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

通过 Vit 测试食欲抑制肽 PYY3-36 的口服递送

• 批准号: 8574414
• 负责人: Robert P. Doyle
• 金额: $ 22.14万
• 依托单位: SYRACUSE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8574414
• 关键词: Adolescent; Affinity; Agonist; Animal Model; Animals; Anti-Obesity Agents; Appetite Depressants; Area; Asia; Australia; Bioavailable; Biochemical; Biological; Biological Assay; Biological Availability; Body Weight decreased; Brain; Child; Circular Dichroism; Clinical; Data; Desire for food; Development; Eating; Endopeptidases; Europe; FOS gene; Future; Glucose; Health; Hormones; In Vitro; Injection of therapeutic agent; Insulin; Investigation; Licensing; Literature; Measures; Metabolic; North America; Obesity; Oral; Oral Administration; Outcome; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Prevalence; Production; Property; Proteins; Public Health Education; Reaction; Recommendation; Relative (related person); Reporting; Route; Safety; Sampling; Series; Serum; Site; Specificity; Stress; System; Testing; Therapeutic; United States National Center for Health Statistics; United States National Institutes of Health; Vitamin B 12; Weight Gain; Work; attenuation; bariatric surgery; base; design; falls; feeding; fundamental research; glucagon-like peptide 1; in vivo; indexing; insight; interest; melting; molecular dynamics; novel; obesity management; obesity treatment; peptide hormone; public health relevance; receptor; screening; secondary outcome; stem; success; trend; uptake

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.

描述（由申请人提供）：肥胖是目前世界面临的最大健康挑战之一。儿童和青少年中肥胖症的流行率不断上升尤其令人关切，这表明未来的趋势会恶化。目前，唯一真正有效的长期外源性肥胖治疗方法是减肥手术，其长期益处实际上可能涉及肠道激素，如PYY，这是该提案的重点。虽然药物治疗通常用于治疗肥胖症，但使用目前许可的减肥药物，平均减去安慰剂的体重减轻不到5%。因此，目前正在寻求具有增加的功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剂，因为它们具有食欲抑制作用。然而，目前可用的肽给药途径（主要是注射）限制了其在临床环境中的适用性。的目的 项目是证明一种有效的口服给药途径和合适的肠道体内激动剂 激素PYY 3 -36，其已被确定为具有食欲抑制特性。此外，理解外周PYY 3 -36给药的作用以及与其他重要的肠道激素如GLP-1的相互作用仍然存在问题。口服活性PYY 3 -36可以在没有应激的情况下对动物给药，这是迄今为止在外周研究中的主要问题，将对该领域具有显著的益处。该建议的三个具体目标明确地设计为我们生产和理解口服活性PYY 3 -36，最终适用于本文提出的动物模型以外的外周体内研究。目标1将基于合理的设计产生四种新的缀合物。目的2将筛选这种缀合物的受体特异性和效力，目的3将提供对体内代谢作用的了解。C1）目标1。合成四种维生素B12-PYY 3 -36缀合物（和一种乱序PYY 3 -36对照）用于体外筛选。使用合理的设计，将化学合成和表征一系列B12-PYY 3 -36缀合物。C2）目标2。筛选缀合物的Y1相对于Y2受体选择性和激动活性。减肥效果被认为源于Y2-R的激活，而相反的效果由Y1激活触发。将筛选出对Y2-R的选择性优于Y1-R且对Y2-R具有等效（与PYY 3 -36相比）或类似低纳摩尔效力的缀合物用于体内研究C3）目的3。使用成功筛选的结合物进行生物学和体内摄取研究。我们将试图证明B12-PYY 3 -36缀合物是生物可利用的形式，并将导致与皮下施用游离PYY 3 -36类似的厌食作用。除了喂食之外，口服给药引发的生化效应将是Lee肥胖指数和c-Fos。次要结果包括来自血清样本的PYY、胰岛素和葡萄糖。