Development and Application of Ghrelin O-acyltransferase Inhibitors

描述（由申请人提供）：该R24种子计划提案涉及关键酶--胃饥饿素0-酰基转移酶（GOAT）的新型化学抑制剂的开发和分析，该酶催化酰基胃饥饿素（一种体重和葡萄糖调节激素）生物合成中的关键步骤。美国和全球人口体重过重的趋势导致了人类健康的主要发病率，更不用说螺旋式上升的医疗成本了。同样，II型糖尿病的患病率不断增加，预计到2050年将达到美国人口的30%，这是一个巨大的流行病学问题。因此，迫切需要能够对抗肥胖症和糖尿病的有效治疗剂。阻断GOAT的合成化合物为这种代谢疗法提供了潜力。领队菲利普科尔（PI，约翰霍普金斯），杰夫·伯克（约翰霍普金斯）（辛辛那提大学）和保罗·普弗卢格（Paul Pfluger）（辛辛那提大学），在各自领域的专家，最近联手创建一个跨学科的，最先进的研究计划，整合合成化学，酶学，细胞药理学，药代动力学，和小鼠代谢研究，以开发新型GOAT抑制剂并评估其治疗潜力。基于重要的初步数据，这些数据表明设计的基于肽的GOAT抑制剂在体外、细胞和小鼠中起作用，以减少酰基生长素释放肽，防止体重增加，并改善葡萄糖耐量（B.巴内特等人，科学，2010年12月），该团队将尝试开发具有上级药理学特性的合成化合物。 这些新的化合物沿着与原型GOAT抑制剂GO-CoA-达特将被用于剖析酰基/去酰基ghrelin变化的程度和机制如何影响野生型和遗传改变的小鼠模型在一系列饮食中的详细能量和葡萄糖/胰岛素谱。总之，该计划提供了令人兴奋的潜力，以产生下一代疗法，可以安全地帮助克服日益增加的肥胖和糖尿病的公共卫生挑战。 公共卫生相关性：该提案可能会产生治疗糖尿病和肥胖症的主要药物。

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.