Nonprotonophoric Electrogenic Cl⁻ Transport Mediated by Valinomycin-like Carriers

Xin Wu, Luke W. Judd, Ethan N.W. Howe, Anne M. Withecombe, Vanessa Soto-Cerrato, Hongyu Li, Nathalie Busschaert, Hennie Valkenier, Ricardo Pérez-Tomás, David N. Sheppard, Yun-Bao Jiang, Anthony P. Davis* and Philip A. Gale*

Chem 2016, 1, 127-146.


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.