Single-Stranded Nucleic Acid Transmembrane Molecular Carriers Based on Positively Charged Helical Foldamers.

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.

A biomimetic ion channel shortens the QT interval of type 2 long QT syndrome through efficient transmembrane transport of potassium ions.

Potassium ion transport across myocardial cell membrane is essential for type 2 long QT syndrome (LQT2). However, the dysfunction of potassium ion transport due to genetic mutations limits the therapeutic effect in treating LQT2. Biomimetic ion channels that selectively and efficiently transport potassium ions across the cellular membranes are promising for the treatment of LQT2. To corroborate this, we synthesized a series of foldamer-based ion channels with different side chains, and found a biomimetic ion channel of K+ (BICK) with the highest transport activity among them. The selected BICK can restore potassium ion transport and increase transmembrane potassium ion current, thus shortening phase 3 of action potential (AP) repolarization and QT interval in LQT2. Moreover, BICK does not affect heart rate and cardiac rhythm in treating LQT2 model induced by E4031 in isolated heart as well as in guinea pigs. By restoring ion transmembrane transport tactic, biomimetic ion channels, such as BICK, will show great potential in treating diseases related to ion transport blockade. STATEMENT OF SIGNIFICANCE: Type 2 long QT syndrome (LQT2) is a disease caused by K+ transport disorder, which can cause malignant arrhythmia and even death. There is currently no radical cure, so it is critical to explore ways to improve K+ transmembrane transport. In this study, we report that a small-molecule biomimetic ion channel BICK can efficiently simulate natural K+ channel proteins on the cardiomyocyte and cure E4031-induced LQT2 in guinea pig by restoring K+ transport function for the first time. This study found that the potassium transmembrane transport by BICK significantly reduced the QT interval, which provides a conceptually new strategy for the treatment of LQT2 disease.

Efficient Sodium Transmembrane Permeation through Helically Folded Nanopores with Natural Channel-Like Ion Selectivity.

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.

Highly Selective Transmembrane Transport of Exogenous Lithium Ions through Rationally Designed Supramolecular Channels.

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.

Soft 2D Covalent Organic Framework with Compacted Honeycomb Topology.

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.

Study on the strategy of improving the life cycle economic sustainability of wind power heating projects in northern China.

The profitability of electric heating projects in Northern China is poor. A kind of combined market-oriented trading strategy to improve the economy of electric heating projects is put forward. The price game model for direct power purchase, compensation model for carbon emission reduction benefits and load aggregation revenue model are constructed, and the optimal proportion of clean energy and conventional energy consumed under the condition of ensuring heating reliability is analyzed. An electric heating project was analyzed as an example, the results showed that in the direct power purchase transaction, the power price is 0.2125 RMB/kWh, which is 0.0591 RMB/kWh lower than the catalogue tariff. Revenue from carbon trading and auxiliary service transaction is 469,913.87 RMB and 289,218.09 RMB, respectively, which is equivalent to reducing electricity cost of 0.0253 RMB/kWh and 0.0156 RMB/kWh, respectively. The ultimate power cost is 0.1716RMB/kWh, which is 0.1 RMB/kWh lower than the current catalogue tariff. Besides, the more clean energy an electric heating project consumes, the better its economy will be, and in this example, the best proportion of clean energy and conventional energy is 80% and 20%. The research results could help to promote the sustainable development of clean heating in northern China.

Supramolecular 2D monolayered nanosheets constructed by using synergy of non-covalent interactions.

Here, a straightforward and rational approach to construct supramolecular assemblies with ordered nanostructures in a two-dimensional arrangement is reported. Taking advantage of the synergistic effect of multiple non-covalent interactions (hydrogen bonding and π-π interactions), the designed molecular monomer has a specific orientation in the self-assembly process, thus realizing two-dimensional control. Supramolecular two-dimensional nanosheets with single-layer thickness and controllable dimensions have been obtained, which can be clearly confirmed using TEM, SEM, AFM and XRD and by comparing with the self-assembled structures of the control system. The strategy of collaborative self-assembly proposed here using multiple non-covalent interactions is expected to be extended to the construction of various kinds of unique supramolecular 2D materials.

Foldamer-Based Potassium Channels with High Ion Selectivity and Transport Activity.

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.

Anion Transmembrane Nanochannels from Pore-Forming Helices Constructed by the Dynamic Covalent Reaction of Dihydrazide and Dialdehyde Units.

Anion transmembrane nanochannels constructed from dynamic covalent helices (DCHs) are reported. The dynamic covalent structures can be synthesized by one-pot dynamic covalent reactions and helically self-fold into nanotubes through intramolecular hydrogen bonding and π-π interactions. Such helical structures can vertically self-assemble into long nanofibers under π-π stacking and their hollow nanocavities finally form ion permeation pathways across the lipid membranes. Single-channel electrophysiology signals provide solid evidence of DCHs following the channel rather than the carrier mechanism. Owing to the pore-forming capacity of DCHs, nanochannels are able to accelerate the movement of anions across lipid membranes with high transport activity (EC50 =0.08 mol %). Moreover, DCH channels show dehydration energy dependent anion selectivity. This report highlights the importance of such DCHs as general channel scaffolds with economical synthesis and special nanocavities.

Controlling Keto-Enol Tautomerism of Ureidopyrimidinone to Generate a Single-Quadruple AADD-DDAA Dimeric Array.

