Development of intracellular VNARs as novel tools to dissect intracellular biological processes

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The human body has over 20,000 genes, from which the proteins that make up each human cell are generated. The study of the roles of these proteins is therefore central to our understanding of life. The best way to determine the role of individual proteins is to block their function. As Scientists, we have a number of approaches for inhibiting protein functions, including synthetic compounds prepared by Chemists that bind to the proteins as well as a number of genetic approaches that delete or deplete the gene that generates a particular protein. However, useful as these approaches are, they are not without significant drawbacks. For example, synthetic compounds normally only work on proteins that have particular types of docking sites (e.g. deep pockets or grooves in their surfaces), and it is very difficult (and expensive) to develop compounds that selectively target specific proteins using this approach. Approaches that target a particular protein's gene can be more selective, but often the cell adapts to the loss of a protein in the time it takes to generate experimental models in which the gene is deleted or depleted; this can limit the usefulness of the information that can be gleaned from such studies.In this LINK proposal, we aim to bring together academic biological expertise at Queen's University Belfast (QUB) with the industrial expertise of Elasmogen Ltd to develop a completely new approach that will generate a novel type of molecule that can rapidly and highly specifically bind to and inhibit target proteins and thereby enable the function of those proteins to be accurately determined without the potentially confounding effects of the approaches described above. VNARs are antibodies produced by the immune system of sharks, and having evolved 420 million years ago, they are the oldest antibodies so far identified in vertebrates, and they are also the smallest. Despite their small size, VNARs have a unique structure that gives them a potentially greater number of ways of binding to target proteins than the antibodies produced by our own immune systems; this means that VNARs exhibit an extremely high degree of specificity and selectivity for their target proteins.Elasmogen have established a unique set of over 100 billion individual synthetic VNARs, each of which has a different structure and can therefore bind to a different protein. Given the sheer number of VNARs in the Elasmogen collection, it will be possible to identify individual VNARs that can bind to each protein in the human body. Elasmogen and others have already demonstrated the ability of VNARs to bind to proteins expressed on the surface of human cells and proteins secreted from cells. In this project QUB and Elasmogen will collaborate together to examine the possibility of adapting VNARs so that they can get inside cells and target intracellular proteins. If successful, would open up a number of hugely exciting possibilities, including:1. Establishment of a novel class of highly selective, potent intracellular inhibitors that could become powerful research tools for dissecting important biological processes.2. Evidence that intracellular VNARs could potentially be used as novel therapeutics in a range of diseases.