Designed Small Molecule Inhibitors of Ghrelin O-Acyl Transferase

描述（由申请人提供）：在美国，肥胖和II型糖尿病的发病率上升是对健康和医疗保健的普遍威胁。人们正在探索许多应对这一趋势的方法。这些措施包括生活方式的改变、减肥手术和药物。在后者中，许多候选药物未能达到疗效和/或安全性标准-通常是因为与靶向大脑中复杂受体系统相关的意外副作用。我们建议研究在胃中验证一种新的酶靶点。这种酶在中枢神经系统之外起作用。胃饥饿素是胃粘膜X/ a细胞分泌的一种肽类激素。在人类中，胃饥饿素的全身管理促进进食和阻止胰岛素从胰腺细胞的释放。胃饥饿素由一个含有117个氨基酸的前体发育而成，只有在Ser-3上与辛酸酯酰化后才能获得其内分泌功能。数据显示，这种修饰是由胃饥饿素o -酰基转移酶（GOAT）完成的，山羊是膜结合o -酰基转移酶（MBOAT）家族的新成员。迄今为止，山羊没有其他已知的功能，辛烷酰化似乎是胃饥饿素/山羊系统特有的修饰。GOAT的选择性，其定位于消化道而不是中枢神经系统，以及其在胃饥饿素成熟过程中的重要作用，使其成为药物开发计划的主要候选酶。最近的一份报告描述了一种具有体内活性的山羊肽抑制剂，进一步证实了这一观点。GO-CoA-Tat是一种“双底物”模拟物，可降低小鼠循环胃饥饿素水平，减少喂食高脂肪饮食的小鼠体重增加，并提高野生型动物的葡萄糖耐受性。然而，在饮食诱导或遗传性肥胖的情况下，长期抑制GOAT可能改善胰岛素敏感性的假设尚未得到验证。在与德克萨斯大学西南医学中心的Michael Brown和Joseph Goldstein的合作中，我们发现了在体外强烈抑制GOAT的小肽模拟物。这些化合物比其他已知的抑制剂更有效，并且明显比GO-CoATat更像药物。我们建议进一步完善这些铅结构以用于体内。在啮齿类动物疾病模型中，保留靶标效力并具有良好药代动力学特征的分子将被彻底评估。通过这些研究，我们将在动物模型中确定GOAT抑制剂是否代表一种治疗代谢性疾病的新策略。本实验将为今后针对GOAT在人类药物治疗中的转化研究奠定基础。

DESCRIPTION (provided by applicant): Rising rates of obesity and type II diabetes are a pervasive threat to health and healthcare in the United States. Numerous means to counter the trend are being explored. These include lifestyle changes, bariatric surgeries and pharmaceuticals. Among the latter, numerous drug candidates have failed to meet efficacy and/or safety criteria - often because of unanticipated side effects associated with targeting complex receptor systems in the brain. We propose studies to validate a new enzyme target in the stomach. This enzyme functions outside of the central nervous system. Ghrelin is a peptide hormone secreted by X/A cells in the gastric mucosa. In humans, systemic administration of ghrelin promotes feeding and blocks release of insulin from pancreatic �-cells. Ghrelin matures from a 117-amino acid precursor, and gains its endocrine functions only when acylated on Ser-3 with octanoate. Data show this modification is performed by ghrelin O-acyl transferase (GOAT), a newly discovered member of the membrane bound O-acyl transferase (MBOAT) family of enzymes. To date, GOAT has no other known functions, and octanoylation appears to be a modification unique to the ghrelin/GOAT system. The selectivity of GOAT, its localization to the digestive tract rather than the central nervous system, and its essential role in ghrelin maturatio make the enzyme a prime candidate for drug discovery programs. A recent report describing a peptide inhibitor of GOAT with activity in vivo furthers this view. GO-CoA-Tat, a 'bi-substrate' mimetic, decreases circulating ghrelin levels in mice, reduces weight gain in mice fed a high fat diet, and improves glucose tolerance in wild type animals. The hypothesis that chronic inhibition of GOAT may improve insulin sensitivity in the setting of diet-induced or genetic obesity, however, has not been tested. In collaboration with Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center, we have discovered small peptidomimetics that strongly inhibit GOAT in vitro. These compounds are orders of magnitude more potent than other known inhibitors, and are markedly more drug-like than GO-CoATat. We propose to further refine these lead structures for use in vivo. Molecules that retain potency at the target and possess favorable pharmacokinetic profiles will be thoroughly evaluated in rodent disease models. Through these studies we will ascertain whether GOAT inhibitors represent a new strategy for treating metabolic disease in animal models. The experiments will lay a foundation for future translational studies aimed at targeting GOAT in human drug therapy.