Melanocortin receptors which are widely distributed, control multiple key physiological functions of the body. While, Melanocortin receptor 5 (MC5R) is known to control sebaceous secretions, recent studies show that MC5R has a role in glucose uptake and glucose homeostasis[1]. This makes a potent and selective MC5R agonist, a potential treatment option for Type 1 diabetes. Extensive effort placed in the development of melanocortin ligands have led to the discovery of potent melanocortin agonists. But these agonists lack selectivity at MC5R. My research aims to develop a peptide that is potent and selective at MC5R, which can be converted into a drug for use as an adjunctive therapy with insulin for Type 1 diabetes.
Compounds were developed based on the key lead compounds Melanotan II (MTII), PG901 andOBP-MTII[2,3]. They were screened for MC5R agonist activity and receptor subtype selectivity using a cAMP assay performed on HEK293 cells transfected with melanocortin receptors. Glucose uptake assays were performed on L6 cells and Non-Human Primate (NHP) skeletal muscle satellite cells to characterise activity of lead compounds and selected top compounds.
Out of over 75 compounds that were screened, we identified 8 compounds retaining sub-nanomolar agonist activity at MC5R and were completely selective over MC3R and MC4R. Most of our identified compounds were also more than 100-fold selective over MC1R. We demonstrated an increase in glucose enhancement on L6 cells upon stimulation with our identified non-selective leads and selective MC5R agonists, both alone and in the presence of insulin. An increase in glucose uptake was also demonstrated upon stimulation of NHP skeletal muscle satellite cells with selective MC5R agonists.
Overall, our data shows that a selective MC5R agonist increases glucose uptake in an in-vitro model. This has enabled us in identifying compounds to be administered in future in-vivo studies.