image: Complementary hydrogen bonding interactions guide the molecules to form ribbon-type assembly in phospholipids, where the hanged crown-ether rings can be arranged into channels to transport ions across the lipid bilayer.
Credit: ©Science China Press
Ion channel proteins are concerned with inorganic ion transport, which is crucial for maintaining cellular homeostasis and metabolism. Their structural and functional abnormalities are related to the occurrence and development of many diseases. Due to the inherent difficulties in studying natural channel proteins, researchers are encouraged to use simple artificial receptor molecules to simulate the structure and function of their counterparts. It not only helps people to understand the working mechanism and simulate the functions of those natural channel proteins, but also provides a theoretical basis for the diagnosis of related diseases and discovery of specific therapeutic drugs.
Compared to the complex single molecule-based ion channels, supramolecular channels have simpler molecular structures that are easier to chemically modify. Inspired by the complementary hydrogen bonding interactions of DNA/RNA, a team of researchers from East China University of Science and Technology reported a simple and small nucleobase derivative molecule, which could generate a supramolecular channel for ion transport across the lipid membranes. Through comprehensive study on the self-assembly, researchers found that the directional and complementary hydrogen bonding interactions enable the Janus-type molecules to form a stable ribbon-type assembly, which guides the arrangement of the hanged crown ethers on both sides to form ion channels. Ion transport activity analysis on both liposomes and planar bilayer membrane indicate that the supramolecular channel can mediate efficient and selective K+ transport across the lipid membranes with an EC50 value (effective concentration required to reach 50 % activity) at 4.72 μmol L−1. Moreover, the supramolecular channel can trigger K+ efflux from the cancer cells, thus disrupting the balance of ion potential inside and outside of the cells and inducing cancer cell apoptosis, with a half-maximum inhibitory concentration (IC50) of 100.0 μmol L−1 for HeLa and 120.0 μmol L−1 for HCT116 after 48 h of co-culture.
This represents one of the few examples of using complementary H-bonding interaction to construct effective ion channels, and the simple design and excellent performance make it a promising tool for practical application in drug development to treat ion channel-related diseases.