Nonprotonophoric electrogenic chloride transport mediated by valinomycin-like carriers

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 identify 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 for the first time that a valinomycin equivalent for Cl?-selective transport is achievable.