Transmembrane Transport of Inorganic Phosphate by a Strapped Calix[4]pyrrole.

Synthetic anion receptors are increasingly being explored for the transport of anions across lipid membranes because of their potential therapeutic applications. A considerable amount of research focuses on the transport of chloride, whereas the transmembrane transport of inorganic phosphate has not been reported to date, despite the biological relevance of this anion. Here we present a calix[4]pyrrole with a bisurea strap that functions as a receptor and transporter for H2PO4-, relying on the formation of eight hydrogen bonds and efficient encapsulation of the anion. Using a phosphate-sensitive lanthanide probe and 31P NMR spectroscopy, we demonstrate that this receptor can transport phosphate into vesicles by H2PO4-/Cl- antiport, H2PO4- uniport, and Cs+/H2PO4- symport mechanisms. This first example of inorganic phosphate transport by a neutral receptor opens perspectives for the future development of transporters for various biological phosphates.

Dissecting transmembrane bicarbonate transport by 1,8-di(thio)amidocarbazoles.

Synthetic ionophores able to transport bicarbonate and chloride anions across lipid bilayers are appealing for their wide range of potential biological applications. We have studied the bicarbonate and chloride transport by carbazoles with two amido/thioamido groups using a bicarbonate-sensitive europium(III) probe in liposomes and found a highly remarkable transporter concentration dependence. This can be explained by a combination of two distinct transport mechanisms: HCO3-/Cl- exchange and a combination of unassisted CO2 diffusion and HCl transport, of which the respective contributions were quantified. The compounds studied were found to be highly potent HCl transporters. Based on the mechanistic insights on anion transport, we have tested the antimicrobial activity of these compounds and found a good correlation with their ion transport properties and a high activity against Gram-positive bacteria.

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.

Transmembrane transport of fluoride studied by time-resolved emission spectroscopy.

Here we present a new method to monitor fluoride transmembrane transport into liposomes using a europium(III) complex. We take advantage of the long emission lifetime of this probe to measure the transport activity of a fluorescent transporter. The high sensitivity, selectivity, and versatility of the assay allowed us to study different types of fluoride transporters and unravel their mechanisms of action.