Development and Application of Ghrelin O-acyltransferase Inhibitors

Ghrelin O-酰基转移酶抑制剂的开发及应用

基本信息

批准号：
8215389
负责人：
PHILIP A COLE
金额：
$ 49.08万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2013-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This R24 Seed Program proposal concerns the development and analysis of novel chemical inhibitors of a key enzyme, ghrelin 0-acyltransferase (GOAT) that catalyzes a critical step in the biosynthesis of acyl ghrelin, a body mass and glucose regulatory hormone. The trend toward excessive body weight in the U.S. and global populations contributes to major morbidity in human health, not to mention spiraling medical costs. Likewise, the increasing prevalence of type II diabetes mellitus, predicted to reach 30% of the American population by 2050, is a tremendous epidemiologic concern. There is thus an urgent need for effective therapeutics that can combat obesity and diabetes. Synthetic compounds that block GOAT offer the potential for such metabolic therapies. The team leaders Philip Cole (PI, Johns Hopkins), Jef Boeke (Johns Hopkins), Matthias Tschop (Univ. Cincinnati), and Paul Pfluger (Univ. Cincinnati), experts in their respective fields, have recently joined forces to create an interdisciplinary, state-of the-art research program that integrates synthetic chemistry, enzymology, cellular pharmacology, pharmacokinetics, and mouse metabolic studies to develop novel GOAT inhibitors and evaluate their therapeutic potential. Building on significant preliminary data that show that designed peptide-based GOAT inhibitors work in vitro, in cells, and in mice to reduce acyl ghrelin, prevent weight gain, and improve glucose tolerance (B. Barnett et al. Science, Dec. 2010), this team will attempt to develop synthetic compounds with superior pharmacologic properties. These new compounds along with the prototype GOAT inhibitor GO-CoA-Tat will be used to dissect how the extent and mechanism of acyl/desacyl ghrelin changes affect the detailed energy and glucose/insulin profiles in wild-type and genetically altered mouse models on a range of diets. In summary, this program offers the exciting potential to generate next generation therapeutics that may safely help overcome the increasing public health challenges of obesity and diabetes. PUBLIC HEALTH RELEVANCE: This proposal could generate lead agents for the treatment of diabetes and obesity.

描述（由申请人提供）：该R24种子计划提案涉及对关键酶的新型化学抑制剂，Ghrelin 0-酰基转移酶（山羊）的开发和分析，该酶是促促酰基蛋白，体重和葡萄糖调节激素的生物合成的关键步骤。美国和全球人口过度体重过度的趋势有助于人类健康的主要发病率，更不用说医疗费用了。同样，预计到2050年，II型糖尿病的患病率不断增加，预计将达到美国人口的30％，这是一个极大的流行病学问题。因此，迫切需要有效的治疗剂，可以打击肥胖症和糖尿病。阻断山羊的合成化合物为这种代谢疗法提供了潜力。团队负责人Philip Cole（PI，Johns Hopkins），Jef Boeke（Johns Hopkins），Matthias Tschop（Cincinnati Univ）和Paul Pfluger（Univ。Cincinnati）（Univ。Cincinnati），他们各自领域的专家，最近都与跨学科的研究中的阶层进行了跨学科的研究，该计划集成了整合性的研究，该计划是合成的，是合成的，是合成的。药理学，药代动力学和小鼠代谢研究，以开发新的山羊抑制剂并评估其治疗潜力。基于重要的初步数据，该数据表明设计了基于肽的山羊抑制剂在体外，细胞和小鼠中起作用，以减少酰基生长素蛋白，预防体重增加并提高葡萄糖耐受性（B. Barnett等人，B.Barnett等人，2010年12月），该团队将试图与高级药理学性质一起发展合成化合物。这些新化合物以及原型山羊抑制剂GO-COA-TAT将用于剖析抗饮食范围的酰基/乙酰血状素器蛋白变化的程度和机制如何影响野生型和遗传改变小鼠模型的详细能量和葡萄糖/胰岛素谱。总而言之，该计划为产生下一代治疗剂提供了令人兴奋的潜力，这些治疗方法可以安全地克服肥胖和糖尿病的公共健康挑战日益增长的挑战。公共卫生相关性：该提案可能会为治疗糖尿病和肥胖症的治疗而产生主要代理。