The 5-HT2CR: Mining a new experimental approach to therapeutics for Prader-Willi syndrome

Prader-Willi Syndrome (PWS) is a complex genetic disorder in which several genes are missing or not functional. PWS is characterized by initial loss of muscle tone and failure to thrive neonatally; children with PWS develop behavioral and cognitive problems, reproductive defects, and excessive overeating. A major medical concern is the morbid obesity that results from incessant food-seeking and an inability to feel full. The chromosomal defect in PWS patients deletes a gene sequence involved in regulating a receptor found in the brain, the serotonin 5-HT2C receptor (5-HT2CR). Brain serotonin (5-HT) pathways are well-characterized to regulate feeding, satiety, and mood. Drugs that enhance 5-HT function have been shown to reduce weight and severity of illness in obese patients. The 5-HT2CR appears to be an important component for the weight reducing effects of these drugs, as the drugs are ineffective when the 5-HT2CR is blocked, or in mice that lack the 5-HT2CR. Thus, the brain 5-HT2CR plays a critical role in the control of food intake and satiety, however its potential as a therapeutic target for obesity associated with PWS has not been investigated. We hypothesize that selective and sustained activation of 5-HT2CR may therapeutically enhance the health and lifestyles of PWS patients. A specific part of the 5-HT2CR molecule makes a physical interaction with a protein known as PTEN. This association of PTEN with 5-HT2CR limits downstream effects caused by stimulation of 5-HT2CR. Thus, a selective inhibitor of the 5-HT2CR:PTEN interaction would enhance 5-HT2CR signaling. In the proposed studies, we will characterize the 5-HT2CR:PTEN interaction by measuring intracellular responses in cultured cells containing 5-HT receptors in the presence or absence of PTEN. We will design, synthesize and evaluate novel peptides that inhibit interaction between the 5-HT2CR and PTEN. These studies will enable us to ultimately design small molecules to enhance 5-HT2CR function and identify their efficacy in preclinical models as potential therapeutics for treatment of PWS.

RESEARCH OUTCOMES: Therapeutic gains in PWS patients may be achieved through the selective and sustained activation of the 5-HT2CR. We have demonstrated that a particular peptide (3L4F) which disrupts the interaction of 5-HT2CR with another protein (PTEN) selectively increases the signaling response to 5-HT2CR activation vs. the closely related 5-HT2AR. These data suggest this peptide provides a novel way to selectively enhance 5-HT2CR activation. The synthesis and analysis of additional, related peptides enabled us to pinpoint the active site of the 3L4F peptide. These studies are the first step to design novel small molecules that have similar activity as the peptides to disrupt this protein complex and enhance 5-HT2CR function, but have better drug-like properties. Such molecules can subsequently be evaluated for efficacy in preclinical models as potential therapeutics to enhance the health and lifestyle of PWS patients.

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