Rescue of defective MC4R cell-surface expression and signaling by a novel pharmacoperone Ipsen 17.
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.
Key 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.
Xiao-Hua
XH
Wang
Key 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.
Hao-Meng
HM
Wang
Key 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.
Bao-Lei
BL
Zhao
Key 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.
Peng
P
Yu
Key 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 ChinaKey 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 fanzhen@tust.edu.cn.
Zhen-Chuan
ZC
Fan
D019943:Amino Acid Substitution; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009767:Obesity, Morbid / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000521:alpha-MSH / Q000378:metabolism / Q000494:pharmacology
C484860:2-(2-(2-(5-bromo-2-methoxyphenyl)ethyl)-3-fluorophenyl)-4,5-dihydro-1H-imidazole; D001562:Benzimidazoles; D007093:Imidazoles; C000602265:Ipsen 17; C470072:MC4R protein, human; D050505:Mutant Proteins; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; D000242:Cyclic AMP
functional rescue; melanocortin 4 receptor; pharmacological chaperone; severe early-onset morbid obesity