Current and Future Drug Targets in Weight Management Table II Some Examples of Pharmacological Interventions Via Gut Hormone Signaling Gut hormone Amylin PYY Pancreatic polypeptide GLP-1 Oxyntomodulin Ghrelin Leptin Approach Peptide analogues PYY(3-36) analogues PP analogues/Y4 agonists Stable analogues Analogues Vaccination/mRNA aptamers Analogues (in combinations) leptin. Normally, sensitivity to leptin is reduced in obesity, which limits its therapeutic potential. However, pramlintide was found to inhibit this process. In a 20-week trial, the combination induced a weight loss of 12.7±0.9% (11.5 ± 0.9 kg) in obese persons (89). Another second-generation amylin analogue in development was davalintide (30). However, recently, Amylin Pharmaceuticals and Takeda (Japan) announced they were giving priority to the pramlin- tide/metreleptin combination and discontinuing develop- ment of davalintide. Phase II studies demonstrated that the weight-loss efficacy and tolerability profile of davalintide was not better than that of pramlintide and was inferior to that of the pramlintide/metreleptin combination (90). PYY Analogues PYY (1–36) is a 36-amino-acid polypeptide synthesized by entero-endocrine cells of the L-type, mainly in the distal gut. The main circulating form of the hormone is PYY(3– 36), which is formed after partial cleavage of PYY(1–36) by dipeptidyl peptidase IV (56). PYY is considered to be a principal mediator of the ‘ileal brake’ reflex, which is a feedback mechanism that slows gastric emptying and intestinal transit in response to nutrients (fat, protein, and carbohydrates) arriving in the distal small intestine. The effects of PYY3-36 are mediated via the Y2-receptor, which is found throughout the central nervous system, in the nodose ganglion, and on Vagal afferents. It has also been suggested that weight loss induced by PYY3-36 occurs in part by modulating energy expenditure and fuel partitioning (56). Following the discovery of Batterham et al. (91) that peripheral administration of PYY3-36 can cause a reduction of food intake in rodents and in obese and normal-weight humans, other studies confirmed the anorectic action of PYY3-36. However, in their review, Boggiano et al. (92) take a very skeptical position on the potential of PYY3-36-based therapies in practice. A phase II trial in 2008 with a PYY3- 36 nasal spray showed encouraging results (56). Nevertheless, the development of that formulation was stopped, as the results did not meet the primary endpoints. At present, there appears to be little activity with PYY-based approaches (30). 1801 Example(s) Pramlintide Nasal formulations, development discontinued for the time being TM-30339, obinepitide (dual-analogue of PYY3-36 and PP) Exenatide, liraglutide ? TKS1225 NOX-B11 Spiegelmers Metreleptin-pramlintide combination Pancreatic Polypeptide Analogues Pancreatic polypeptide (PP) is a 36-amino-acid peptide categorized in the same family as PYY. However, in contrast to PYY, it is mainly secreted by the pancreas and, to a lesser extent, by the colon (56). Plasma PP concentrations rise in a biphasic manner following nutrient ingestion. This increase is proportional to the caloric load of the meal with concentrations remaining elevated up to 6 h after a meal. This suggests that PP exerts its effects on feeding mainly by inducing satiety. PP has highest affinity for Y4-receptors in brainstem and hypothalamus, followed by Y1- and Y5- receptors. Several studies demonstrate that PP can reduce food intake. Danish 7TM Pharma has developed TM- 30339, a synthetic analogue of PP and a selective Y4- receptor agonist. The compound demonstrated weight loss in diet-induced obese mice. According to the company, the compound showed good safety and tolerability data and is now in phase II. However, indications have apparently shifted to gastrointestinal disorders, including mucositis, malabsorphtion, ulcerative colitis, Crohn’s disease and short bowel syndrome (93). The same company has also developed the dual PP and PYY (3–36) analogue obinepitide (http:// www.uniprot.org/uniprot/P01298), with agonist activity both for the Y2 and Y4 receptor (94). According to 7TM Pharma, the compound had greater weight-loss-inducing effects in diet-induced obese mice than PYY3-36. The compound is now in phase I/II, and once-a-day subcutane- ous administration in obese subjects inhibited food intake at a statistically significant level up to 9 h after dosing. GLP-1 Analogues Among the gut hormones, GLP-1 is currently the most promising and advanced target for pharmacological weight management. Natural GLP-1 is synthesized by intestinal L- cells and subsequently cleaved to its active fragments GLP- 17–37 and GLP-17–36 amide, the latter being the major circulating form. GLP-1 is rapidly inactivated by dipeptidyl peptidase IV (DPP-IV), leading to an elimination half-life of only 1–2 min. The peptide acts on the GLP-1 receptor,