Ascomycete derivative to MS therapeutic: S1P receptor modulator FTY720.

Peter C Hiestand, Martin Rausch, Daniela Piani Meier, Carolyn A Foster
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引用次数: 23

Abstract

Fingolimod (FTY720) represents the first in a new class of immune-modulators whose target is sphingosine-1-phosphate (S1P) receptors. It was first identified by researchers at Kyoto University and Yoshitomi Pharmaceutical as a chemical derivative of the ascomycete metabolite ISP-1 (myriocin). Unlike its natural product parent, FTY720 does not interfere with sphingolipid biosynthesis. Instead, its best characterized mechanism of action upon in vivo phosphorylation, leading to the active principle FTY720-P, is the rapid and reversible inhibition of lymphocyte egress from peripheral lymph nodes. As a consequence of S1P1 receptor internalization, tissue-damaging T-cells can not recirculate and infiltrate sites of inflammation such as the central nervous system (CNS). Furthermore, FTY720-P modulation of S1P receptor signaling also enhances endothelial barrier function. Due to its mode of action, FTY720 effectively prevents transplant rejection and is active in various autoimmune disease models. The most striking efficacy is in the multiple sclerosis (MS) model of experimental autoimmune encephalomyelitis, which has now been confirmed in the clinic. FTY720 demonstrated promising results in Phase II trials and recently entered Phase III in patients with relapsing MS. Emerging evidence suggests that its efficacy in the CNS extends beyond immunomodulation to encompass other aspects of MS pathophysiology, including an influence on the blood-brain-barrier and glial repair mechanisms that could ultimately contribute to restoration of nerve function. FTY720 may represent a potent new therapeutic modality in MS, combined with the benefit of oral administration.

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用于多发性硬化治疗的子囊菌衍生物:S1P受体调节剂FTY720。
Fingolimod (FTY720)是一类以鞘氨醇-1-磷酸(S1P)受体为靶点的新型免疫调节剂中的第一种。它最初是由京都大学和吉友制药的研究人员确定为子囊菌代谢物ISP-1(肉豆蔻素)的化学衍生物。与其天然产物母体不同,FTY720不干扰鞘脂的生物合成。相反,FTY720-P在体内磷酸化作用的最佳特征机制是快速可逆地抑制淋巴细胞从周围淋巴结的流出,从而导致FTY720-P的活性原理。由于S1P1受体内化,组织损伤t细胞不能再循环和浸润炎症部位,如中枢神经系统(CNS)。此外,FTY720-P对S1P受体信号的调节也增强了内皮屏障功能。由于其作用方式,FTY720有效地预防移植排斥反应,并在多种自身免疫性疾病模型中活跃。最显著的疗效是在实验性自身免疫性脑脊髓炎的多发性硬化症(MS)模型中,目前已在临床得到证实。FTY720在II期试验中显示出良好的结果,最近在复发性多发性硬化症患者中进入了III期试验。新证据表明,FTY720对中枢神经系统的疗效不仅包括免疫调节,还包括多发性硬化症病理生理的其他方面,包括对血脑屏障和神经胶质修复机制的影响,最终有助于神经功能的恢复。FTY720结合口服给药的益处,可能代表一种强有力的MS新治疗方式。
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