Mullershausen Florian, Zecri Frédéric, Cetin Cihan, Billich Andreas, Guerini Danilo, Seuwen Klaus
Developmental & Molecular Pathways and 2Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
Nat Chem Biol. 2009 Jun;5(6):428-34. doi: 10.1038/nchembio.173.
Targeting sphingosine-1-phosphate receptors with the oral immunomodulator drug FTY720 (fingolimod) has demonstrated substantial efficacy in the treatment of multiple sclerosis. The drug is phosphorylated in vivo, and most of the clinical effects of FTY720-phosphate (FTY720P) are thought to be mediated via S1P1 receptors on lymphocytes and endothelial cells, leading to sequestration of lymphocytes in secondary lymphoid organs. FTY720P was described to act as a "functional antagonist" by promoting efficient internalization of S1P1 receptors. We demonstrate here that S1P1 receptors activated by FTY720P retain signaling activity for hours in spite of a quantitative internalization. Structural analogs of FTY720P with shorter alkyl side chains retained potency and efficacy in a functional assay but failed to promote long-lasting receptor internalization and signaling. We show that persistent signaling translates into an increased chemokinetic migration of primary human umbilical vein endothelial cells, which suggests persistent agonism as a crucial parameter in the mechanism of action of FTY720.
口服免疫调节剂药物FTY720（芬戈莫德）靶向鞘氨醇-1-磷酸受体已在治疗多发性硬化症中显示出显著疗效。该药物在体内被磷酸化，并且磷酸化的FTY720（FTY720P）的大多数临床作用被认为是通过淋巴细胞和内皮细胞上的S1P1受体介导的，导致淋巴细胞滞留在二级淋巴器官中。FTY720P被描述为通过促进S1P1受体的有效内化而作为“功能性拮抗剂”起作用。我们在此证明，尽管FTY720P激活的S1P1受体发生了定量内化，但仍保持数小时的信号传导活性。具有较短烷基侧链的FTY720P结构类似物在功能测定中保留了效力和功效，但未能促进持久的受体内化和信号传导。我们表明，持续的信号传导转化为原代人脐静脉内皮细胞趋化运动的增加，这表明持续激动是FTY720作用机制中的关键参数。
