1.D.247. The Unimolecular Artificial Potassium Ion (K+) Channel (UAK+C) Family
Unimolecular APTs attempt to mimic the functions and properties of natural ones by using a single molecular backbone (Yuan et al. 2024). In comparison to supramolecular self-assembled channels whose components might dissociate from time to time, they are generally characterized by having greater channel stability and thus often a long channel duration. By introducing different functional groups or side chains on both the interior and exterior of the channels, it becomes possible to drastically modulate the channel's solubility and ion transport properties. Classical macrocycles such as crown ethers, cyclodextrins, pillar[n]arenes, and cucurbituron are commonly used for constructing macrocyclic ion channels. These macrocycles possess cavity structures for selective ion binding and a certain degree of lipophilicity for insertion into lipid membranes.
First reported by Pedersen in 1967 and characterized by having multiple –OCH2CH2–ether repeating units, crown ethers exhibit hydrophilic cavities due to the inward-facing O-atoms, with the outward-facing ethyl portions provide a lipophilic shell. The optimal polyether ring size for binding different alkali cations was systematically evaluated by Frensdorff, revealing a close correlation between ring size (hole) and ionic radius that 15-crown-5, 18-crown-6 and 21-crown-7 selectively favors Na+, K+, and Cs+, respectively (Yuan et al. 2024). Both the unique amphiphilicity and binding selectivity make crown ethers a good ion-binding and -transporting motif for constructing APCs, and in some cases, selective recognition and transport of specific ions have been achieved.
While the crystal structure of a polyfunctional macrocyclic K+ complex provides a solid-state model of a K+ channel, Nolte reported the very first artificial channel-type ionophore system constructed by appending benzo-18-crown-6 groups to the isocyanide-based helical polymeric scaffold in 1984 (Yuan et al. 2024). In 1990, Gokel et al. elegantly conceptualized an entirely new class of crown ether-derived ion channels called hydraphiles (e.g., 4 in Fig. 3). These hydrophile molecules feature two end crown ethers with a tunable separation distance, reaching into the two sides of the bilayer membrane to receive and release ions, and one central crown ether, providing an internal relay station to balance out the energetic penalty the ion experienced in the membrane center. Despite their extremely simple structures, these hydraphiles can serve as excellent ion channels, inspiring further studies on the development of artificial ion channels based on crown ethers.
Recently, Liu et al. studied a new class of APTs, 6a–6c, derived from single-chain block copolymer through a “one-pot” copolymerization reaction (Yuan et al. 2024).Up to four types of functional motifs including Benzo-18-crown-6 groups were appended onto the polymeric backbone (Fig. 4a–c). Among these four motifs, the crown units allow the selective transport of potassium ions at certain monomer ratios. The introduction of cholesterol groups helps to firmly anchor the polymer into the hydrophobic lipid membrane region while increasing their membrane insertion ability. They may also align the crown units in some ways, eventually generating a transmembrane pathway for transporting K+ ions, with SK+/SNa+ values of 4.3 to 11.3 for 6a and 6b, respectively. Considering a strong binding between the ammonium ion and the 8-crown-6 unit, the incorporation of hexylamine groups, which interact with crown ethers strongly in low pH but weakly in high pH, provides the channel with a pH-dependent gating ability. That is, under acidic conditions, the protonated amine group forms a complex with the crown ether, thereby blocking the channel, with the channel re-opened after such complexes dissociate under alkaline conditions (Fig. 4e).

