Molecular Pharmacology of Sphingosine 1-Phosphate

描述(申请人提供)：1-磷酸鞘氨醇(SIP)是一种多效性脂质介质，最常见的与细胞迁移、细胞存活和血管生成有关。最近发现的新的鞘氨醇类药物FTY720是一种前体药物，在磷酸化后靶向S1P受体，这为S1P生物学提供了一个迷人的洞察力。FTY720治疗将淋巴细胞隔离在次级淋巴组织中，并远离发炎的周围组织和移植物部位。该药物在同种异体移植和自身免疫性疾病模型中都具有保护作用，在人类肾移植试验中被发现是安全有效的。重要的是，FTY720治疗的动物对系统性病毒感染具有抵抗力；如果在人类身上得到证实，这比现有的免疫抑制治疗方案具有显著的优势。然而，确切的分子靶点-激活的激酶、S1P受体类型和失活的磷酸酶-仍然没有确定。此外，FTY720也不是没有问题，即大约30%的患者在开始治疗时会经历一过性、无症状的心动过缓。因此，我们目前的目标可以简明扼要地表述为：(1)合成模拟FTY720引起的淋巴细胞隔离引起的淋巴细胞减少的鞘氨醇和S1P样化合物，(2)表征这些新的化学实体在单个S1P受体和代谢酶上的活性，以及(3)发现通过磷酸化激活FTY720和类似物的激酶。我们计划的优势是合成化学和分子药理学的结合-这种相互作用因目标蛋白的分子定义而得到加强，包括S1P受体和S1P磷酸水解酶。至少，我们的努力将极大地扩展关于S1P受体、磷酸酶和脂蛋白激酶的结构活性关系(SAR)的知识。最好的情况是，我们将发现新的FTY720-1ilike实体，具有更高的选择性和更低的毒性，我们还将发现更多的脂蛋白激酶。我们的工作还将导致发现S1P受体选择性拮抗剂和激动剂--事实上，我们已经发现了几种这样的化合物。这些药物将能够确定阻断或模仿S1P信号的影响，从而提供关于哪些额外的S1P信号通路可能是治疗干预的有效靶点的关键信息。

DESCRIPTION (provided by applicant): Sphingosine 1-phosphate (SIP) is a pleiotropic lipid mediator that is most commonly associated with cell migration, cell survival and vasculogenesis. The recent discovery that the novel sphingosine-like drug, FTY720, is a pro-drug that after phosphorylation targets S1P receptors provides a fascinating insight into S1P biology. FTY720 treatment sequesters lymphocytes in secondary lymphoid tissue and away from inflamed peripheral tissues and graft sites. The drug is protective in both allogenic transplant and autoimmune disease models and was found to be safe and effective in a human renal transplantation trial. Importantly, FTY720-treated animals are resistant to systemic viral infection; if confirmed in humans, this represents a striking advantage over existing immunosuppressive therapeutic regimens. However, the precise molecular targets - the activating kinase, the S1P receptor types and the inactivating phosphatase - remain undefined. Further, FTY720 is not without problems, i.e. about 30% of patients experience a transient, asymptomatic bradycardia with onset of therapy. Thus our present Aims can be stated succinctly as: (1) synthesize sphingosine-like and S1P-like compounds that mimic the FTY720- evoked lymphopenia due to lymphocyte sequestration, (2) characterize these new chemical entities regarding activity at individual S1P receptors and metabolic enzymes and (3) discover the kinase that activates FTY720 and like compounds by phosphorylation. The strength of our program is the combination of synthetic chemistry and molecular pharmacology - an interaction strengthened by the molecular definition of target proteins including the S1P receptors and S1P phosphohydrolases. Minimally, our efforts will extend significantly knowledge of the structure activity relationships (SAR) for S1P receptors, phosphatases and lipid kinases. Optimally, we will discover new FTY720-1ike entities with enhanced selectivity and lessened toxicity and we will discover additional lipid kinases. Our work will also lead to the discovery of S1P receptor selective antagonists and agonists - indeed we have already found several such compounds. These agents will enable a determination of the effects of blockage or mimicry of S1P signaling and thus provide crucial information as to what additional S1P signaling pathways might be valid targets for therapeutic intervention.