Voltage-Switchable HCl Transport Enabled by Lipid Headgroup-Transporter Interactions

Synthetic anion transporters that facilitate transmembrane H⁺ /Cl^- symport (cotransport) have anti-cancer potential due to their ability to neutralize pH gradients and inhibit autophagy in cells. However, compared to the natural product prodigiosin, synthetic anion transporters have low-to-modest H⁺ /Cl^- symport activity and their mechanism of action remains less well understood. We report a chloride-selective tetraurea macrocycle that has a record-high H⁺ /Cl^- symport activity similar to that of prodigiosin and most importantly demonstrates unprecedented voltage-switchable transport properties that are linked to the lack of uniport activity. By studying the anion binding affinity and transport mechanisms of four other anion transporters, we show that the lack of uniport and voltage-dependent H⁺ /Cl^- symport originate from strong binding to phospholipid headgroups that hampers the diffusion of the free transporters through the membrane, leading to an unusual H⁺ /Cl^- symport mechanism that involves only charged species. Our work provides important mechanistic insights into different classes of anion transporters and a new approach to achieve voltage-switchability in artificial membrane transport systems.