Designed Small Molecule Inhibitors of Ghrelin O-Acyl Transferase

描述(由申请人提供)：肥胖率和II型糖尿病的上升是对美国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。这些措施包括改变生活方式、减肥手术和制药。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的受体系统有关的意想不到的副作用。我们建议进行研究，以验证胃中一种新的酶靶点。这种酶在中枢神经系统之外发挥作用。Ghrelin是一种由胃粘膜X/A细胞分泌的多肽类激素。在人类中，全身服用Ghrelin可以促进摄食，并阻止胰腺�细胞释放胰岛素。Ghrelin由117个氨基酸组成的前体成熟，只有在Ser-3上与辛酸酰化后才能获得内分泌功能。资料表明，这种修饰是由Ghrelin O-酰基转移酶(山羊)完成的，它是膜结合O-酰基转移酶(MBOAT)家族中新发现的成员。到目前为止，山羊没有其他已知的功能，辛酰化似乎是Ghrelin/山羊系统独有的修饰。山羊的选择性，它对消化道而不是中枢神经系统的定位，以及它在Ghrelin成熟过程中的关键作用，使该酶成为药物发现计划的首选候选药物。最近的一份报告描述了一种具有体内活性的山羊多肽抑制剂，进一步支持了这一观点。Go-CoA-Tat是一种‘双底物’模拟物，可以降低小鼠循环中的Ghrelin水平，减少高脂饮食小鼠的体重增加，并改善野生动物的葡萄糖耐量。然而，在饮食诱导或遗传性肥胖的背景下，长期抑制山羊可能会改善胰岛素敏感性的假设尚未得到检验。在与德克萨斯大学西南医学中心的迈克尔·布朗和约瑟夫·戈尔茨坦的合作下，我们发现了在体外对山羊有强烈抑制作用的小肽仿制药。这些化合物比其他已知的抑制剂效力大几个数量级，而且明显比Go-Coatat更像药物。我们建议进一步改进这些铅结构，以便在体内使用。在靶点保持效力并具有良好药代动力学特征的分子将在啮齿动物疾病模型中进行彻底评估。通过这些研究，我们将确定山羊抑制剂是否代表了一种在动物模型中治疗代谢性疾病的新策略。这些实验将为未来在人类药物治疗中针对山羊的转译研究奠定基础。

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.