RESUMEN
The selective transmembrane permeation of sodium ions achieved by biomimetic chemistry shows great potential to solve the problem of sodium ion transport blockade in diseases, but its implementation faces enormous difficulties. Herein, we design and synthesize a series of helically folded nanopores by employing a quinoline-oxadiazole structural sequence to finely replicate the pentahydrate structure of sodium ions. Surprisingly, these nanopores are capable of achieving sodium transmembrane permeation with ion selectivity at the level of natural sodium channels, as observed in rationally designed nanopores (M1-M5) with Na+/K+ ion selectivity ratio of up to 20.4. Moreover, slight structural variations in nanopore structures can switch ion transport modes between the channel and carrier. We found that, compared to the carrier mode, the channel mode not only transports ions faster but also has higher ion selectivity during transmembrane conduction, clearly illustrating that the trade-off phenomenon between ion selectivity and transport activity does not occur between the two transport modes of channel and carrier. At the same time, we also found that the spatial position and numbers of coordination sites are crucial for the sodium ion selectivity of the nanopores. Moreover, carrier M1 reported in this work is totally superior to the commercial Na+ carrier ETH2120, especially in terms of Na+/K+ ion selectivity, thus being a potentially practical Na+ carrier. Our study provides a new paradigm on the rational design of sodium-specific synthetic nanopores, which will open up the possibility for the application of artificial sodium-specific transmembrane permeation in biomedicine and disease treatment.
RESUMEN
In this work, we report a new type of interface modes between helical secondary structures by noncovalent assembly along the helical axis. The dimerization of helical secondary structures mediated by aromatic π-stacking leads to discrete heterochiral dimeric helical rods consisting of left-handed helix and right-handed helix, which has been demonstrated by single-crystal X-ray diffraction. We conduct chiral induction studies on discrete heterochiral dimers to regulate the preference of the helical sense. Surprisingly, we found a novel supramolecular chirality potentially occurring inside the super-secondary structure of chirality-induced heterochiral helical dimers, rather than the racemization of helical chirality. Furthermore, chirality-induced heterochiral helical dimers can exhibit unique chiral switches when formed or not formed. In order to identify the emerging supramolecular chirality of discrete heterochiral dimeric helix, we covalently synthesized meso-helix structures with opposite helical handedness. The chirality of aromatic chromophore linker was confirmed by chiral induction despite competition from opposite handed helices, which strongly demonstrates the occurrence of emerging supramolecular chirality in heterochiral dimeric helix. This study not only reports the heterochiral π-stacking dimerization of helical secondary structures for the first time, but also discovers novel supramolecular chirality hidden in the structure of noncovalent and even covalent meso-helices.
RESUMEN
Lithium ions have been applied in the clinic in the treatment of psychiatric disorders. In this work, we report artificial supramolecular lithium channels composed of pore-containing small aromatic molecules. By adjusting the lumen size and coordination numbers, we found that one of the supramolecular channels developed shows unprecedented transmembrane transport of exogenous lithium ions with a Li+ /Na+ selectivity ratio of 23.0, which is in the same level of that of natural Na+ channels. Furthermore, four coordination sites inside channels are found to be the basic requirement for ion transport function. Importantly, this artificial lithium channel displays very low transport of physiological Na+ , K+ , Mg2+ , and Ca2+ ions. This highly selective Li+ channel may become an important tool for studying the physiological role of intracellular lithium ions, especially in the treatment of psychiatric disorders.
Asunto(s)
Litio , Sodio , Humanos , Transporte Biológico , Iones , Transporte IónicoRESUMEN
In this contribution, we report the synthesis of an imine-based soft 2D covalent organic framework (S-COF) with compacted honeycomb topology via inveterately selecting a helically folded ditopic flexible linker and a trigonal building block. In contrast to various topological structures of rigid monomer-based COFs (R-COFs) reported so far, owing to the presence of flexible skeleton S-COF can spontaneously form a compacted and nonporous topological structure via intramolecular π stacking of presupposed honeycomb-like topology. Such S-COFs with a compacted honeycomb topology have neither been proposed theoretically nor been achieved experimentally. The compacted topological structure of 2D S-COF was clearly characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), and circular dichroism (CD) measurements. This study opens a new window to the development of S-COFs and will significantly expand the scope of COF materials.
