We report our optimisation of peptide macrocycles targeting the melanocortin receptor family of GPCRs. This receptor family modulates metabolic function and provides important targets for a range of metabolic diseases including, diabetes, obesity and cancer. Melanocortin receptors are activated by endogenous peptides, including α-melanocortin stimulating hormone (α-MSH), but these molecules must be modified substantially to become drug candidates. The optimisation of peptides and high molecular weight drug leads for preclinical and clinical application is particularly challenging. We describe our approach, and some of our promising drug candidates developed through this process. In particular we report a new selective melanocortin 5 receptor agonist for the treatment of Type 1 diabetes. Our lead molecule enhances glucose uptake into skeletal muscle and achieves lower blood glucose levels without risking hypoglycaemia. We have demonstrated both the blood glucose lowering effect and the insulin sparing effect of our lead in mouse models of Type 1 diabetes. We have also demonstrated the glucose lowering effect of melanocortin 5 receptor activation in humans using α-MSH.
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