydrolyzed under alkaline conditions and by PHA depolymerase enzymes, altering their physicochemical properties. Using 2D Langmuir monolayers as model system to study the degradation behavior of macromolecules, we aim to describe the the interdependency between the degradation of two PHAs and the surface potential, which influences material-proteins interaction and cell response. We hypothesize that the mechanism of hydrolysis of the labile ester bonds in (co)polyesters defines the evolution of the surface potential, owing to the rate of accumulation of charged insoluble degradation products. The alkaline hydrolysis and the enzymatically catalyzed hydrolysis of PHAs were previously defined as chain-end scission and random-scission mechanisms, respectively. In this study, these two distinct scenarios are used to validate our model. The surface potential change during the chain-end scission of poly(3-R-hydroxybutyrate) (PHB) under alkaline conditions was compared to that of the enzymatically catalyzed hydrolysis (random-scission) of poly[(3-R-hydroxyoctanoate)-co-(3-R-hydroxyhexanoate)] (PHOHHx), using the Langmuir monolayer technique. In the random-scission mechanism the dissolution of degradation products, measured as a decrease in the area per molecule, was preceded by a substantial change of the surface potential, provoked by the negative charge of the broken ester bonds accumulated in the air-water interface. In contrast, when chains degraded via the chain-ends, the surface potential changed in line with the dissolution of the material, presenting a kinetic dependent on the surface area of the monolayers. These results provide a basis for understanding PHAs degradation mechanism. Future research on (co)polymers with different main-chain lengths might extend the elucidation of the surface potential development of (co)polyesters as Langmuir monolayer.

Peppy


 
 
 Science students are traditionally taught protein structure and function through textbook pictures and/or physical model building. This is not effective for most students because conceiving large, complex three-dimensional chemicals structure and dynamic molecular interactions requires a very high degree of abstract thought, imagination and extrapolation. It is intuitively reasonable to believe that a virtual reality approach would aid appreciation of nanoscale molecular structure, function and dynamics.
 I will describe the Virtual Reality (VR) tool, “Peppy” (1), that we have developed for exploring the molecular forces which drive protein secondary structure. Peppy allows students to build, visualise and manipulate polypeptides within the six degrees of freedom that characterises the VR environment. Peppy not only recreates traditional secondary structures dependent on hydrogen- bonding in a generic peptide backbone, it also permits students to insert any and all of the 20 amino acids and to examine the effect of the shapes and electrostatic forces of these on secondary structure. The highly extrapolative environment created by Peppy is extended with features that encourage student engagement, such as a selfie camera, interactive Ramachandran plot, and even features to emphasise the dynamics of a vibrant macromolecular structure. Being able to physically and directly grab and manipulate the atoms and angles with the virtual hand enhances the connection of students with the molecules and results in an exploration experience unmatched by traditional 3D visualisation software.
 I will also describe the testing and iterative improvement of Peppy during deployment to large undergraduate classes at the University of Sydney, which boasts the Immersive Learning Lab, with 26 VR (Oculus Rift) headsets. Remarkably, even students with no prior VR experience are able to interact with Peppy in an engaged and meaningful way within just 10 minutes and, after less than an hour many are able to build highly complex multi-peptide structures such as β-barrels or experiment with long peptides containing a variety of side chains and disulphide bonds. The experience resonates with the students well after the session, as evidenced by their reflections and follow-up questions regarding the physics of the simulation and ideas for extension of the software.
 
 

Initiation of Protein Synthesis with Non‐Canonical Amino Acids In Vivo

AbstractBy transplanting identity elements into E. coli tRNAfMet, we have engineered an orthogonal initiator tRNA (itRNATy2) that is a substrate for Methanocaldococcus jannaschii TyrRS. We demonstrate that itRNATy2 can initiate translation in vivo with aromatic non‐canonical amino acids (ncAAs) bearing diverse sidechains. Although the initial system suffered from low yields, deleting redundant copies of tRNAfMet from the genome afforded an E. coli strain in which the efficiency of non‐canonical initiation equals elongation. With this improved system we produced a protein containing two distinct ncAAs at the first and second positions, an initial step towards producing completely unnatural polypeptides in vivo. This work provides a valuable tool to synthetic biology and demonstrates remarkable versatility of the E. coli translational machinery for initiation with ncAAs in vivo.

