Synthetic anion channels: achieving precise mimicry of the ion permeation pathway of CFTR in an artificial system.

CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), a naturally occurring anion channel essential for numerous biological processes, possesses a positively charged ion conduction pathway within its transmembrane domain, which serves as the core module for promoting the movement of anions across cell membranes. In this study, we developed novel artificial anion channels by rebuilding the positively charged ion permeation pathway of the CFTR in artificial systems. These synthetic molecules can be efficiently inserted into lipid bilayers to form artificial ion channels, which exhibit a preference for anions during the transmembrane transport process.

A unimolecular artificial cation channel based on cascaded hydrated acid groups.

A cation channel possessing cascaded hydrated acid groups has been successfully constructed using pillar[5]arene integrated with dual cyclodextrins. As a proof-of-concept, the secondary side of cyclodextrin substituted by 24 -COH groups presents high coordination sites, which helps hydrated cations to quickly dehydrate and accelerates efficient cation transport (Rb > Cs > K > Na > Li). Notably, benefitted by the protonation and deprotonation of -COH groups, ion permeation activity of the channel molecules under acidic condition (pH = 6.

Crown-Ether-Based Artificial K Selective Ionic Filter.

In this study, we have successfully synthesized bis (cholesterol-dibenzo-18-crown-6-ether)-pillar[5]arene compound 1 through a click reaction, which could spontaneously insert into lipid bilayers to form ion channel due to the membrane anchor cholesterol group and show significant transport activity of K superior to Na, with a permeability ratio of K/Na equal to 4.58. Compound 1 two crown ether modules act as selective filters similar to natural K channel, which are determined to 1 : 2 binding stoichiometry to K by Job's plot and NMR titration.

Recent Advances in Artificial Anion Channels and Their Selectivity.

Nature performs critical physiological functions using a series of structurally and functionally diverse membrane proteins embedded in cell membranes, in which native ion protein channels modify the electrical potential inside and outside the cell membrane through charged ion movements. Consequently, the cell responds to external stimuli, playing an essential role in various life activities, such as nerve excitation conduction, neurotransmitter release, muscle movement, and control of cell differentiation. Supramolecular artificial channels, which mimic native protein channels in structure and function, adopt unimolecular or self-assembled structures, such as crown ethers, cyclodextrins, cucurbiturils, column arenes, cyclic peptide nanotubes, and metal-organic artificial channels, in channel construction strategies.

Synthetic cation channel: reconstructing the ion permeation pathway of TRPA1 in an artificial system.

A novel artificial cation channel was developed by rebuilding the ion permeation pathway of the natural channel protein (TRPA1) in a synthetic system. This tubular molecule can effectively embed into lipid bilayers and form transmembrane channels, thereby mediating cation transport. Furthermore, due to its carboxyl-modified ion permeation pathway, the transport activity of this artificial channel can be modulated by the pH of the buffer solution.

Addressing Challenges in Ion-Selectivity Characterization in Nanopores.

Ion selectivity is the basis for designing smart nanopore/channel-based devices, e.g., ion separators and biosensors.

Redox-Regulated Synthetic Channels: Enabling Reversible Ion Transport by Modulating the Ion-Permeation Pathway.

Natural redox-regulated channel proteins often utilize disulfide bonds as redox sensors for adaptive regulation of channel conformations in response to diverse physiological environments. In this study, we developed novel synthetic ion channels capable of reversibly switching their ion-transport capabilities by incorporating multiple disulfide bonds into artificial systems. X-ray structural analysis and electrophysiological experiments demonstrated that these disulfide-bridged molecules possess well-defined tubular cavities and can be efficiently inserted into lipid bilayers to form artificial ion channels.

Non-Covalently Stapled H /Cl Ion Channels Activatable by Visible Light for Targeted Anticancer Therapy.

The development of stimuli-responsive artificial H /Cl ion channels, capable of specifically disturbing the intracellular ion homeostasis of cancer cells, presents an intriguing opportunity for achieving high selectivity in cancer therapy. Herein, we describe a novel family of non-covalently stapled self-assembled artificial channels activatable by biocompatible visible light at 442 nm, which enables the co-transport of H /Cl across the membrane with H /Cl transport selectivity of 6.0.

Synthetic K Channels Constructed by Rebuilding the Core Modules of Natural K Channels in an Artificial System.

Different types of natural K channels share similar core modules and cation permeability characteristics. In this study, we have developed novel artificial K channels by rebuilding the core modules of natural K channels in artificial systems. All the channels displayed high selectivity for K over Na and exhibited a selectivity sequence of K ≈Rb during the transport process, which is highly consistent with the cation permeability characteristics of natural K channels.

Effect of charge status on the ion transport and antimicrobial activity of synthetic channels.

A class of unimolecular channels formed by pillararene-gramicidin hybrid molecules are presented. The charge status of the peptide domain in these channels has a significant impact on their ion transport and antimicrobial activity. These channels exhibited different membrane-association abilities between microbial cells and mammalian cells.

Artificial K Channels Formed by Pillararene-Cyclodextrin Hybrid Molecules: Tuning Cation Selectivity and Generating Membrane Potential.

A class of artificial K channels formed by pillararene-cyclodextrin hybrid molecules have been designed and synthesized. These channels efficiently inserted into lipid bilayers and displayed high selectivity for K over Na in fluorescence and electrophysiological experiments. The cation transport selectivity of the artificial channels is tunable by varying the length of the linkers between pillararene and cyclodexrin.

