Synthetic chloride transporters are potential therapeutic agents for cystic fibrosis and cancer. Reported herein are macrocyclic transmembrane chloride transporters prepared by a onepot condensation reaction. The most efficient macrocycle possesses a fine balance of hydrophobicity for membrane permeation and hydrophilicity for ion recognition. The macrocycle transports chloride ions by forming channels in the membrane. Hydrogen bonds and anion−π interactions assist chloride transport. Letter pubs.acs.org/OrgLett

Synthetic channels with high ion selectivity are attractive drug targets for diseases involving ion dysregulation. Achieving selective transport of divalent ions is highly challenging due their high hydration energies. A small tripeptide amphiphilic scaffold installed with a pybox ligand selectively transports Cu II ions across membranes. The peptide forms stable dimeric pores in the membrane and transports ions by a Cu 2 + /H + antiport mechanism. The ligand-induced excellent Cu II selectivity as well as high membrane permeability of the peptide is exploited to promote cancer cell death. The peptide's ability to restrict mycobacterial growth serves as seeds to evolve antibacterial strategies centred on selectively modulating ion homeostasis in pathogens. This simple peptide can potentially function as a universal, yet versatile, scaffold wherein the ion selectivity can be precisely controlled by modifying the ligand at the C terminus.

Selective transport of cations across cell membranes is essential for various biological functions in the body. Synthetic pores that mimic the selectivity of natural ion channels are attractive for development of drugs and materials. Peptides are now emerging as attractive therapeutic agents due to their biocompatibility and ready accessibility. Herein, we report a systematic study that identifies key elements to design cation‐selective channels using tetrapeptide scaffolds. The scaffolds are derived from picolinic acid and alanine. Their ion transport activity is enhanced by hydrophobic long alkyl chains at the N‐terminus. These scaffolds are exciting as cation‐selectivity can be induced as well as switched by varying the oligoether groups at the C‐terminus.

Figure 1. Peptides containing two types of selectivity inducers. Article pubs.acs.org/bc