RESUMEN
Small molecules that independently perform natural channel-like functions show greatly potential in the treatment of human diseases. Taking advantage of aromatic helical scaffolds, we develop a kind of foldamer-based ion channels with lumen size varying from 3.8 to 2.3 Å through a sequence substitution strategy. Our results clearly elucidate the importance of channel size in ion transport selectivity in molecular detail, eventually leading to the discoveries of the best artificial K+ channel by far and a rare sodium-preferential channel as well. High K+ selectivity and transport activity together make foldamers promising in therapeutic applications.
Asunto(s)
Materiales Biomiméticos/química , Transporte Iónico , Oxadiazoles/química , Potasio/metabolismo , Piridinas/química , Sodio/metabolismo , Membrana Dobles de Lípidos/metabolismo , Conformación Molecular , Canales de Potasio/química , Canales de Sodio/químicaRESUMEN
Understanding of the structure-function relationships of natural protein channels remains a challenging task because of their unattainable physiological functions in terms of selectivity. To achieve this, a synthetic system of chemically modified channels has been constructed based on helical polymer scaffolds. Here, we report a type of positively charged channels in which multiple quaternary ammonium groups are covalently modified on the lumen surface of helical polymer while the helical conformation is intact. Compared to unmodified channels, the existence of multiple charged groups in the cavity not only makes the lumen size narrower but also essentially changes the channel properties without obstructing channel structure. Our study indicates that positively charged channels preferentially transport anions with size-dependent selectivity, whereas alkali metal ions are almost completely suppressed by electrostatic repulsion. As a consequence, a specific artificial channel with high Cl-/Na+ selectivity ratio of 41:1 is obtained.
RESUMEN
An effective method is reported to synthesize aromatic helical polymer nanochannels by combining both the well-studied aromatic amide helical codons with pyridine-oxadiazole helical codons into helical structure sequences. With this strategy, a type of helical polymer nanochannel that shows structure-directed transmembrane transport functions is synthesized. Although such nanochannels show relatively weak selectivity for the transportation of alkali metal ions, accessible chemical mutation of helical structure sequences will provide a great chance for the design of desired channel property. The straightforward preparation of well-established pyridine-oxadiazole helical structure will significantly promote the synthesis of this kind of aromatic helical polymer nanochannels. With the development of aromatic amide foldamers, moreover, a number of "monomers" will be available for the preparation of helical polymer nanochannels.
Asunto(s)
Amidas , Polímeros , Sustancias Macromoleculares , Oxadiazoles , PiridinasRESUMEN
Glycyrrhiza uralensis (liquorice) is a well-known medicinal plant. Its roots and rhizomes are used as the popular Chinese herbal medicine Gan-Cao. An ethanol extract of the aerial parts of G. uralensis showed antidiabetic effects on db/db mice. It decreased the blood glucose level by 30.3% and increased the serum insulin level by 41.8% compared to the control group. Eighty-six phenolic compounds (1-86) were obtained from the aerial parts, including the new prenylated isoflavanones (1-5), isoflavans (6-9), and a 2-phenylbenzofuran (10). The structures were identified by NMR and HRESIMS data analyses, and the absolute configurations were established by comparing the calculated and experimental ECD spectroscopic data. Compounds 2, 6, and 10 inhibited PTP1B with IC50 values of 5.9, 6.7, and 5.3 µM, respectively. Compound 2 and the known compounds glycycoumarin (76) and glyurallin A (79) inhibited α-glucosidase with IC50 values of 20.1, 0.1, and 0.3 µM, respectively. Compound 4 at 10 µM increased the glucose uptake rate to 95% in an insulin resistance HepG2 cell model (p < 0.01).
