title: Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity.
abstract: 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.
authors.affiliation: Department of Biochemistry, Institute for Research in Immunology and Cancer, and University Drug Research Group, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: René
authors.forename: Christian
authors.initials: C
authors.lastname: Le Gouill
authors.forename: Irina D
authors.initials: ID
authors.lastname: Pogozheva
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Henry I
authors.initials: HI
authors.lastname: Mosberg
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Valenzano
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
mesh_terms: D017668:Age of Onset; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D020125:Mutation, Missense / Q000502:physiology*; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics*; D004364:Pharmaceutical Preparations / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D010599:Pharmacokinetics; D017510:Protein Folding / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C470072:MC4R protein, human; D004364:Pharmaceutical Preparations; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D000242:Cyclic AMP