Iyer Malliga R, Wood Casey M, Kunos George
Medicinal Chemistry Core and Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIAAA/NIH) , 5625 Fishers Lane , Rockville , MD 20852 , USA . Email:
RSC Med Chem. 2020 Sep 4;11(10):1136-1144. doi: 10.1039/d0md00210k. eCollection 2020 Oct 1.
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 -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.
胃饥饿素是一种由胃产生的肽激素，可刺激食欲。胃饥饿素要发挥其促食欲作用，该肠脑肽丝氨酸-3残基上的辛酰化至关重要。胃饥饿素的辛酰化由一种名为胃饥饿素酰基转移酶（GOAT）的独特酰基转移酶介导。因此，调节这种酶为改变进食行为提供了可行的方法。在过去十年中，出现了几种基于小分子的方法，用于发现能够调节这种酶以治疗肥胖症和2型糖尿病的化合物。学术团体和几家制药公司的药物研发工作已经筛选出了在动物模型中能有效改变酰化胃饥饿素水平的化合物，但迄今为止，调节GOAT酶活性的化合物尚未成为临床选择。这篇小型综述涵盖了自发现GOAT酶以来过去十年的药物研发方法。