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Glycyrrhiza uralensis/química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Fenoles/química , Fenoles/farmacología , Componentes Aéreos de las Plantas/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Animales , Glucemia/análisis , Células Hep G2 , Humanos , Resistencia a la Insulina , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Espectrometría de Masa por Ionización de Electrospray , alfa-GlucosidasasRESUMEN
A type of aromatic helical capsules was synthesized. The crystal structure proved an inner cavity that could perform switchable encapsulation and release of potassium ion through protonation/deprotonation-mediated extension and contraction of molecular motion.
RESUMEN
Prenylated pterocarpans are valuable natural products that play significant roles in plant defence and possess diverse biological activities. However, structural diversity of prenylated pterocarpans is still limited. Prenyltransferases (PTs) could catalyze the transfer of prenyl moieties to acceptor molecules and increase the structural diversity and biological activity of natural products. Up to date, only two pterocarpan PTs have been identified from plants. In this study, a new pterocarpan prenyltransferase gene, designated as PcM4DT, was identified from Psoralea corylifolia. The deduced polypeptide is predicted to be a membrane-bound protein with eight transmembrane regions. Functional characterization of recombinant PcM4DT demonstrated this enzyme could catalyze C-4 prenylation of pterocarpans, and exhibited strict substrate specificity to maackiain and 3-hydroxy-9-methoxy-pterocarpan. It also showed a strict donor specificity to DMAPP. Furthermore, removal of the putative transit peptide of PcM4DT obviously increased the catalytic activity (up to 90%). PcM4DT represents the first PT identified from the Psoralea genus.
Asunto(s)
Membrana Celular/metabolismo , Dimetilaliltranstransferasa/metabolismo , Prenilación , Psoralea/enzimología , Pterocarpanos/química , Pterocarpanos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Células HL-60 , Humanos , Cinética , Psoralea/citología , Pterocarpanos/farmacología , Estereoisomerismo , Especificidad por SustratoRESUMEN
Potassium ion channels specifically transport K+ ions over Na+ ions across a cell membrane. A queue of four binding sites in the K+ channel pore plays significant roles during highly selective conduction. A kind of aromatic helical oligomer was synthesized that can selectively bind K+ over Na+ . By aromatic stacking of helical oligomers, a type of artificial K+ channels with contiguous K+ binding sites was constructed. Such artificial channels exhibited exceptionally high K+ /Na+ selectivity ratios during transmembrane ion conduction.
RESUMEN
Glutathione peroxidase (GPx) is a major defense against hydroperoxides as a kind of seleno-enzyme that protects cells from oxidative damage. A supramolecular vesicle with controllable GPx activity and morphology has been successfully constructed by the self-assembly of supra-amphiphiles formed by host-guest recognition between cyclodextrin and adamantane derivatives. By introducing thermosensitive poly(N-isopropylacrylamide) (PNIPAM) scaffolds and the catalytic moiety selenium into adamantane and cyclodextrin, respectively, the complex of catalysis-functionalized cyclodextrin with thermosensitivity-functionalized adamantane directed the formation of a supramolecular vesicle which acted as a GPx mimic at 37 °C. The self-assembled nanoenzyme exhibited an obvious temperature responsive characteristic and high GPx-like catalytic activity promoting the reduction of hydrogen peroxide (H2O2) with glutathione (GSH) as the reducing substrate at 37 °C. However, the vesicle disassembled when the temperature decreased to 25 °C due to the transition of PNIPAM between the coil and the globule. Interestingly, the catalytic activity changed along with the transformation of morphologies. The vesicle structure self-assembled at 37 °C provided the favorable microenvironment for the enzymatic reaction, hence we successfully developed a temperature-responsive nanoenzyme model. Moreover, the catalytic activity of the thermosensitive GPx mimic exhibited excellent reversibility and typical saturation kinetics behaviour similar to a natural enzyme catalyst. It is assumed that the proposed GPx model not only has remarkable advantages such as easy functionalization and facile preparation but also provided a new way to develop intelligent responsive materials.
