Obesity and insatiable appetite (hyperphagia) are among the most serious symptoms experienced by Prader-Willi syndrome (PWS) patients. While many of the causes underlying PWS symptoms remain unknown, the discovery of the protein hormone ghrelin and its role in controlling appetite has led researchers to investigate the possible role of ghrelin in PWS. Patients with PWS have elevated levels of ghrelin in their bloodstreams, suggesting that the voracious appetite that accompanies PWS may arise from overstimulation of ghrelin-mediated signaling. Based on this hypothesis, novel therapeutic agents targeting ghrelin have potential as treatment options for PWS-associated hyperphagia.
Ghrelin O-acyltransferase (GOAT), an enzyme that modifies ghrelin, offers an excellent target for specifically blocking ghrelin activity. GOAT attaches a fatty acid to ghrelin, with only the modified form of ghrelin demonstrated to activate hunger signaling. This fatty acid modification is unique to ghrelin among appetite-regulating hormones, making it likely that blocking it with GOAT-specific inhibitors will only affect ghrelin signaling. However, designing inhibitors for GOAT is currently difficult because very little is known about how GOAT binds ghrelin and catalyzes ghrelin modification. To relieve this bottleneck in developing GOAT inhibitors, our research will determine the interactions between ghrelin and GOAT that are required for GOAT-catalyzed ghrelin modification. We will then use synthetic chemistry to create molecules that block these interactions for evaluation as potential GOAT inhibitors. By gathering fundamental knowledge about how GOAT recognizes and modifies the appetite-stimulating hormone ghrelin, we will lay the foundation for creating a novel class of therapeutics for treating hyperphagia in patients with PWS.