EP/G002576/1 - Selective Receptors for the Transmembrane Transport of Bicarbonate Anion - Gale

The bicarbonate (HCO3-) anion plays a central role in many biochemical processes maintaining stable pH levels inside and outside cells, activating sperm for fertilization and playing roles in diseases such as cystic fibrosis. Despite its obvious importance, however, there is surprisingly little known about the selective coordination of HCO3- by organic receptor compounds. Similarly, the transmembrane transport of HCO3- by synthetic transporters has not yet been tackled. Despite its importance, the supramolecular chemistry of bicarbonate is largely unexplored. Inspired by bicarbonate's central role in crucial biological and environmental processes, we propose to study the binding and transmembrane transport of this central anion. This is, to our knowledge, the first comprehensive research program aimed at understanding the molecular recognition and transmembrane transport of the important bicarbonate (HCO3-) anion. The project will tackle both these challenges by combining the expertise from two established research groups in the first comprehensive study of the molecular recognition and supramolecular chemistry of bicarbonate. Philip Gale is an inorganic chemist at the University of Southampton in the UK. Gale is an international leader in the field of Supramolecular Chemistry. He has an established worldwide reputation in the synthesis and structural determination of anion-receptor complexes. Jeffery Davis, from the University of Maryland in the US, brings experience in the in the synthesis and characterization of supramolecular assemblies designed to bind and transport ions and neutral molecules across phospholipid membranes. This combination of expertise from the UK and the US will take the development of synthetic membrane transporters into the new area of facilitated bicarbonate transport. We will design and synthesize different types of receptors that are able to selectively bind bicarbonate and go on to demonstrate the ability of these compounds to transport HCO3- across lipid membranes - these receptors will include compounds designed to function as transmembrane carriers and channels. Carrier compounds will consist of lipid soluble organic receptors designed to have complementary hydrogen bonding arrays to HCO3- or to bind this anion via reversible covalent bond formation. We will also design carriers to bind bicarbonate dimers / a structural motif commonly observed with bicarbonate in the solid state. Channels will also be synthesised that span the lipid bilayer facilitating the diffusion of HCO3- across the membrane that employ revisable covalent bond formation.In addition we will develop a range of new techniques to assay for the transmembrane transport of bicarbonate. This will include using so-called 'base pulse assays' that have previously been used to monitor NO3- and Cl- transport. New methods will include the use of bicarbonate sensitive dyes such as pyrene functionalised cyclodextrins, NMR methods employing 13C[HCO3-] and extravesicular paramagnetic reagents allowing the populations intravesicular and extravesicular bicarbonate to be monitored, and patch-clamp experiments that will allow us to unambiguously determine the mechanism by which the transport agents function. The compounds produced will be useful tools for use by scientists studying models of diseases such as cystic fibrosis. Other applications of these systems could include synthesis involving HCO3- inside a vesicle environment with the systems developed here controlling the entry of bicarbonate to an encapsulated reaction mixture. Applying these new systems directly, we selectively transport HCO3- into liposomes as a means to template the formation of crystalline CaCO3 as a model system for biomineralization.