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（由申请人提供）：该项目的目标是为谷氨酸/胱氨酸转运体系统Xc- (SXc-)开发小分子荧光探针，该转运体越来越被认为是相关的生理和治疗靶点。基于其正常的交换作用，SXc-将l -胱氨酸（L-Cys2）的进口与L-Glu的出口联系起来。L-Cys2的摄取对谷胱甘肽（GSH）的合成和氧化保护至关重要，而L-Glu的外排是一个点源，通过该点源，这种兴奋性递质可能有助于信号传导或兴奋性毒性病理。SXc-与中枢神经系统中许多重要的生理过程有关，包括：神经递质释放的突触前调节、受体组织、突触可塑性和氧化保护。然而，最近，通过SXc-出口L-Glu已经引起了相当大的关注，因为它与两种看似不同的病理过程：脑肿瘤生长和药物成瘾有关（以及潜在的治疗干预）。不幸的是，我们对SXc-在这些和其他神经疾病以及正常CSN功能中的潜在作用的日益认识，已经迅速超过了用于评估或修改其活性的药理学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亲脂基团（包括荧光团）不仅可以被转运体耐受，而且实际上可以产生增强的抑制效能。在这个项目中，我们将准备一个探针库，其中荧光团，系链和链接将在三种已证实的SXc-抑制剂/底物模板上系统地变化。提出的化合物优化和相关的分析条件应该产生SXc荧光探针-在一系列应用中具有相当大的实用性，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。