New Synthetic Chaperones to Enhance Protein Activity

3D structure is fundamental to the biological function, level of activity and very nature of a protein. Key interactions between the protein and its ligand albeit a small molecule or another protein exploit specific structure.

Variations in primary, secondary and tertiary structure can therefore result in significant changes in a protein's behaviour. These changes can range from a simple increase or decrease in enzymatic activity caused by alterations to its structure (caused by the presence of another molecular entity); through to the misfold pathogenesis observed in diseases such as Diabetes and Alzheimer's.

Nature has developed control mechanisms to regulate structure/function in many biological systems. The big idea here is that nanoscale polymeric materials with exceptional selectivity, affinity and biocompatibility will act as biomimetics of these control mechanisms and influence protein behaviours. The vision is that these materials will act as role-specific artificial chaperones, opening a new field of bio-inspired materials with a single design process but multiple applications.

The proposed programme of research is a unified design approach to the development of these artificial biomimetics using the principle of Molecular Imprinting. Molecular modelling techniques will identify target binding sites alongside compatible polymer components. These simple, elegant biomimetics incorporate binding sites bearing steric and chemical functionality complementary to a given target and as such represent a generic, versatile, scalable, cost-effective approach to the creation of synthetic molecular receptors. They currently are used in separation sciences, purification, sensors and catalysis; but this proposal will broaden their application, allowing the technology to reach its true potential.

In activities 1 and 2, nanoscale MIPs including aptaMIPs (nucleic acid-hybrids in which the PI is a leading proponent) will be targeted towards specific binding sites (epitope or larger domain) with the aim to modulate the function of its target. The ability to enhance or inhibit enzymatic activity in relevant environments will be explored, all while building an understanding how these materials interact, and how the composition/target site generates the desired activity.

In activities 3 and 4, the ability to guide the folding of protein into specific structures will be explored. By providing MIPs that favour binding a specific shape or conformation, we will look at the creation of misfolds to produce biomaterials for further use (tissue engineering). We will also explore the potential of these materials to reduce or reverse misfolding itself, providing proof-of-concept data for potential future therapeutics.

Throughout commercial and clinically relevant targets are used to increase impact of the study, but also to show the power of the developed methodologies.

The project will use facilities at DMU, and with an experienced project team, this interdisciplinary proposal which covers protein, polymer and analytical chemistry will take a deep-dive approach to MIP synthesis. It will build on existing proof-of-concept ideas, translating novel synthetic processes into viable options for artificial chaperones which can be exploited in multiple ways.

The University of Auckland will host the PI on sabbatical who will study effects of MIPs on folding during this period. The host Dr Laura Domigan, as a visiting researcher, will visit the UK to learn MIP design prior to this, to best support the sabbatical goals.

Project partners will support the program throughout, with experience in rational design, sensor application, circular dichroism expertise and folding experience. We will develop the synthetic methods to be scalable through clear step processes, with automation in mind. Potential commercialisation exists through UK based industrial project partners (MIP Diagnostics and Aptamer Group).