In Europe, 58 million people live with type 2 diabetes and 36 million people are at risk of developing the condition. Macrovascular disease is the commonest cause of morbidity and mortality in type 2 diabetes, yet current diabetes therapies have failed to consistently reduce cardiovascular events. We recently discovered that a circulating protein, IGF binding protein-1, possesses several characteristics pertinent to potential therapeutic action in cardio-metabolic disease – including insulin sensitisation, amelioration of glucose intolerance, blood pressure lowering, reduced atherosclerosis and increased vascular repair. These effects were mediated by the interaction of the protein’s RGD-domain with cell-surface α5β1 integrin receptors, which increase insulin-stimulated glucose uptake in skeletal muscle cells and glucose-stimulated insulin secretion in pancreatic islets. This raises the concept that the RGD-integrin interaction could be exploited therapeutically in diabetes.
To date, we have identified small molecule RGD-mimetic integrin agonists as putative diabetes therapeutics via computational screening and de novo design. In this project, the student will further develop these agonists using our structural understanding of the RGD-integrin interaction to improve integrin receptor activation and enhance insulin-signalling. They will also use matched molecular pair analysis to improve the physicochemical properties of the agonists. The student will have a background in synthetic and/or medicinal chemistry and will be expected to perform both the chemistry and molecular biology aspects, with the appropriate training.
The project will combine medicinal chemistry and molecular biology approaches to develop and test new agonist analogues to treat diabetes. The student will gain experience in a wide range of transferable skills, including synthetic chemistry, molecular biology, in silico ligand design, cell-based assays and in vivo metabolic characterisation.