Designed Small Molecule Inhibitors of Ghrelin O-Acyl Transferase

描述（由申请人提供）：肥胖和II型糖尿病的发病率上升是对美国健康和医疗保健的普遍威胁。目前正在探讨各种办法来扭转这一趋势。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有效性和/或安全性标准-通常是因为与靶向大脑中的复杂受体系统相关的意外副作用。我们提出了一项研究，以验证一种新的酶在胃中的目标。这种酶在中枢神经系统之外发挥作用。Ghrelin是胃粘膜X/A细胞分泌的一种肽类激素。在人类中，全身施用ghrelin促进进食并阻断胰腺细胞释放胰岛素。Ghrelin由117个氨基酸的前体成熟，并且只有当Ser-3被辛酸酰化时才获得其内分泌功能。数据显示，这种修饰是由生长素O-酰基转移酶（GOAT），一个新发现的成员膜结合O-酰基转移酶（MBOAT）家族的酶。到目前为止，GOAT没有其他已知的功能，辛酰化似乎是ghrelin/GOAT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ghrelin成熟中的重要作用，使该酶成为药物发现计划的主要候选者。最近的一份报告描述了一种具有体内活性的GOAT肽抑制剂，进一步证实了这一观点。GO-CoA-达特是一种“双底物”模拟物，可降低小鼠循环中的饥饿素水平，减少高脂饮食喂养小鼠的体重增加，并改善野生型动物的葡萄糖耐量。然而，长期抑制GOAT可能改善饮食诱导或遗传性肥胖的胰岛素敏感性的假设尚未得到验证。与德克萨斯大学西南医学中心的Michael Brown和Joseph Goldstein合作，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有效几个数量级，并且比GO-CoATat明显更像药物。我们建议进一步完善这些铅结构用于体内。将在啮齿类动物疾病模型中彻底评价在靶点保持效力并具有有利药代动力学特征的分子。通过这些研究，我们将确定GOAT抑制剂是否代表了在动物模型中治疗代谢性疾病的新策略。这些实验将为将来在人类药物治疗中靶向GOAT的翻译研究奠定基础。

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.