Recent progress in the discovery of ghrelin O-acyltransferase (GOAT) inhibitors,RSC Medicinal Chemistry

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Recent progress in the discovery of ghrelin O-acyltransferase (GOAT) inhibitors
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-09-04 , DOI: 10.1039/d0md00210k
Malliga R Iyer ₁ , Casey M Wood ₁ , George Kunos ₁

Affiliation

Ghrelin is a stomach-derived peptide hormone which stimulates appetite. For ghrelin to exert its orexigenic effect, octanoylation on the serine-3 residue of this gut–brain peptide is essential. The octanoylation of ghrelin is mediated by a unique acyltransferase enzyme known as ghrelin O-acyltransferase (GOAT). Thus modulating this enzyme offers viable approaches to alter feeding behaviors. Over the past decade, several small-molecule based approaches have appeared dealing with the discovery of compounds able to modulate this enzyme for the treatment of obesity and type 2 diabetes. Drug discovery efforts from academic groups and several pharmaceutical companies have fielded compounds having efficacy in altering acylated ghrelin levels in animal models but to date, compounds modulating the activity of the GOAT enzyme do not yet represent clinical options. This mini-review covers the drug discovery approaches of the last decade since the discovery of the GOAT enzyme.

中文翻译：

生长素释放肽O-酰基转移酶（GOAT）抑制剂的发现最新进展

生长素释放肽是一种胃源性肽激素，可刺激食欲。为了使生长素释放肽发挥其促进食欲的作用，这种肠脑肽的丝氨酸 3 残基的辛酰化是必不可少的。生长素释放肽的辛酰化是由一种称为生长素释放肽O-酰基转移酶 (GOAT) 的独特酰基转移酶介导的。因此，调节这种酶提供了改变进食行为的可行方法。在过去的十年中，出现了几种基于小分子的方法，旨在发现能够调节这种酶的化合物，以治疗肥胖和 2 型糖尿病。学术团体和多家制药公司的药物发现工作已经开发出了能够有效改变动物模型中酰化生长素释放肽水平的化合物，但迄今为止，调节 GOAT 酶活性的化合物尚未代表临床选择。这篇简短的评论涵盖了自 GOAT 酶发现以来过去十年的药物发现方法。

更新日期：2020-09-05

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