Lipid bilayer membranes form compartments requisite for life. Interfacing supramolecular systems, including receptors, catalysts, signal transducers and ion transporters, enables the function of the membrane to be controlled in artificial and living cellular compartments. In this perspective, we take stock of the current state of the art of this rapidly expanding field, and discuss prospects for the future in both fundamental science and applications in biology and medicine.

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Supramolecular chemistry in lipid bilayer membranes.

The combination of catalysis and transport across lipid bilayer membranes promises directional access to a solvent-free and structured nanospace that could accelerate, modulate, and, at best, enable new chemical reactions. To elaborate on these expectations, anion transport and catalysis with pnictogen and tetrel bonds are combined with polyether cascade cyclizations into bioinspired cation transporters. Characterized separately, synergistic anion and cation transporters of very high activity are identified. Combined for catalysis in membranes, cascade cyclizations are found to occur with a formal rate enhancement beyond one million compared to bulk solution and product formation is detected in situ as an increase in transport activity. With this operational system in place, intriguing perspectives open up to exploit all aspects of this unique nanospace for important chemical transformations.

Pnictogen-Bonding Catalysis and Transport Combined: Polyether Transporters Made In Situ

Ion channels and transporters typically consist of biomolecules that play key roles in a large variety of physiological and pathological processes. Traditional therapies include many ion-channel blockers, and some activators, although the exact biochemical pathways and mechanisms that regulate ion homeostasis are yet to be fully elucidated. An emerging area of research with great innovative potential in biomedicine pertains the design and development of synthetic ion channels and transporters, which may provide unexplored therapeutic opportunities. However, most studies in this challenging and multidisciplinary area are still at a fundamental level. In this review, we discuss the progress that has been made over the last five years on ion channels and transporters, touching upon biomolecules and synthetic supramolecules that are relevant to biological use. We conclude with the identification of therapeutic opportunities for future exploration.

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Ion Channels and Transporters as Therapeutic Agents: From Biomolecules to Supramolecular Medicinal Chemistry

Dodecabenzylbambus[6]uril (Bn12BU[6]) is an anion receptor that binds the perchlorate ion the most tightly (stability constant ~1010 M−1) of all anions due to the excellent match between the ion size in relation to the receptor cavity. This new bambusuril compound was used as an ionophore in the ion-selective membrane (ISM) to develop ion selective electrodes (ISEs) for determination of perchlorate concentration utilizing the poly(3,4-ethylenedioxythiophene) (PEDOT) polymer film as a solid-contact material. Variation of the content of Bn12BU[6] and tridodecylmethylammonium chloride (TDMACl) in the plasticized poly(vinyl chloride)-based ISM was also tested. All the prepared solid-contact ISEs and their analytical performance were characterized by potentiometry, cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and chronopotentiometry. The ISEs showed rapid response and a sub-Nernstian slope (~57 mV/decade) during potentiometric measurements in perchlorate solutions in the concentration range from 10−1 to 10−6 M simultaneously with their high stability and sufficient selectivity to other common inorganic anions like bromide, chloride, nitrate and sulphate. The function of the ISE was further verified by analysis of real water samples (lake, sea, and mineral water), which gave accurate and precise results.

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Perchlorate Solid-Contact Ion-Selective Electrode Based on Dodecabenzylbambus[6]uril

Abstract The development of synthetic anion transporters is motivated by their potential application as treatment for diseases that originate from deficient anion transport by natural proteins. Transport of bicarbonate is important for crucial biological functions such as respiration and digestion. Despite this biological relevance, bicarbonate transport has not been as widely studied as chloride transport. Herein we present an overview of the synthetic receptors that have been studied as bicarbonate transporters, together with the different assays used to perform transport studies in large unilamellar vesicles. We highlight the most active transporters and comment on the nature of the functional groups present in active and inactive compounds. We also address recent mechanistic studies that have revealed different processes that can lead to net transport of bicarbonate, as well as studies reported in cells and tissues, and comment on the key challenges for the further development of bicarbonate transporters.

/pdf/transmembrane-transport-of-bicarbonate-by-anion-receptors-3sbg60nv.pdf

Transmembrane Transport of Bicarbonate by Anion Receptors

Anion receptors can be used to transport ions across lipid bilayers, which has potential for therapeutic applications. Synthetic bicarbonate transporters are of particular interest, as defects in transmembrane transport of bicarbonate are associated with various diseases. However, no convenient method exists to directly observe bicarbonate transport and study the mechanisms involved. Here, an assay is presented that allows the kinetics of bicarbonate transport into liposomes to be monitored directly and with great sensitivity. The assay utilises an encapsulated europium(III) complex, which exhibits a large increase in emission intensity upon binding bicarbonate. Mechanisms involving CO2 diffusion and the dissipation of a pH gradient are shown to be able to lead to an increase in bicarbonate concentration within liposomes, without transport of the anion occurring at all. By distinguishing these alternative mechanisms from actual bicarbonate transport, this assay will inform the future development of bicarbonate transporters.

Nicola Alessandro De Simone

Papers

Transmembrane Transport of Bicarbonate Unravelled

Cover profile: Transmembrane Transport of Bicarbonate Unravelled