Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity.

J Pharmacol Exp Ther

Department of Biochemistry, Institute for Research in Immunology and Cancer, and University Drug Research Group, University of Montreal, Montreal, Quebec, Canada.

Published: December 2010

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.

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.110.172098DOI Listing

Publication Analysis

Top Keywords

cell surface
12
pharmacological chaperone
12
pharmacological chaperones
8
early-onset obesity
8
melanocortin-4 receptor
8
surface expression
8
function mutant
8
pharmacological
5
function
5
mc4r
5

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!