Controlling Membrane Translocation for Artificial Signal Transduction

The aim of the proposal is to develop chemical methods for controlling the motion of molecules backwards and forwards across lipid bilayer membranes. This molecular motion will be coupled to catalytic reactions inside vesicles, opening the way to a new class of chemical systems for sensing and signalling. Many of the unique properties and functions of complex biological systems arise from the compartmentalisation afforded by lipid bilayer membranes. These membranes form an important barrier between the cell's internal fluid and the external medium. However, extracellular molecules, such as hormones, nutrients and pathogens, can change the intracellular chemistry by signalling across the cell membrane via membrane-spanning proteins. Vesicles have the potential to store, amplify, transduce and communicate information in the same way as cells do, and this proposal aims to unlock this untapped capability in entirely synthetic systems, by coupling an external molecular recognition event with an internal catalytic process via a novel transmembrane signal transduction pathway. Vesicles are already used in drug-delivery applications, but there is huge potential for responsive vesicles - those that can react in some specific and targeted way to an external signal such as a molecular binding event - which could be used in sophisticated sensing applications and targeted drug delivery. The compartmentalisation afforded by the bilayer membrane separates the inside and outside solutions and allows otherwise incompatible chemical processes and networks on the interior and exterior to co-exist independently. The development of synthetic constructs that facilitate transmembrane signalling is the first step towards realising compartmentalised-coupled chemistry, analogous to the complex phosphorylation cascades found in Nature. The ability to change the internal chemistry of a synthetic construct, such as a vesicle, in response to its external environment will offer new opportunities: coupling the external signal to an internal catalytic process (as biology does for amplification of weak molecular signals) has applications in sensing and diagnostics, or in the catalytic activation of a pro-drug for controlled-release applications. Furthermore, multivalent vesicles that are capable of efficient transduction of chemical information will provide a platform for the construction of biocompatible interfaces for communication with cellular systems.

This project is fundamental research but in a highly topical area that is attracting worldwide attention and will impact on many current research problems. In addition to the new signaling systems that we invent in the course of the research project, design rules for the application of supramolecular principles in the construction of novel functional materials will emerge, and these will have general utility. Thus success will impact not only on research in supramolecular chemistry, but more widely in areas such as biology, materials and nanotechnology. Non-covalent interactions play an important role in almost all molecular processes in the chemical, biological and material sciences, and any step towards understanding how they work will have significant benefits in both academia and in industry. The insights arising from this research programme will be directly applicable in catalyst design, process chemistry, drug design and sensor technology. The UK is currently one of the world-leaders in this area, and it is important to maintain a competitive advantage in what will become an increasingly significant area economically.
In the long term, impact can be expected in the fields of biology, materials science and nanotechnology. The aim is to design responsive vesicle assemblies that will release chemical signals in response to signals in their environment. These vesicles will be molecular machines that work in water, and they will therefore have the potential to interface with biological systems, particularly cell surfaces. Immediate applications can be envisaged in the development of drug delivery systems that release active compounds at a specific site in response to a specific signal. An attractive feature of the supramolecular design described here is that the output signal that is generated can be massively amplified by a catalytic cascade, similar to that induced in biological signaling, and this amplification provides the opportunity for the development of new types of sensor with extremely high sensitivity. There is no doubt that nanotechnology will have a huge impact across the industrialised societies in the coming decades, and the development of complex multiple component molecular machines such as the one described in this proposal will underpin the development of these new technologies.
There are well-established infrastructures in both Sheffield and Cambridge for commercial exploitation of research and knowledge transfer. Cambridge Enterprise (CE) promotes the Universities' research and commercialisation activities to potential research sponsors and collaborators and investors, and the University of Sheffield has a partnership with IP Group, who provide their expertise in building intellectual property-based businesses. The project will produce scientists with training and expertise that spans the traditional disciplines of organic, biological, inorganic and physical chemistry, with a rigorous insight into key problems that are related to the biological sciences. The interdisciplinary nature of the work will equip the appointees for work at the interfaces with other disciplines, which is likely to have to most impact in their future research careers, and which is the area where largest impact on the development of UK science will be felt. The researchers employed on the grant will also be strongly encouraged to participate in public engagement activities.