Design and development of pharmacological chaperones to restore function to MC4R mutants responsible for severe early-onset obesity.
"Melanocortin 4 receptor (MC4R) is a is a G protein-coupled receptor (GPCR) and key regulator of energy homeostasis. MC4R mutations represent the largest monogenic cause of obesity, resulting mainly from receptor misfolding and intracellular retention by the cellular quality control system. The efficacy of several lead compounds on restoring the cell surface expression and function of mutated MC4R has already been tested in our laboratory. One compounds restored the anorexic response to MC4R agonist in a KI mice model. Combined with its ability to reach the central nervous system and its selectivity for the MC4R, this pharmacological chaperone (PC) may represent a candidate for the development of a targeted therapy. The project includes medicinal chemistry and computer-aided drug design approaches to improve the properties of existing PC candidates, followed by in vivo studies to assess the therapeutic potential of these candidate and establish their Parmaco-kineticK/Pharmaco-dynamic relationship as well as a high throughput screen to identify backup PC series. The intern has a Ph.D. in cell and molecular biology with expertise in computer-aided drug design and cell signaling interrogation.