A Novel Peptide Therapeutic for Obesity

描述（由申请人提供）：本项目的目标是开发一种用于治疗肥胖症的新型肽治疗剂GLP-1-5。今天，美国有三分之一的成年人肥胖，估计每年的医疗负担约为1500亿美元。据预测，到2030年，美国将有超过50%的成年人肥胖，预计每年的医疗保健负担将超过8600亿美元，约占美国医疗保健总成本的18%。GLP-1是一种葡萄糖肠促胰岛素激素，可增强葡萄糖依赖性胰岛素分泌。我们发现，GLP-1（9-36）酰胺（循环中存在的GLP-1的主要形式）的给药导致在5分钟内在小鼠血浆中形成两种肽：九肽GLP-1（28-36）酰胺（称为GLP-1-9）和五肽GLP-1（32- 36）酰胺（称为GLP-1-5）。这两种肽都是脑啡肽酶裂解GLP-1的产物，并且似乎都通过与现有肥胖药物（包括GLP-1受体激动剂）不同的机制起作用。这些肽似乎进入细胞并通过呼吸解偶联（氧化磷酸化）改变线粒体功能以增加基础能量消耗。最近，我们在喂食高脂饮食的小鼠中证明，输注GLP-1-9可增加BEE（Tomas和Habener，手稿正在编写中）并抑制体重增加。我们现在已经证明，输注GLP-1-5也可以通过增加BEE来减少高脂饮食小鼠的体重增加和脂肪量。虽然两种肽似乎通过相同的新机制起作用，但GLP-1-9在生理溶液中溶解性差，被认为不适合配制，使得GLP-1-5成为临床开发的更好候选物。我们的目标是将GLP-1-5定位为一种新的治疗剂，其在生理学上作为减肥药用于治疗肥胖症。据我们所知，市场上或临床开发中没有批准的药物能够诱导能量消耗，并且是天然蛋白质的产物，在这种情况下是GLP-1。拟定的I期研究有三个关键目标：1）确定GLP-1-5与GLP-1受体激动剂GLP-1（7-36）酰胺相比的最佳剂量，用于肥胖小鼠的最大BEE和体重减轻; 2）验证GLP-1-5剂量增加时肥胖小鼠的体温和肌肉强度得以维持; 3）建立可靠的效价生物测定法以验证GLP-1-5生物活性的完整性。

DESCRIPTION (provided by applicant): The goal of this project is to develop a novel peptide therapeutic, GLP-1-5, for the treatment of obesity. Today, one-third of adults in the United States (US) are obese, with an estimated annual healthcare burden of approximately $150 billion. By 2030, it is projected that over 50% of adults in the US will be obese with a yearly healthcare burden expected to exceed $860 billion, which will account for approximately 18% of the total US health-care costs. GLP-1 is a glucoincretin hormone that augments glucose-dependent insulin secretion. We discovered that the administration of GLP-1(9-36)amide, the major form of GLP-1 present in the circulation, leads to the formation of two peptides; a nonapeptide, GLP-1(28-36)amide (referred to as GLP-1-9) and a pentapeptide, GLP-1(32- 36)amide (referred to as GLP-1-5) in mouse plasma within 5 minutes. Both of these peptides are the product of GLP-1 cleavage by neprilysin, and both appear to act by a different mechanism than existing obesity drugs, including that of GLP-1 receptor agonists. The peptides appear to enter cells and modify mitochondria function to increase basal energy expenditure via uncoupling of respiration (oxidative phosphorylation). Recently, we demonstrated in mice fed a high-fat diet that infusions of GLP-1-9 increase BEE (Tomas and Habener, manuscript in preparation) and inhibits weight gain. We have now demonstrated that infusions of GLP-1-5 also curtail weight gain and diminish fat mass in mice fed a high-fat diet through increased BEE. While both peptides appear to act through the same novel mechanism, GLP-1-9 is poorly soluble in physiological solutions and considered unsuitable for formulation, making GLP-1-5 a better candidate for clinical development. Our goal is to position GLP-1-5 as a novel therapeutic that functions physiologically as a weight reducer for the treatment of obesity. To our knowledge, no approved drug on the market or in clinical development is able to induce energy expenditure and is the product of a natural protein, in this case GLP-1. The proposed Phase 1 has three key objectives: 1) determine the optimal dose of GLP-1-5, in comparison to the GLP-1 receptor agonist GLP-1(7-36) amide, for maximum BEE and weight loss in obese mice; 2) validate that body temperature and muscle strength are maintained in obese mice with increased GLP-1-5 dosing; 3) establish a reliable potency bioassay to validate the integrity of GLP-1-5 bioactivity.