Anions and the bilayer. Structural and mechanistic studies towards synthetic anion carriers for therapeutic applications

Abstract

Synthetic transmembrane anion transporters have attracted a great deal of interest due to their potential as therapeutic agents for the treatment of channelopathies such as cystic fibrosis or in the treatment of cancer. Despite a great deal of progress in the field over recent years, there are currently several hurdles that need to be overcome before anionophores become genuine therapeutic candidates. These include knowledge of how carriers behave in more cell-like bilayer systems, what molecular properties govern the rate determining step of the transport process and issues with solubility and deliverability. This thesis aims to explore some of these areas to help overcome some of these future barriers.
The effect of lipid environment on the transport ability of a series of alkyl-substituted thioureas was investigated. The series covered a wide range of lipophilicity, to determine whether the optimum lipophilic range varied depending on the composition of the bilayer. Despite the different lipids appearing to modulate the overall transport rate, the relative order of the transporter efficacy appeared unaffected.
Data is also presented demonstrating the use of dynamic covalent chemistry to generate an active transporter molecule in situ within the membrane. The compound formed by DCC was observed by measuring its transport response from vesicle experiments after the addition of two precursors (which do not facilitate transport alone) to the membrane. Comparison of the transport ability of the pre-formed compound and the rate of the DCC reaction measured by NMR spectroscopy gave insight into the balance required between these two factors in the design of these compounds.
Finally, the effect of the fluorination of alkyl chains in tripodal tris-thiourea receptors was explored. Vesicle assays with and without accompanying protonophores to couple to the transport process were carried out to determine the mechanism of the transport process and discover whether fluorination had any effect on the selectivity of the transporter molecules. The activity of the compounds in FRT-YFP cell assays was also determined and comparison with the vesicle data gave insights into the vesicle tests required to accurately predict the transporters’ efficacy in cell epithelia.

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ORCID for Philip Gale: orcid.org/0000-0001-9751-4910

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