Units of ureidopyrimidinone (UPy) which dimerize via strong quadruple hydrogen bonding are widely used for the construction of supramolecular systems. This self-complementary system exists in the tautomerism equilibrium of 4[1H]-pyrimidinone dimer and pyrimidin-4-ol dimer, making generated supramolecular assembly systems essentially complicated. In this contribution, a rational but simple design concept is described for preorganizing the self-complementary quadruple hydrogen bonding of UPy via supramolecular strategy into a single-quadruple DDAA-AADD dimeric array. With this concept, the designed UPy derivatives form only 4[1H]-pyrimidinone dimer with a ketone configuration via intermolecular hydrogen-bonding interactions, both in the solid state as well as in solution, as is evident from single-crystal X-ray diffraction and 1H NMR spectroscopy. The single DDAA-AADD dimeric array provides defined noncovalent driving forces that can be used to generate constitutionally clear supramolecular structures that are vitally important in the fields of supramolecular chemistry and materials.

Hybrid Helical Polymer Nanochannels Constructed by Combining Aromatic Amide and Pyridine-Oxadiazole Structural Sequences.

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.

Highly Efficient Exclusion of Alkali Metal Ions via Electrostatic Repulsion Inside Positively Charged Channels.

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.

Prenylated Phenolic Compounds from the Aerial Parts of Glycyrrhiza uralensis as PTP1B and α-Glucosidase Inhibitors.

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).

Light-responsive vesicles for enantioselective release of chiral drugs prepared from a supra-amphiphilic M-helix.

A kind of light-responsive vesicle was prepared by aqueous self-assembly of α-CD and an azobenzene-containing M-helical foldamer, which displayed dynamic disassembly-reassembly structural transformation when alternately irradiated by UV and visible light. Distinctively, this vesicle also exhibited enantioselective release abilities toward racemic propranolol (a ß-blocker), owing to the M-helical building blocks.

Helical supramolecular polymer nanotubes with wide lumen for glucose transport: towards the development of functional membrane-spanning channels.

The manipulation of strong noncovalent interactions provides a concise and versatile strategy for constructing highly ordered supramolecular structures. By using a shape-persistent building block consisting of phenanthroline derivatives and two quadruply hydrogen-bonding AADD moieties, a type of precise helical supramolecular polymer (HSP) nanotube has been developed. The helical conformation of the supramolecular polymers has been proved via various techniques, showing significantly expanded topologies of supramolecular polymers. From the production of new topological structures of supramolecular polymers, predictable properties and functions have arisen. In this study, the helical folding of supramolecular polymers gave rise to the generation of specific wide lumen structures that can be directly visualized via TEM, and the resulting HSP nanotubes can puncture the lipid bilayer membrane to facilitate the transportation of glucose.

Biomimetic Pulsating Vesicles with Both pH-Tunable Membrane Permeability and Light-Triggered Disassembly-Re-assembly Behaviors Prepared by Supra-Amphiphilic Helices.

The reversible unfolding-refolding transition is considerably important for natural elastomeric proteins (e.g., titin) to fulfill their biological functions. It is of great importance to develop synthetic versions by borrowing their unique stretchable design principles. Herein, we present a novel pulsating vesicle by means of the aqueous self-assembly of supra-amphiphilic helices. Interestingly, this vesicle simultaneously features dynamic swelling and shrinkage movements in response to external proton triggers. Titin-like unfolding-refolding transformation of artificial helices was proved to play a crucial role in this pulsatile motion. Moreover, the vesicular membrane of this vesicle has exhibited tunable permeability during reversible expansion and contraction circulation. Meanwhile, light can also be used as a driving force to further regulate the disassembly-reassembly transformation of the pulsating vesicle. In addition, the drug delivery system was also employed as an investigating model to estimate the permeability variation and disassembly-reassembly behaviors of the pulsating vesicles, which displayed unique dual quick- and sustained-release behaviors toward anti-cancer agents. It is anticipated that this work opens an avenue for fabricating novel stretchable biomimetics by using the exclusive unfolding-refolding nature of artificial foldamers.

Supramolecular nanochannels self-assembled by helical pyridine-pyridazine oligomers.

Herein, we demonstrate a supramolecular nanochannel formed by intermolecular π stacking of pyridine-pyridazine helical oligomers, wherein alkali ions could be easily recognized and transported. Importantly, this nanochannel also revealed reversible collection and triggered-release behaviors via modulating the folded and unfolded states of helical pyridine-pyridazine oligomers.

Regio-specific prenylation of pterocarpans by a membrane-bound prenyltransferase from Psoralea corylifolia.

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.

Reductive-Responsive, Single-Molecular-Layer Polymer Nanocapsules Prepared by Lateral-Functionalized Pillar[5]arenes for Targeting Anticancer Drug Delivery.

Herein, a new reductive-responsive pillar[5]arene-based, single-molecule-layer polymer nanocapsule is constructed for drug delivery. The functionalized system shows good biocompatibility, efficient internalization into targeted cells and obvious triggered release of entrapped drugs in a reducing environment such as cytoplasm. Besides, this smart vehicle loaded with anticancer drug shows excellent inhibition for tumor cell proliferation and exhibits low side effect on normal cells. This work not only demonstrates the development of a new reductive-responsive single molecular layer polymer nanocapsule for anticancer drug targeting delivery but also extends the design of smart materials for biomedical applications.

A Switchable Helical Capsule for Encapsulation and Release of Potassium Ion.

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.