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Pharmacological chaperones for the misfolded melanocortin-4 receptor associated with human obesity

Hui Huang1, Wei Wang1, Ya-Xiong Tao1

  • 1Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, United States.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|March 13, 2017
PubMed

Insights

Mutant melanocortin-4 receptors (MC4R) causing obesity can be rescued. This review explores methods to stabilize and target these misfolded proteins to the cell surface for potential therapeutic benefits.

Area of Science:

  • Biochemistry
  • Genetics
  • Pharmacology

Background:

  • The melanocortin-4 receptor (MC4R) is crucial for regulating energy balance.
  • MC4R mutations lead to early-onset severe obesity, with many mutants misfolded and retained intracellularly.
  • Some misfolded MC4R mutants may regain function if correctly targeted to the cell surface.

Purpose of the Study:

  • To review strategies for rescuing misfolded MC4R mutants.
  • To discuss the potential of chaperones in correcting MC4R protein folding defects.

Main Methods:

  • Review of literature on MC4R mutant rescue.
  • Analysis of chaperone-assisted protein stabilization and trafficking.
  • Evaluation of pharmacological chaperones like Ipsen 5i and Ipsen 17.

Main Results:

  • Misfolded MC4R mutants can be stabilized and trafficked to the plasma membrane by various chaperones.
  • Molecular and chemical chaperones show potential but have limitations like non-specific action and high dosage requirements.
  • Specific pharmacological chaperones, such as Ipsen 5i and Ipsen 17, demonstrate high potency and efficacy.

Conclusions:

  • Different approaches exist to rescue misfolded MC4R mutants.
  • Targeting MC4R misfolding presents a therapeutic avenue for obesity treatment.
  • Further research into effective chaperone strategies is warranted.
Keywords:
G protein-coupled receptorMelanocortin-4 receptorObesityPharmacological chaperone/pharmacoperone

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