Analysis of Triterpenoid Saponins Reveals Insights into Structural Features Associated with Potent Protein Drug Enhancement Effects

Plant-based saponins are amphipathic glycosides composed of a hydrophobic aglycone backbone covalently bound to one or more hydrophilic sugar moieties. Recently, the endosomal escape activity of triterpenoid saponins has been investigated as a potentially powerful tool for improved cytosolic penetration of protein drugs internalized by endocytic uptake, thereby greatly enhancing their pharmacological effects. However, only a few saponins have been studied, and the paucity in understanding the structure-activity relationship of saponins imposes significant limitations on their applications. To address this knowledge gap, 12 triterpenoid saponins with diverse structural side chains were screened for their utility as endosomolytic agents. These compounds were used in combination with a toxin (MAP30-HBP) comprising a type I ribosome-inactivating protein fused to a cell-penetrating peptide. Suitability of saponins as endosomolytic agents was assessed on the basis of cytotoxicity, endosomal escape promotion, and synergistic effects on toxins. Five saponins showed strong endosomal escape activity, enhancing MAP30-HBP cytotoxicity by more than 106 to 109 folds. These saponins also enhanced the apoptotic effect of MAP30-HBP in a pH-dependent manner. Additionally, growth inhibition of MAP30-HBP-treated SMMC-7721 cells was greater than that of similarly treated HeLa cells, suggesting that saponin-mediated endosomolytic effect is likely to be cell-specific. Furthermore, the structural features and hydrophobicity of the sugar side chains were analyzed to draw correlations with endosomal escape activity and derive predictive rules, thus providing new insights into structure-activity relationships of saponins. This study revealed new saponins that can potentially be exploited as efficient cytosolic delivery reagents for improved therapeutic drug effects.

Impact of oligoether chain lengths on the relaxation processes in poly(oligo(ethylene glycol) methyl ether methacrylate) networks that are synthesized by radiation-induced crosslinking polymerization

The molecular mobility in poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) networks with varying side chain lengths (n = 2–19 oxyethylene groups), which are synthetized by radiation-induced crosslinking polymerization, has been investigated by dielectric spectroscopy. A complete relaxation map for these materials with four processes was created for the first time. At higher temperatures, α relaxation corresponding to the dynamic glass transition and α’ relaxation, which was likely correlated with sub-Rouse processes, were found. Below the dynamic glass transition, two Arrhenius-type processes were distinguished: the γ-process, which was assigned to the end (methoxy-) group; and weak β-relaxation, which was dependent on the oligoether chain length and was related to side chain movements. The fragility index for all of the POEGMA networks proves that these are strong glass-forming materials. In the partially crystalline samples with n > 7, the relaxation processes are strongly disturbed by cold crystallization and melting.

A novel approach for obtaining α,β-diaminophosphonates bearing structurally diverse side chains and their interactions with transition metal ions studied by ITC.

Aminophosphonates are an important group of building blocks in medicinal and pharmaceutical chemistry. Novel representatives of this class of compounds containing nontypical side chains are still needed. The aza-Michael-type addition of amines to phosphonodehydroalanine derivatives provides a simple and effective approach for synthesizing N′-substituted α,β-diaminoethylphosphonates and thus affords general access to aminophosphonates bearing structurally diverse side chains. Thermodynamic analysis of the chosen aminophosphonates at physiological pH proves that they serve as potent chelators for copper(ii) ions and moderate chelators for nickel(ii) ions.