Smart Molecular Machines for Transmembrane Ion Transport

Ion transport across cell membranes is an essential process of life. It plays important roles
in a range of biological functions, such as the activity of muscles, blood cells, and neurons. In nature, the transport of ions is regulated by ion channels and pumps, the malfunction or deficiency of which can contribute to a variety of conditions, including cardiac, respiratory, and neurodegenerative disorders. Where the genetic mutations that cause such disorders are difficult to treat, such as in the case of cystic fibrosis, artificial ion transporters may have therapeutic potential. Additionally, ion transporters have shown promise in the treatment of cancer. Accordingly, the design of artificial ion transporters has received great attention over the past few decades.
Membrane anchored molecular machines have recently emerged as a new class of synthetic transporters that exploit the nanomechanical motion of the machine to facilitate and control ion transport. The two key features of an anchored carrier are its immobilisation in the membrane and the presence of a mobile arm capable of binding ions and moving them across the membrane. Relay transporters are a sub-set of anchored carriers that facilitate ion permeation by passing the ion from a transporter in one membrane leaflet to a partner in the opposite leaflet. These systems can be further functionalised with photo-responsive groups that allow to regulate ion transport using light, whilst the presence of both hydrophilic and hydrophobic regions in the relay structure is potentially advantageous in terms of therapeutic delivery. However, one of the main obstacles to the therapeutic use of relays is their inability to reach the inner side of the membrane when delivered to pre-formed vesicles or cells.
This project will prepare the next generation of membrane-anchored molecular machine ion transporters, including those derived from transmembrane ion relays. We will explore the ion transport activity, selectivity, and mechanisms of these ion transporters. Furthermore, the project aims to explore how state of the art, non-invasive drug delivery systems may be exploited to achieve efficient cellular uptake of relay ion transporters as potential therapeutic agents. We will focus on exploiting technologies already in clinical use to enhance the delivery of these compounds into lipid bilayer membranes.
This project falls within the EPSRC synthetic coordination chemistry, synthetic supramolecular chemistry, chemical biology and biological chemistry, and clinical
technologies (excluding imaging) research areas.