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Controlling sphingosine 1-phosphate synthesis and trafficking

控制 1-磷酸鞘氨醇的合成和运输

基本信息

批准号：
9330886
负责人：
KEVIN R. LYNCH
金额：
$ 52.77万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330886
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adrenergic alpha-Antagonists Agonist Animal Model Autoimmune Diseases Bioavailable Biological Assay Biological Availability Biology Blood Blood Vessels Bradycardia Cells Chemicals Chemistry Clinic Clinical Trials Computer Simulation Crystallization Data Development Disease Disease Progression Disease model Docking Dose Drug Kinetics Drug Targeting Endothelial Cells Erythrocytes G-Protein-Coupled Receptors Goals Hematopoietic Stem Cell Mobilization Homology Modeling Human Immune Immune response Immunosuppressive Agents Injury Isoenzymes Kidney Kidney Diseases Lead Leukocytes Libraries Ligands Liquid substance Lymph Lymphocyte Lymphoid Lymphoid Tissue Malignant Neoplasms Mediating Mediator of activation protein Medicine Methanol Methods Molecular Multiple Sclerosis Mus Oral Organ Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Plasma Prodrugs Productivity Property Pyrrolidines Resolution Rodent Route Sepsis Sickle Cell Sickle Cell Anemia Signal Transduction Signaling Molecule Structure Structure-Activity Relationship Synthesis Chemistry Testing Therapeutic Therapeutic Agents Tissues Validation Virus Diseases Work X-Ray Crystallography base design edg-1 Protein efficacy testing extracellular human disease immune function immunoregulation improved in vivo inhibitor/antagonist insight macular edema mouse model multiple sclerosis patient nanomolar novel novel therapeutic intervention prevent programs scaffold sphingosine 1-phosphate sphingosine kinase structural biology synergism targeted agent tool trafficking

项目摘要

Sphingosine kinases (SphK1, SphK2) catalyze the formation of an important extracellular mediator, sphingosine 1-phosphate (S1P). A fundamental aspect of S1P biology is the large difference in S1P abundance between blood or lymph (high) and tissue (low), which is termed the S1P vascular gradient. This gradient maintains vascular endothelial barrier function and facilitates lymphocyte mobilization from lymphoid tissues. Indeed, S1P1 receptor agonist drugs (e.g. fingolimod) are therapeutically beneficial because S1P signaling is highly sensitive to changes in S1P gradient. We used our SphK2 inhibitors to demonstrate that interdicting S1P signaling at the level of synthesis steepens the S1P vascular gradient by slowing S1P clearance from the blood. This result suggests that SphK2 inhibitors will be extremely useful in treating conditions where the endothelial barrier is compromised, e.g. acute kidney injury and sepsis. Although our recently discovered SphK2 inhibitors are active in vivo, improvements in potency, oral availability and chemical diversity are needed to advance them to the clinic. We will accomplish these goals by generating additional inhibitors on our current chemical scaffold and by developing a novel second scaffold. The current scaffold has also yielded a few SphK1 inhibitors but these lack potency at mouse SphK1, which precludes their testing for efficacy in some key disease models. In contrast to SphK2, inhibition of Sphk1 decreases the S1P vascular gradient and to probe the resulting physiological consequences, multiple inhibitors are needed. We will use iterative rounds of synthesis and testing to generate a library of SphK1 inhibitors with emphases on increasing their potency at mouse SphK1 and discovering inhibitors that have suitable pharmacokinetic properties in rodents. To understand the molecular mechanism of SphK inhibition as well as to inform the synthetic chemistry strategies, we will solve the structures of both isozymes with bound inhibitors using X-ray crystallography. Finally, we will discover a blocker of the S1P exporter, SPNS2, which provides the S1P to lymph and thereby maintains the S1P vascular gradient that is required for lymphocyte egress from lymphoid organs to lymph. Currently, due to the unavailability of SPNS2 inhibitors, this particular approach to the manipulation of S1P gradient and subsequent immunomodulation remains completely unexplored. The strength of our program is the synergism in the combination of chemistry (Santos) and pharmacology (Lynch) to which we now add structural biology (Faham). Our central theme of is to understand the therapeutic potential of manipulating the S1P gradients either at the level of synthesis (SphK inhibition) or transport (SPNS2 blockade). We have a track record of productivity that enabled a fundamental insight into S1P biology, e.g. our discovery that SphK2 inhibition modulates S1P signaling to protect endothelial function, a new therapeutic strategy. Now, we propose the development and detailed characterization of greatly improved SphK inhibitors and to make the chemical tools necessary to interrogate SPNS2 as a potential drug target.

鞘氨醇激酶（SphK 1，SphK 2）催化重要的细胞外介质的形成， 1-磷酸鞘氨醇（S1 P）。S1 P生物学的一个基本方面是S1 P的巨大差异血液或淋巴（高）和组织（低）之间的丰度，这被称为S1 P血管梯度。这梯度维持血管内皮屏障功能，促进淋巴细胞从淋巴细胞动员组织中实际上，S1 P1受体激动剂药物（例如芬戈莫德）是治疗有益的，因为S1 P 信号传导对S1 P梯度的变化高度敏感。我们使用SphK 2抑制剂证明，在合成水平阻断S1 P信号通过减慢S1 P而使S1 P血管梯度变陡从血液中清除。这一结果表明，SphK 2抑制剂将在治疗中非常有用。内皮屏障受损的病症，例如急性肾损伤和脓毒症。虽然我们的最近发现的SphK 2抑制剂在体内是有活性的，在效力、口服利用度和化学性质方面都有改善，需要多样性来推动他们进入诊所。我们将通过创造更多的机会来实现这些目标。抑制剂在我们当前的化学支架上，并通过开发新型的第二支架。目前的脚手架也产生了一些SphK 1抑制剂，但这些抑制剂对小鼠SphK 1缺乏效力，这妨碍了它们的测试在一些关键疾病模型中的疗效。与SphK 2相反，Sphk 1的抑制降低了S1 P血管紧张素Ⅱ的表达。梯度和探测产生的生理后果，需要多种抑制剂。我们将使用迭代合成和测试，以生成SphK 1抑制剂库，重点是增加它们对小鼠SphK 1的效力，并发现具有合适的药代动力学特性的抑制剂，啮齿动物为了了解SphK抑制的分子机制，并为合成SphK提供信息，化学策略，我们将解决这两种同工酶的结构与结合抑制剂使用X射线结晶学最后，我们将发现S1 P导出器SPNS 2的拦截器，它将S1 P提供给淋巴，从而维持淋巴细胞从淋巴细胞中流出所需的S1 P血管梯度。器官转移到淋巴目前，由于SPNS 2抑制剂的不可用，这种特定的方法， S1 P梯度的操作和随后的免疫调节仍然完全未被探索。的我们项目的优势在于化学（桑托斯）和药理学（林奇）的协同作用我们现在加入结构生物学（Faham）。我们的中心主题是理解治疗在合成（SphK抑制）或转运水平操纵S1 P梯度的潜力（SPNS 2阻断）。我们有生产力的跟踪记录，可以从根本上洞察S1 P 生物学，例如，我们发现SphK 2抑制调节S1 P信号传导以保护内皮功能，这是一种新的治疗策略现在，我们提出的发展和详细的表征大大改善 SphK抑制剂，并使必要的化学工具来询问SPNS 2作为一个潜在的药物靶点。