A dual-responsive hyperbranched supramolecular polymer constructed by cooperative host-guest recognition and hydrogen-bond interactions.

A homotritopic pillar[5]arene (H3) containing adenine units was synthesized and employed to interact with a uracil derivative (6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)hexanenitrile, G) to form a hyperbranched supramolecular polymer. The hyperbranched supramolecular polymer showed a dual stimulus response both to heat and acid/base. The cooperative host-guest binding and hydrogen-bond interactions play a key role in the supramolecular polymerization.

A unimolecular channel formed by dual helical peptide modified pillar[5]arene: correlating transmembrane transport properties with antimicrobial activity and haemolytic toxicity.

Five unimolecular channels with different lengths are presented. The varying length of these channels has significant impact on their transmembrane transport properties, which are directly correlated with their antimicrobial activity and inversely correlated with their haemolytic toxicity. By further structural optimization, these new channels could reach high antimicrobial activity and very low haemolytic toxicity, with the potential to serve as systemic antibiotics.

ADP-ribosyl-N₃: A Versatile Precursor for Divergent Syntheses of ADP-ribosylated Compounds.

Adenosine diphosphate-ribose (ADP-ribose) and its derivatives play important roles in a series of complex physiological procedures. The design and synthesis of artificial ADP-ribosylated compounds is an efficient way to develop valuable chemical biology tools and discover new drug candidates. However, the synthesis of ADP-ribosylated compounds is currently difficult due to structural complexity, easily broken pyrophosphate bond and high hydrophilicity.

One-pot formation of hydrazide macrocycles with modified cavities: an example of pH-sensitive unimolecular cation channels.

A series of pH-sensitive, cation-selective hydrazide macrocyclic channels have been synthesized. The macrocyclic channels bear multiple carboxyls in the inner cavity, which have a significant impact on their membrane-incorporation ability and NH transport activity. Moreover, the K/Cl selectivities of the macrocyclic channels can be tuned by the pH value of the electrolyte.

Synthetic Channel Specifically Inserts into the Lipid Bilayer of Gram-Positive Bacteria but not that of Mammalian Erythrocytes.

A series of tubular molecules with different lengths have been synthesized by attaching Trp-incorporated peptides to the pillar[5]arene backbone. The tubular molecules are able to insert into the lipid bilayer to form unimolecular transmembrane channels. One of the channels has been revealed to specifically insert into the bilayer of the Gram-positive bacteria.

Functionalized hydrazide macrocycle ion channels showing pH-sensitive ion selectivities.

Transmembrane channels formed by functionalized hydrazide macrocycles are reported. The different pH values of buffer solutions have a significant effect on the K/Cl selectivity of the macrocycles. This unique transport behavior is mainly induced by the different distributions of charges in the tubular channels under various pH values.

A four-unit [c2]daisy chain connected by hydrogen bonds.

A mono-adenine-functionalized pillar[5]arene and a guest including uracil were prepared. They formed a novel four-unit [c2]daisy chain both in the solid state and in a chloroform solution. As far as we know, this [c2]daisy chain is the first one without a covalently bound linear thread.

Tubular Unimolecular Transmembrane Channels: Construction Strategy and Transport Activities.

Lipid bilayer membranes separate living cells from their environment. Membrane proteins are responsible for the processing of ion and molecular inputs and exports, sensing stimuli and signals across the bilayers, which may operate in a channel or carrier mechanism. Inspired by these wide-ranging functions of membrane proteins, chemists have made great efforts in constructing synthetic mimics in order to understand the transport mechanisms, create materials for separation, and develop therapeutic agents.

Hydrazide macrocycles as effective transmembrane channels for ammonium.

Three shape-persistent aromatic hydrazide macrocycles that bear phenylalanine tripeptide chains have been synthesized. These macrocycles can insert into lipid bilayers to form single-molecular ion channels which exhibit a high NH4(+)/K(+) selectivity.

Hydrogen-bonded helical hydrazide oligomers and polymer that mimic the ion transport of gramicidin A.

A new series of hydrogen-bonded helical aromatic hydrazide oligomers and polymer that bear phenylalanine tripeptide chains have been designed and synthesized. It was revealed that the helical structures could insert into lipid bilayers to form unimolecular channels. The longest oligomeric and polymeric helical channels exhibited an NH4(+)/K(+) selectivity that was higher than that of natural gramicidin A, whereas the transport of a short helical channel for Tl(+) could achieve an efficiency as high as that of gramicidin A.

Nickel catalyzed alkylation of N-aromatic heterocycles with Grignard reagents through direct C-H bond functionalization.

A novel protocol for nickel-catalyzed direct sp(2) C-H bond alkylation of N-aromatic heterocycles has been developed. This new reaction proceeded efficiently at room temperature using a Grignard reagent as the coupling partner. This approach provides new access to a variety of alkylated N-aromatic heterocycles which are potentially of great importance in medicinal chemistry.

Nickel-catalyzed sp2 C-H bonds arylation of N-aromatic heterocycles with Grignard reagents at room temperature.

A novel protocol for nickel-catalyzed direct sp(2) C-H bond arylation of purines has been developed. This new reaction proceeded efficiently at room temperature using Grignard reagent as the coupling partner within 5 hours in good to high yields. This approach provides a new access to a variety of C8-arylpurines which are potentially of great importance in medicinal chemistry.