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Published on: June 7, 2020
Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity
Patricia René1, Christian Le Gouill, Irina D Pogozheva
1Department of Biochemistry, Institute for Research in Immunology and Cancer, and University Drug Research Group, University of Montreal, Montreal, Quebec, Canada.
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.
Insights
Pharmacological chaperones can restore cell surface expression and function of mutant melanocortin-4 receptors (MC4R) linked to obesity. This approach may offer a personalized therapy for MC4R-deficient obesity.
Area of Science:
- Endocrinology
- Molecular Biology
- Pharmacology
Background:
- Mutations in the melanocortin-4 receptor (MC4R) gene are a common cause of early-onset obesity.
- Many MC4R mutations result in intracellular receptor retention, impairing function.
- Restoring cell surface expression of mutant MC4Rs is a potential therapeutic strategy.
Purpose of the Study:
- To investigate the efficacy of pharmacological chaperones in restoring cell surface expression and function of mutant MC4Rs.
- To identify potential therapeutic candidates for MC4R-deficient obesity.
Main Methods:
- Tested five cell-permeant, MC4R-selective ligands as pharmacological chaperones.
- Assessed the ability of these ligands to restore cell surface expression and function of 10 different MC4R mutations.
- Evaluated ligand properties including CNS penetration and MC4R selectivity.
Main Results:
- Five tested compounds exhibited pharmacological chaperone activity, restoring MC4R targeting and function.
- Efficacy varied among mutations, suggesting mutation-specific structure-activity relationships.
- One compound demonstrated broad efficacy across most tested mutants and possesses favorable pharmacokinetic properties.
Conclusions:
- Pharmacological chaperones can rescue cell surface expression and function of various MC4R mutants.
- A specific chaperone shows promise as a potential therapeutic agent for a significant portion of patients with MC4R-deficient obesity.
- This approach may lead to personalized therapies for obesity linked to MC4R dysfunction.
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