Testing Oral Delivery of the Appetite Suppressing Peptide PYY3-36 Through the Vit

描述（由申请人提供）：肥胖是当今世界面临的最大健康挑战之一。儿童和青少年肥胖率的上升尤其令人担忧，并表明未来的趋势会恶化。目前，唯一真正有效的长期外源性治疗肥胖的方法是减肥手术，其长期益处实际上可能涉及肠道激素，如PYY，这是本提案的重点。虽然药物治疗通常是用来控制肥胖的，但目前获得许可的抗肥胖药物平均减去安慰剂后的体重减轻不到5%。因此，目前正在寻找具有更高疗效和安全性的新型抗肥胖药物。一个非常感兴趣的领域集中在选择内源性肽作为潜在的抗肥胖治疗药物，因为它们的食欲抑制作用。然而，目前可用的多肽给药途径（主要是注射）限制了它们在临床环境中的适用性。这样做的目的

DESCRIPTION (provided by applicant): Obesity is one of the greatest health challenges currently facing the world. The rising prevalence of obesity among children and adolescents is of particular concern and suggests worsening trends for the future. Currently, the only truly effective long-term exogenous treatment for obesity is bariatric surgery, the long-term benefits of which may actually involve gut hormones such as PYY, the focus of this proposal. While drug treatment is often prescribed for the management of obesity, average placebo-subtracted weight losses are less than 5% with currently licensed antiobesity drugs. As a consequence, novel antiobesity drugs with increased efficacy and safety are currently being sought. One area of great interest focuses on select endogenous peptides as potential antiobesity therapeutics due to their appetite suppressing effects. Currently available administration routes for peptides (primarily injection) have limited their suitability in a clinical setting however. The aim of this project is to demonstrate an effective oral delivery route and suitable in vivo agonism for the gut hormone PYY3-36, which has been established as having appetite suppressing properties. In addition, understanding the effects of peripheral PYY3-36 administration and the interactions with other important gut hormones such as GLP-1 for instance, remains in question. An orally active PYY3-36 that can be administered without stress to the animal, a major issue to date in peripheral studies, would be of significant benefit to the field. The three specific aims of this proposal are clearly designed towards our production and understanding of an orally active PYY3-36, ultimately suitable for peripheral in vivo investigations beyond the animal models proposed here. Aim 1 will produce four new conjugates based on a rational design. Aim 2 will screen such conjugates for receptor specificity and potency and aim 3 will provide insight into the metabolic effects in vivo. C1) Aim 1. Synthesize four vitamin B12-PYY3-36 conjugates (and one scrambled PYY3-36 control) for in vitro screening. Using rational design a series of B12-PYY3-36 conjugates will be chemically synthesized and characterized. C2) Aim 2. Screen conjugates for Y1 versus Y2 Receptor selectivity and agonistic activity. Weight loss effects are believed to stem from activation of Y2-R, with the opposite effects triggered by Y1 activation. Conjugates with selectivity for Y2-R over Y1-R with equipotent (compared to PYY3-36) or similarly low nanomolar potency for Y2-R will be screened out for in vivo investigations C3) Aim 3. Conduct biological and in vivo uptake studies with successfully screened conjugate. We will attempt to show that the B12-PYY3-36 conjugate is in a bioavailable form and will result in an anorectic effect similar to that of subcutaneously administered free PYY3-36. Biochemical effects triggered by oral administration in addition to feeding will be Lee adiposity index, and c-Fos. Secondary outcomes include PYY, insulin and glucose from serum samples.