A Novel Peptide Therapeutic for Obesity

描述（由申请人提供）：该项目的目标是开发一种新型肽治疗药物GLP-1-5，用于治疗肥胖。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。到2030年，预计美国将有超过50%的成年人肥胖，每年的医疗负担预计将超过8600亿美元，约占美国医疗保健总成本的18%。GLP-1是一种葡萄糖促生成素激素，可增加葡萄糖依赖型胰岛素的分泌。我们发现，GLP-1（9-36）酰胺是循环中GLP-1的主要形式，给药可导致两种肽的形成；非肽GLP-1（28-36）酰胺（简称GLP-1-9）和五肽GLP-1（32- 36）酰胺（简称GLP-1-5）在5分钟内出现在小鼠血浆中。这两种多肽都是neprilysin切割GLP-1的产物，它们的作用机制似乎与现有的减肥药（包括GLP-1受体激动剂）不同。肽似乎进入细胞并改变线粒体功能，通过呼吸解偶联（氧化磷酸化）增加基础能量消耗。最近，我们在喂食高脂肪饮食的小鼠中证明，注入GLP-1-9可以增加BEE （Tomas和Habener，论文正在准备中）并抑制体重增加。我们现在已经证明，在喂食高脂肪饮食的小鼠中，注入GLP-1-5也可以通过增加BEE来减少体重增加和脂肪量。虽然这两种肽似乎通过相同的新机制起作用，但GLP-1-9在生理溶液中难溶，被认为不适合配方，使GLP-1-5成为临床开发的更好候选者。我们的目标是将GLP-1-5定位为一种新的治疗方法，在生理上作为减肥剂治疗肥胖。据我们所知，市场上或临床开发中没有一种已批准的药物能够诱导能量消耗，并且是一种天然蛋白质的产物，在这种情况下是GLP-1。拟议的1期研究有三个关键目标：1)确定GLP-1-5的最佳剂量，与GLP-1受体激动剂GLP-1（7-36）酰胺相比，最大限度地减少肥胖小鼠的BEE和体重；2)证实增加GLP-1-5的剂量可以维持肥胖小鼠的体温和肌肉力量；3)建立可靠的效价生物测定方法，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.