Molecular Pharmacology of Sphingosine 1-Phosphate

描述（由申请人提供）：1-磷酸鞘氨醇（SIP）是一种多效性脂质介质，通常与细胞迁移、细胞存活和血管生成相关。最近发现，新型鞘氨醇样药物FTY 720是一种前药，磷酸化后靶向S1 P受体，这为S1 P生物学提供了一个迷人的见解。FTY 720治疗隔离次级淋巴组织中的淋巴细胞，使其远离发炎的外周组织和移植部位。该药物在同种异体移植和自身免疫性疾病模型中均具有保护作用，并在人类肾移植试验中发现安全有效。重要的是，FTY 720治疗的动物对全身性病毒感染具有抗性;如果在人类中得到证实，这代表了比现有免疫抑制治疗方案的显著优势。然而，精确的分子靶点-活化激酶，S1 P受体类型和失活磷酸酶-仍然不确定。此外，FTY 720并非没有问题，即约30%的患者在治疗开始时经历短暂的无症状心动过缓。因此，我们目前的目的可以简单地表述为：（1）合成鞘氨醇样和S1 P样化合物，其模拟由于淋巴细胞隔离引起的FTY 720诱发的淋巴细胞减少症，（2）表征这些新的化学实体对单个S1 P受体和代谢酶的活性，以及（3）发现通过磷酸化激活FTY 720和类似化合物的激酶。我们计划的优势是合成化学和分子药理学的结合-通过靶蛋白的分子定义加强的相互作用，包括S1 P受体和S1 P磷酸水解酶。最低限度，我们的努力将扩大显着的S1 P受体，磷酸酶和脂质激酶的结构活性关系（SAR）的知识。最理想的是，我们将发现新的FTY 720样实体，具有增强的选择性和降低的毒性，我们将发现其他脂质激酶。我们的工作还将导致S1 P受体选择性拮抗剂和激动剂的发现-事实上，我们已经发现了几种这样的化合物。这些试剂将能够确定S1 P信号传导的阻断或模拟的影响，从而提供关于哪些额外的S1 P信号传导途径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.