Cyclodextrins are oligosaccharides composed of 6–8 glucose molecules linked by α-1,4-glycosidic bonds. They possess hydrophobic cavity interiors capable of forming complexes with various guest molecules. Artificial ion channels are formed by designing suitable cyclodextrin structures and introducing appropriate functional groups. Xin et al. successfully synthesized artificial potassium ion channels, 7a–7c, by combining columnar aromatic hydrocarbons with cyclodextrins (Fig. 5a) (Yuan et al. 2024). Among these molecules 7a, with the shortest connecting chain between columnar aromatic hydrocarbons and cyclodextrins, exhibited a more rigid structure and showed the highest activity in transporting potassium ions compared to the longer connecting chains 7a–7c. All three molecules showed stronger potassium ion selectivity relative to sodium ions, with K+/Na+ permeability ratios of 4.3, 4.5, and 4.0, respectively. More recently, Xin et al. used α-cyclodextrin as the backbone and introduced peptide chains containing characteristic sequences (TVGYG) to simulate a pore-forming core in a natural potassium channel. Additionally, multiple tryptophan residues were incorporated at the molecular end as anchors to enhance the channel's ability to insert into the membrane (Yuan et al. 2024). The synthesized channels, namely 8a–8c (Fig. 5b), all exhibit high selectivity for K+/Na+ ions. Their K+/Na+ permeability (P) ratios, calculated using the Goldman–Hodgkin–Katz equation, are 7.8 (8a), 8.0 (8b), and 8.2 (8c). The transport activities of these channels align with those of natural potassium channels, where K+ ≈ Rb+ > Cs+ > Na+ > Li+. In cells, excessive efflux of potassium ions disrupts cellular homeostasis and induces cell apoptosis. In cytotoxicity assays, channel 8b exhibited excellent anticancer activity. For the cell lines HeLa, MCF-7 and HCT-116, the IC50 values of channel 8b are 0.80 μM, 0.94 μM and 4.83 μM, respectively.

Columnar aromatic hydrocarbons such as pillar[n]arenes consist of interconnected aromatic rings arranged cyclically with high lipophilicity, enabling their insertion into cell membranes. These molecules possess a central cavity that can encapsulate guest molecules. Chemists have shown interest in columnar aromatic hydrocarbons due to their straightforward synthesis, presence of functional groups at both ends of the macrocycle, customizable structural designs, fixed inner cavity diameter, symmetrical structure, and inherent rigidity. In 2021, Feng et al. constructed a stable unimolecular nanopore using the extended pillararene macrocycle 9 as the macrocyclic backbone (Fig. 5c). The benzene ring constituting the cavity of molecule 9 is electron-rich, enabling interactions with cations and exhibiting remarkable selectivity for potassium/sodium ions. With increasing ion concentration, the selectivity of potassium ions is enhanced, and the ratio of potassium ion conductance to sodium ion conductance reaches 21 at 2 M. Unlike the folding of polymers and ab initio design of proteins, this purely chemical synthesis method enables precise control over the chemical composition and structure of nanopores, providing a promising strategy for designing novel synthetic nanopores. Zhu et al. designed and synthesized a novel class of synthetic transmembrane channel molecules 10 based on acyclic cucurbiturils (ACBs) and pillar[5] arene (PA[5]). In this study, three channel molecules with varying chain lengths, namely 10a, 10b and 10c (Fig. 5d), were prepared. Fluorescence vesicle experiments revealed that all three channel molecules could efficiently integrate into the phospholipid bilayer and exhibit selectivity towards potassium ions. The order of transport activity for 10 was found to be K+ > Na+ > Li+ > Rb+ > Cs+, resembling the selectivity pattern observed in natural potassium channels. Notably, possessing the shortest chain length that closely matches the thickness of the lipid bilayer, 10a displays the best alkali metal cation transport ability. Subsequent whole-cell patch clamp experiments confirmed that all three channel molecules are capable of forming ion channels in HEK293T cell membranes. This structural design offers a novel approach to the development of biomimetic potassium ion channels.
Aside from conventional macrocyclic molecules, aromatic helical foldamers have also emerged as promising scaffolds for constructing artificial potassium channels. They offer a rigid non-collapsible cavity, with their modular backbones readily tunable to access diverse architectures, enabling more tailored structure-based design with improved predictability of folding patterns, cavity dimensions and functions. In 2020, the Zeng group developed a facile one-pot protocol for preparing pyridine/diazine-containing helical foldamers with high K+/Na+ selectivity (Fig. 6a). The foldamer backbone adopts a stable helical conformation enforced through differential electrostatic repulsions among the heteroaromatic N- and O-atoms arrayed along the main chain helical trajectory. The lengths of channels P23 and P27 measure 2.3 nm and 2.7 nm, respectively, matching the thickness of the lipid membrane. Enclosing a channel cavity diameter of about 0.3 nm, the helically arranged N- and O-atoms create a strongly electron-rich environment, allowing for selective transport of K+ ions, demonstrating K+/Na+ selectivity factors of 16.3 and 12.6 for P23 and P27, respectively, values that exceed many other potassium channels.
