Sayama Misa, Uwamizu Akiharu, Ikubo Masaya, Chen Luying, Yan Ge, Otani Yuko, Inoue Asuka, Aoki Junken, Ohwada Tomohiko
Department of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Med Chem. 2021 Jul 22;64(14):10059-10101. doi: 10.1021/acs.jmedchem.1c00347. Epub 2021 Jul 7.
Three human G protein-coupled receptors (GPCRs)-GPR34/LPS, P2Y10/LPS, and GPR174/LPS-are activated specifically by lysophosphatidylserine (LysoPS), an endogenous hydrolysis product of a cell membrane component, phosphatidylserine (PS). LysoPS consists of l-serine, glycerol, and fatty acid moieties connected by phosphodiester and ester linkages. We previously generated potent and selective GPCR agonists by modification of the three modules and the ester linkage. Here, we show that a novel modification of the hydrophilic serine moiety, that is, N-acylations of the serine amine, converted a GPR174 agonist to potent GPR174 antagonists. Structural exploration of the amide functionality provided access to a range of activities from agonist to partial agonist to antagonist. The present study would provide a new strategy for the development of lysophospholipid receptor antagonists.
三种人类G蛋白偶联受体（GPCRs）——GPR34/LPS、P2Y10/LPS和GPR174/LPS——被溶血磷脂酰丝氨酸（LysoPS）特异性激活，LysoPS是细胞膜成分磷脂酰丝氨酸（PS）的内源性水解产物。LysoPS由通过磷酸二酯键和酯键连接的L-丝氨酸、甘油和脂肪酸部分组成。我们之前通过修饰这三个模块和酯键生成了强效且选择性的GPCR激动剂。在此，我们表明对亲水性丝氨酸部分的一种新型修饰，即丝氨酸胺的N-酰化，将GPR174激动剂转化为强效的GPR174拮抗剂。对酰胺官能团的结构探索提供了从激动剂到部分激动剂再到拮抗剂的一系列活性。本研究将为溶血磷脂受体拮抗剂的开发提供一种新策略。
