Abstract
In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.
Highlights
It is with great pleasure we dedicate this review article to Prof
Setmelanotide, an eight amino acid cyclic melanocortin-4 receptor (MC4R) agonist peptide (Table 1), is being investigated in several clinical studies for the treatment of obesity, including rare genetic disorders of obesity. These genetic deficiencies include subjects with pro-opiomelanocortin (POMC) deficiency, proprotein-convertase (PCSK1) deficiency, leptin receptor (LEPR) deficiency, Prader-Willi syndrome (PWS), Bardet-Biedl syndrome (BBS), Alström syndrome (AS), and selected other genetic forms of early-onset severe obesity arising from defects that impair the MC4R pathway
It is well established that MC4R signals through Gαs under equilibrium ligand binding conditions using human embryonic kidney (HEK), Chinese hamster ovary (CHO), or monkey kidney tissue derived fibroblast-like cell (COS) cell-based systems stably transfected with MC4R [3,4,14,19,24,28,29,30,31]
Summary
It is with great pleasure we dedicate this review article to Prof. Victor J. Setmelanotide, an eight amino acid cyclic MC4R agonist peptide (Table 1), is being investigated in several clinical studies for the treatment of obesity, including rare genetic disorders of obesity. These genetic deficiencies include subjects with pro-opiomelanocortin (POMC) deficiency, proprotein-convertase (PCSK1) deficiency, leptin receptor (LEPR) deficiency, Prader-Willi syndrome (PWS), Bardet-Biedl syndrome (BBS), Alström syndrome (AS), and selected other genetic forms of early-onset severe obesity arising from defects that impair the MC4R pathway. This initial evidence of possible divergence in signaling pathways downstream of MC4R is of interest and requires in depth follow-up to understand its impact in physiologically relevant signaling events The results of these studies are summarized here and include evaluations of setmelanotide, a related compound RM-511 [28], and the LY2112688 MC4R agonist peptide
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