Rescue of defective MC4R cell-surface expression and signaling by a novel pharmacoperone Ipsen 17
Xiao-Hua Wang1, Hao-Meng Wang1, Bao-Lei Zhao1
1Key Laboratory of Food Nutrition and Safety (Tianjin University of Science and Technology)College of Food Engineering and Biotechnology, Ministry of Education, No. 29 13rd Road, Tianjin Economy-and-Technology Development Area, Tianjin 300457, People's Republic of ChinaObesita and Algaegen LLCCollege Station, Texas 77845, USACollege of BiotechnologyTianjin University of Science and Technology, Tianjin 300457, People's Republic of China.
Abstract:
Melanocortin 4 receptor (MC4R) is a key factor in regulating energy homeostasis, and null mutations occurring in the gene encoding MC4R cause severe early-onset morbid obesity in humans. Many obesity-causing mutations affecting MC4R clinically identified so far lead to failure of mutant receptors to shuttle to the plasma membrane. In this study, we show that a novel human MC4R antagonist, Ipsen 17, acted as an pharmacological chaperone of human MCR4. As tested with 12 obesity-causing human MC4R variants including S58C, E61K, N62S, I69T, P78L, C84R, G98R, T162I, R165W, W174C, C271Y, and P299H, Ipsen 17 was found to be the most universal pharmacological chaperone of MC4R reported so far because it can completely rescue nearly all mutant receptors (except P299H) with the highest potency (an EC50 value of approximately 10(-8) M) and efficiency when compared with results for other tested pharmacological chaperones of MC4R including ML00253764, PBA, MTHP, PPPone, MPCI, DCPMP, and NBP described in the literature. Once restored to the plasma membrane, defective human MC4R variants responded to α-MSH stimulation with an EC50 value of approximately 10(-8) M and displayed dramatically enhanced signaling ability (except for G98R) in a mutant-specific efficacy and potency profile. Taken together, these results indicate that Ipsen 17 represents a candidate for the development of a targeted treatment of severe early-onset morbid obesity caused by a large subset of inherited mutations in the human MC4R gene.
Insights
A novel compound, Ipsen 17, acts as a universal pharmacological chaperone for the melanocortin 4 receptor (MC4R). It effectively rescues most obesity-linked MC4R mutations, offering a promising treatment for severe early-onset obesity.
Area of Science:
- Endocrinology
- Molecular Biology
- Pharmacology
Background:
- Melanocortin 4 receptor (MC4R) is crucial for energy homeostasis.
- MC4R gene mutations cause severe early-onset obesity by impairing receptor function.
- Many disease-causing MC4R mutations result in the receptor failing to reach the cell surface.
Purpose of the Study:
- To investigate the potential of a novel MC4R antagonist, Ipsen 17, as a pharmacological chaperone.
- To evaluate Ipsen 17's efficacy in rescuing various obesity-associated MC4R variants.
- To compare Ipsen 17's performance with existing MC4R pharmacological chaperones.
Main Methods:
- Tested Ipsen 17 on 12 obesity-causing human MC4R variants.
- Assessed the rescue of mutant MC4R to the plasma membrane.
- Measured the restored receptor's response to alpha-melanocyte-stimulating hormone (α-MSH) stimulation.
Main Results:
- Ipsen 17 demonstrated universal chaperone activity, rescuing most tested MC4R variants (except P299H).
- It exhibited high potency (EC50 ≈ 10⁻⁸ M) and efficiency, surpassing other known chaperones.
- Rescued MC4R variants showed restored signaling to α-MSH, with potency and efficacy varying by mutation.
Conclusions:
- Ipsen 17 is a highly effective and universal pharmacological chaperone for MC4R.
- It shows significant potential for developing targeted therapies for severe obesity linked to MC4R mutations.
- This finding opens new avenues for treating a substantial portion of inherited obesity cases.
