Marciniak Alexander, Camp Sara M, Garcia Joe G N, Polt Robin
Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, United States.
Department of Medicine, The University of Arizona, Tucson, AZ 85724, United States.
Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3585-3591. doi: 10.1016/j.bmcl.2018.10.042. Epub 2018 Oct 26.
Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein-coupled receptor (GPCR) in an attempt to suppress autoimmune disorders. FTY720, also known as fingolimod, is the first oral disease-modifying therapy for MS on the market. In pursuit of improved stability, bioavailability, and efficiency, structural analogues of this initial prodrug have emerged over time. This review covers a brief introduction to the sphingolipid metabolism, the mechanism of action on S1P, and an updated overview of synthetic sphingosine S1P agonists.
鞘脂是所有真核生物中一类重要的脂质，对细胞信号转导有强烈影响。哮喘和多发性硬化症（MS）等自身免疫性疾病是由1-磷酸鞘氨醇受体1（S1P）介导的，表现出各种症状和疾病模式。受其天然底物的启发，人们开发了一系列人工鞘脂衍生物来靶向这种特定的G蛋白偶联受体（GPCR），试图抑制自身免疫性疾病。FTY720，也称为芬戈莫德，是市场上第一种用于治疗MS的口服疾病改善疗法。随着时间的推移，为了追求更高的稳定性、生物利用度和效率，这种初始前药的结构类似物不断涌现。本文综述了鞘脂代谢的简要介绍、对S1P的作用机制以及合成鞘氨醇S1P激动剂的最新概述。
