Nonprotonophoric Electrogenic Cl− Transport Mediated by Valinomycin-like Carriers

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.