Abstract

Synthetic transmembrane anion transporters (anionophores) have potential as tools for biomedical research and as therapeutic agents for diseases associated with anion-channel dysfunction. However, the possibility of H⁺ or OH⁻ transport by anionophores has received little attention, and an anionophore selective for Cl⁻ over H⁺/OH⁻ is currently unavailable. Here, we show that depending on anionophore acidity, many anionophores facilitate electrogenic H⁺ or OH⁻ transport, potentially leading to toxicity. Nevertheless, using several liposome-membrane-based assays, we identified two newly developed small molecules that promote electrogenic Cl⁻ transport without effectively dissipating the transmembrane pH gradient, essentially mimicking the electrogenic cationophore valinomycin. The Cl⁻ > H⁺/OH⁻ selectivity of anionophores showed a consistent positive correlation with the degree of Cl⁻ encapsulation and a negative correlation with the acidity of hydrogen-bond donors. Our study demonstrates that a valinomycin equivalent for Cl⁻-selective transport is achievable.