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. Recent studies have also shown high ghrelin levels early in life can affect regulation of body metabolism throughout life. Based on this hypothesis, novel therapeutic agents targeting ghrelin have potential as PWS treatment options.
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, we have investigated the interactions between ghrelin and GOAT that are required for GOAT-catalyzed ghrelin modification. Using these interactions as guides, we are using synthetic chemistry to create molecules that block these interactions for evaluation as potential GOAT inhibitors. These new classes of GOAT inhibitors are essential for evaluating ghrelin’s potential as a therapeutic avenue for treating hyperphagia in patients with PWS.
Our research has identified novel hGOAT inhibitors, which are being assessed in both in vitro and cell-based ghrelin octanoylation assays to validate new classes of small-molecule inhibitors targeting ghrelin octanoylation. Our proposed research directly addresses the lack of GOAT inhibitors impeding evaluation of ghrelin as a target for treating hyperphagia and obesity in PWS. In addition to these inhibitors, our studies have developed new protocols and assays for studying ghrelin modification and signaling in a range of biological samples.