Asunto(s)
Glutatión Peroxidasa/metabolismo , Nanoestructuras/química , Tensoactivos/química , Resinas Acrílicas/química , Adamantano/química , Catálisis , Ciclodextrinas/química , Glutatión/química , Glutatión Peroxidasa/química , Calor , Peróxido de Hidrógeno/químicaRESUMEN
Membrane channels span the cellular lipid bilayers to transport ions and molecules into cells with sophisticated properties including high efficiency and selectivity. It is of particular biological importance in developing biomimetic transmembrane channels with unique functions by means of chemically synthetic strategies. An artificial unimolecular transmembrane channel using pore-containing helical macromolecules is reported. The self-folding, shape-persistent, pore-containing helical macromolecules are able to span the lipid bilayer, and thus result in extraordinary channel stability and high transporting efficiency for protons and cations. The lifetime of this artificial unimolecular channel in the lipid bilayer membrane is impressively long, rivaling those of natural protein channels. Natural channel mimics designed by helically folded polymeric scaffolds will display robust and versatile transport-related properties at single-molecule level.
RESUMEN
From scanning tunneling microscopy (STM) images of rationally designed helical polymers with a pattern of π-π stacking, we successfully identified the single- and double-helical superstructures. The STM images of the helical structures revealed the smallest helical architecture (diameter ca. 1.3â nm) that has been seen so far. Furthermore, the interconversion of single and double helices was further underpinned by experimental analyses. Significantly, the formation of double helices induced different supramolecular chirality to that observed for the single helices.
Asunto(s)
Microscopía de Túnel de Rastreo/métodos , Estructura MolecularRESUMEN
We previously identified quinoline-based oligoamide helical foldamers and a trimeric macrocycle as selective ligands of DNA quadruplexes. Their helical structures might permit targeting of the backbone loops and grooves of G-quadruplexes instead of the G-tetrads. Given the vast array of morphologies G-quadruplex structures can adopt, this might be a way to achieve sequence selective binding. Here, we describe the design and synthesis of molecules based on macrocyclic and helically folded oligoamides. We tested their ability to interact with the human telomeric G-quadruplex and an array of promoter G-quadruplexes by using FRET melting assay and single-molecule FRET. Our results show that they constitute very potent ligands--comparable to the best so far reported. Their modes of interaction differ from those of traditional tetrad binders, thus opening avenues for the development of molecules specific for certain G-quadruplex conformations.
Asunto(s)
G-Cuádruplex/efectos de los fármacos , Quinolonas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Transferencia Resonante de Energía de Fluorescencia , Ligandos , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Smart supramolecular nanoenzymes with temperature-driven switching property have been successfully constructed by the self-assembly of supra-amphiphiles formed by the cyclodextrin-based host-guest chemistry. The self-assembled nanostructures were catalyst-functionalized and thermosensitively-functionalized through conveniently linking the catalytic center of glutathione peroxidase and thermosensitive polymer to the host cyclodextrin molecules.The ON-OFF switches for the peroxidase activity by reversible transformation of nanostructures from tube to sphere have been achieved through changing the temperature. We anticipate that such intelligent enzyme mimics could be developed to use in an antioxidant medicine with controlled catalytic efficiency according to the needs of the human body in the future.
Asunto(s)
Glutatión Peroxidasa/metabolismo , Nanotubos/química , Temperatura , Resinas Acrílicas/química , Resinas Acrílicas/metabolismo , Biocatálisis , Ciclodextrinas/química , Ciclodextrinas/metabolismo , Glutatión Peroxidasa/química , Tamaño de la Partícula , Transición de Fase , Propiedades de SuperficieRESUMEN
Artificial enzymes capable of achieving tunable catalytic activity through stimuli control of enzymatic structure transition are of significance in biosensor and biomedicine research. Herein we report a novel smart glutathione peroxidise (GPx) mimic with modulatory catalytic activity based on redox-induced supramolecular self-assembly. First, an amphiphilic Fmoc-phenylalanine-based selenide was designed and synthesized, which can self-assemble into nanospheres (NSs) in aqueous solution. The NSs demonstrate extremely low GPx activity. Upon the oxidation of hydroperoxides (ROOH), the selenide can be quickly transformed into the selenoxide form. The change of the molecular structure induces complete morphology transition of the self-assemblies from NSs to nanotubes (NTs), resulting in great enhancement in the GPx catalytic activity. Under the reduction of GSH, the selenoxide can be further reversibly reduced back into the selenide; therefore the reversible switch between the NSs and NTs can be successfully accomplished. The relationship between the catalytic activity and enzymatic structure was also investigated. The dual response nature makes this mimic play roles of both a sensor and a GPx enzyme at the same time, which can auto-detect the signal of ROOH and then auto-change its activity to achieve quick or slow/no scavenging of ROOH. The dynamic balance of ROOH is vital in organisms, in which an appropriate amount of ROOH does benefit to the metabolism, whereas surplus ROOH can cause oxidative damage of the cell instead and this smart mimic is of remarkable significance. We expect that such a mimic can be developed into an effective antioxidant drug and provide a new platform for the construction of intelligent artificial enzymes with multiple desirable properties.
