Fluorescent-based Probes for the Glutamate/Cystine Exchanger System Xc-

用于谷氨酸/胱氨酸交换系统 Xc- 的荧光探针

• 批准号: 7943003
• 负责人: RICHARD J. BRIDGES
• 金额: $ 21.01万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943003
• 关键词: Abbreviations; Amides; Amino Acid Transporter; Amino Acids; Aspartate; Attention; Biological Assay; Brain; Brain Neoplasms; Cells; Central Nervous System Diseases; Cocaine; Cysteine; Cystine; DL-TBOA; Development; Disease; Dose; Drug Addiction; Excitatory Amino Acids; Experimental Designs; Fluorescent Probes; Functional Imaging; Functional disorder; Glioma; Glutamate Dehydrogenase; Glutamate Receptor; Glutamates; Glutathione; Glycoproteins; Goals; Growth; Hand; Isoxazoles; Libraries; Link; Mediating; Metabotropic Glutamate Receptors; Molecular Probes; Montana; Movement; Names; Necrosis; PRTN3 gene; Pathologic Processes; Pathology; Pharmaceutical Preparations; Physiological; Physiological Processes; Positioning Attribute; Predisposition; Primary Brain Neoplasms; Property; Propionic Acids; Pyrrolidines; Reagent; Regulation; Relapse; Reporting; Research; Role; Screening procedure; Signal Transduction; Son of Sevenless Proteins; Source; Structure; Synaptic plasticity; System; Therapeutic Agents; Therapeutic Intervention; Tissues; Tyrosine; Universities; Viral; Withdrawal; addiction; analog; base; design; dicarboxylate; extracellular; fluorophore; high throughput screening; ibotenate; inhibitor/antagonist; migration; nervous system disorder; neurotransmitter release; operation; presynaptic; prevent; public health relevance; pyrrolidine; quisqualate; receptor; response; serine O-sulfate; small molecule; therapeutic target; transmission process; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): The goal of this project is to develop small molecule fluorescent probes for a transporter that is becoming increasingly recognized as a relevant physiological and therapeutic target, the glutamate/cystine transporter system Xc- (SXc-). Based upon its normal operation as an obligate exchanger, SXc- links the import of L-cystine (L-Cys2) with the export of L-Glu. The uptake of L-Cys2 is critical to glutathione (GSH) synthesis and oxidative protection, while the efflux of L-Glu represents a point source through which this excitatory transmitter could contribute to either signaling or excitotoxic pathology. SXc- has been linked to a number of important physiological processes in the CNS, including: presynaptic regulation of neurotransmitter release, receptor organization, synaptic plasticity, and oxidative protection. More recently, however, the export of L-Glu through SXc- has garnered considerable attention because of its association (and potential for therapeutic intervention) with two seemingly disparate pathological processes: brain tumor growth and drug addiction. Unfortunately, our growing appreciation for the potential roles of SXc- in these and other neurological disorders, as well as in normal CSN function, has rapidly outpaced the availability of pharmacological reagents and probes with which to assess or modify its activity. During the course of ongoing SAR studies on SXc- we have found that the addition of large lipophilic groups (including fluorophores) to specific positions on known inhibitors are not only tolerated by the transporter, but actually produce an increase inhibitory potency. In this project we will prepare a library of probes in which the fluorophore, tether and linkage will be systematically varied on three proven SXc- inhibitor/substrate templates. The proposed optimization of compounds and associated assay conditions should yield fluorescent probes of SXc- with considerable utility in an array of applications that range from pharmacological screenings via high-throughput assays to functional imaging in normal and pathological tissues. PUBLIC HEALTH RELEVANCE: The system Xc- transporter regulates the movement of two important amino acids into and out of cells in the brain: L-glutamate and L-cystine. The function and/or dysfunction of this transporter has been linked with a number of CNS disorders, including: addiction, tumor growth, and viral pathology. This project will develop fluorescent molecular probes for system Xc- that will advance our understanding of its roles in these disorders, as well as enhance the development of therapeutic agents with which to regulate its activity.

描述(申请人提供)：该项目的目标是开发一种小分子荧光探针，用于日益被认为是相关生理和治疗靶点的转运体，谷氨酸/胱氨酸转运体系统XC-(SXC-)。基于其作为专用交易所的正常运作，SXC将L-胱氨酸(L-Cys2)的进口与L-Glu的出口挂钩。L-Cys2的摄取对谷胱甘肽的合成和氧化保护至关重要，而L-谷氨酸的外流则是兴奋性递质参与信号转导或兴奋性毒性病理的一个点源。SXC-与中枢神经系统中许多重要的生理过程有关，包括：突触前调节神经递质释放、受体组织、突触可塑性和氧化保护。然而，最近，L(通过SXC出口谷氨酸)引起了相当大的关注，因为它与两个看似截然不同的病理过程有关(以及潜在的治疗干预)：脑瘤生长和药物成瘾。不幸的是，我们对SXC-在这些和其他神经疾病以及正常的CSN功能中的潜在作用的日益认识，已经迅速超过了可用于评估或修改其活性的药理试剂和探针的可用性。在对SXC进行的SAR研究过程中-我们发现，在已知抑制剂的特定位置添加大的亲脂基团(包括荧光团)不仅被转运蛋白耐受，而且实际上产生了增强的抑制效力。在这个项目中，我们将准备一个探针库，其中荧光团、系绳和连接将在三个已证实的SXC-抑制剂/底物模板上系统地变化。拟议的化合物和相关分析条件的优化将产生SXC的荧光探针-在从通过高通量分析进行药理筛选到正常和病理组织的功能成像的一系列应用中具有相当大的实用价值。 与公共健康相关：XC转运体系统调节两种重要氨基酸的进出大脑细胞：L-谷氨酸和L-胱氨酸。这种转运蛋白的功能和/或功能障碍与许多中枢神经系统疾病有关，包括：成瘾、肿瘤生长和病毒病理。该项目将为XC系统开发荧光分子探针，这将促进我们对其在这些疾病中的作用的了解，并加强用于调节其活性的治疗剂的开发。