Sphingosine 1-phosphate receptor 1 as a useful target for treatment of multiple sclerosis.
Sphingosine 1-phosphate receptor 1 as a useful target for treatment of multiple sclerosis.
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DOI：
10.3390/ph5050514
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发表时间：
2012-05-18
期刊：
影响因子：
--
通讯作者：
Adachi K
中科院分区：
文献类型：
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作者：
Chiba K;Adachi K
1-磷酸鞘氨醇 (S1P) 是一种溶血磷脂介质，由鞘氨醇激酶从鞘氨醇生成，并结合五种已知的细胞表面受体。 S1P 受体 1 (S1P1) 在淋巴细胞从次级淋巴器官 (SLO) 排出的过程中发挥重要作用，缺乏淋巴细胞 S1P1 的小鼠淋巴细胞无法从 SLO 排出就证明了这一点。盐酸芬戈莫德 (FTY720) 是一种一流的、口服活性的 S1P 受体调节剂，其结构与鞘氨醇密切相关。 FTY720首先是通过对天然产物多球壳菌素进行化学修饰而合成的。 FTY720 通过鞘氨醇激酶有效转化为活性代谢物 FTY720 磷酸盐 (FTY720-P)。 FTY720-P 对 4 种 S1P 受体（S1P1、S1P3、S1P4 和 S1P5）表现出高亲和力。特别是，FTY720-P 强烈诱导 S1P1 的内化和降解，抑制 SLO 中淋巴细胞的 S1P 反应性，并充当淋巴细胞 S1P1 的功能拮抗剂。因此，FTY720 抑制 S1P1 依赖性淋巴细胞从 SLO 流出，以减少包括自身反应性 Th17 细胞在内的淋巴细胞循环，并且在实验性自身免疫性脑脊髓炎 (EAE)（一种多发性硬化症 (MS) 动物模型）中非常有效。由于与肌内注射干扰素-β-1a (Avonex®) 相比，FTY720 在复发缓解型多发性硬化症患者中显示出更优异的疗效，因此 S1P1 被认为是治疗多发性硬化症的有用靶点。
Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P1) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), as evinced by the inability of lymphocytes to exit from the SLO in mice lacking lymphocytic S1P1. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active, S1P receptor modulator with a structure closely related to sphingosine. FTY720 was first synthesized by chemical modification of a natural product, myriocin. FTY720 is effectively converted to an active metabolite, FTY720 phosphate (FTY720-P) by sphingosine kinases. FTY720-P shows high affinity to 4 of the S1P receptors (S1P1, S1P3, S1P4, and S1P5). In particular, FTY720-P strongly induces internalization and degradation of S1P1, inhibits S1P responsiveness of lymphocytes in the SLO, and acts as a functional antagonist at lymphocytic S1P1. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from the SLO to decrease circulation of lymphocytes including autoreactive Th17 cells and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Because FTY720 shows a superior efficacy in relapsing remitting MS patients compared to intramuscular interferon-β-1a (Avonex®), S1P1 is presumed to be a useful target for the therapy of MS.