Asunto(s)
Materiales Biomiméticos/química , Glutatión Peroxidasa/química , Nanosferas/química , Compuestos de Organoselenio/química , Fenilalanina/análogos & derivados , Peróxido de Hidrógeno/química , Oxidación-Reducción , Fenilalanina/química , Compuestos de Selenio/químicaRESUMEN
Enzyme-mediated self-healing of dynamic covalent bond-driven protein hydrogels was realized by the synergy of two enzymes, glucose oxidase (GOX) and catalase (CAT). The reversible covalent attachment of glutaraldehyde to lysine residues of GOX, CAT, and bovine serum albumin (BSA) led to the formation and functionalization of the self-healing protein hydrogel system. The enzyme-mediated protein hydrogels exhibit excellent self-healing properties with 100% recovery. The self-healing process was reversible and effective with an external glucose stimulus at room temperature.
Asunto(s)
Catalasa/metabolismo , Glucosa Oxidasa/metabolismo , Hidrogeles/metabolismo , Animales , Catalasa/química , Bovinos , Glucosa Oxidasa/química , Hidrogeles/química , Modelos Moleculares , Estructura Molecular , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , TemperaturaRESUMEN
A Ca(2+) -responsive artificial selenoenzyme was constructed by computational design and engineering of recoverin with the active center of glutathione peroxidase (GPx). By combining the recognition capacity for the glutathione (GSH) substrate and the steric orientation of the catalytic selenium moiety, the engineered selenium-containing recoverin exhibits high GPx activity for the catalyzed reduction of H2 O2 by glutathione (GSH). Moreover, the engineered selenoenzyme can be switched on/off by Ca(2+) -induced allosterism of the protein recoverin. This artificial selenoenzyme also displays excellent antioxidant ability when it was evaluated using a mitochondrial oxidative damage model, showing great potential for controlled catalysis in biomedical applications.
Asunto(s)
Antioxidantes/química , Calcio/química , Glutatión Peroxidasa/química , Recoverina/química , Selenocisteína/química , Antioxidantes/farmacología , Sitios de Unión , Catálisis , Peróxido de Hidrógeno/química , Selenio/químicaRESUMEN
Transmembrane delivery of biologically active nucleic acids is an important process in cells and has inspired one to develop advanced drug delivery techniques. In this contribution, molecular-level single-stranded nucleic acid transmembrane carriers are reported based on 3.2 nm long Huc's foldamers (AOrnQ3Q3)8 and (mQ3Q2)8 with linearly and helically aligned positive charges, respectively. These two foldamers not only show very strong DNA affinity via electrostatic interactions but also discriminatively bind single-stranded DNA (ss-DNA) and double-stranded DNA (ds-DNA), corroborating the importance of precise charge arrangement in the electrostatic interactions. More importantly, these two foldamers are capable of efficiently transporting ss-DNA across the lipid membranes, and the ss-DNA transport activity of (AOrnQ3Q3)8 with linearly aligned charges is higher than that of (mQ3Q2)8 with helically aligned charges. Thus a type of novel single-stranded nucleic acid transmembrane molecular carriers based on positively charged helical foldamers are introduced. Further, effective and enhanced expression in EGFP-mRNA transfection experiments strongly demonstrates the potential of positively charged foldamers for RNA transmembrane transport and therapy.