Clinical perspectives for ghrelin-derived therapeutic products.

Because of its orexigenic, adipogenic and diabetogenic activities, acylated ghrelin (AG) has emerged as an attractive target for the treatment of obesity and type 2 diabetes. Pharmacological tools have been designed in order to antagonize or block the hormone's activity, or inhibit ghrelin O-acyltransferase (GOAT), the enzyme that catalyzes its acylation. AG antagonists, shown to be potent inhibitors of growth hormone (GH) secretion, were not able to consistently induce the desirable metabolic effects. Some of them, on the contrary, acted as AG agonists. Similarly, AG-blocking agents including Spiegelmers, vaccines, and monoclonal antibodies, gave mixed results. More encouraging yet very preliminary data were obtained with a novel GOAT inhibitor. However, although significant, the observed decrease in circulating AG levels was partial and improvement work remains to be done. Unacylated ghrelin (UAG) and analogs were shown to potently and rapidly inhibit plasma AG levels, and to improve glucose metabolism in addition to displaying beneficial effects on a variety of cells. These data support the rationale for further development of this new therapeutic class in type 2 diabetes and the Prader-Willi syndrome. A development program is underway with AZP-531, a cyclized UAG(6-13) analog with improved pharmacokinetic properties.