RT Journal Article SR Electronic T1 Pharmacological Chaperones Restore Function to MC4R Mutants Responsible for Severe Early-Onset Obesity JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 520 OP 532 DO 10.1124/jpet.110.172098 VO 335 IS 3 A1 Patricia René A1 Christian Le Gouill A1 Irina D. Pogozheva A1 Gary Lee A1 Henry I. Mosberg A1 I. Sadaf Farooqi A1 Kenneth J. Valenzano A1 Michel Bouvier YR 2010 UL http://jpet.aspetjournals.org/content/335/3/520.abstract AB Heterozygous null mutations in the melanocortin-4 receptor (MC4R) cause early-onset obesity in humans, indicating that metabolic homeostasis is sensitive to quantitative variation in MC4R function. Most of the obesity-causing MC4R mutations functionally characterized so far lead to intracellular retention of receptors by the cell's quality control system. Thus, recovering cell surface expression of mutant MC4Rs could have a beneficial therapeutic value. We tested a pharmacological chaperone approach to restore cell surface expression and function of 10 different mutant forms of human melanocortin-4 receptor found in obese patients. Five cell-permeant MC4R-selective ligands were tested and displayed pharmacological chaperone activities, restoring cell surface targeting and function of the receptors with distinct efficacy profiles for the different mutations. Such mutation-specific efficacies suggested a structure-activity relationship between compounds and mutant receptor conformations that may open a path toward personalized therapy. In addition, one of the five pharmacological chaperones restored function to most of the mutant receptors tested. Combined with its ability to reach the central nervous system and its selectivity for the MC4R, this pharmacological chaperone may represent a candidate for the development of a targeted therapy suitable for a large subset of patients with MC4R-deficient obesity.