Discovery of a Ligand that Compensates for Decreased Endogenous Agonist Potency of Melanocortin-4 Receptor Polymorphisms Identified in Obese Humans

摘要

Genetic studies of morbidly obese human patients and normal weight control patients have resulted in the discovery of over 70 human melanocortin-4 receptor (MC4R) polymorphisms observed as both heterozygous and homozygous forms. A number of laboratories have been studying these hMC4R polymorphisms in attempts to understand the molecular mechanism(s) that might explain the obese human phenotype. Herein, we have studied polymorphic hMC4Rs that have been identified to possess statistically significant decreased endogenous agonist potency [1] in attempts to identify ligands that can pharmacologically "rescue" the polymorphic hMC4R agonist response. The hMC4R polymorphisms included in this study are the S58C, N97D, I102S, L106P, S127L, T150I, R165Q, R165W, G252S, C271Y, and I301T. We have discovered that the peptide template (AMW3-130) possessing nM to sub nM agonist potency, can rescue the functional endogenous agonist defect at these human MC4R polymorphisms.