Ipsen 5i is a novel melanocortin‐4 receptor pharmacological chaperone

The melanocortin‐4 receptor (MC4R) is a critical regulator of energy homeostasis. Mutations in the MC4R gene are the commonest monogenic form of obesity. Functional characterization of the mutants revealed that the most predominant defect is intracellular retention. We reported that ML00253764 could increase cell surface expression and restore signaling in some MC4R mutants. However, the cell surface expression was modest. The objective of this study was to investigate the potential chaperoning activity of Ipsen 5i that has higher affinity for the MC4R. Ipsen 5i dramatically increased cell surface expression of seven mutants: S58C, N62S, P78L, C84R, G98R, W174C, and C271Y. WT MC4R expression was also increased after Ipsen 5i treatment. Confocal microscopy confirmed the flow cytometry data. After 24 h treatment with 100 nM Ipsen 5i, five mutants had significant increases in maximal signaling compared to vehicle‐treated controls, whereas maximal signaling for S58C was decreased. Treatment of G98R did not restore signaling, indicating that it is also defective in ligand binding and/or signaling. In summary, Ipsen 5i is a potent pharmacological chaperone that functionally rescues multiple MC4R mutants. Supported by NIH R15DK077213 and AUCVM Interdisciplinary Grant.