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）：本项目的目标是开发转运蛋白的小分子荧光探针，该转运蛋白越来越被认为是相关的生理和治疗靶点，即谷氨酸/胱氨酸转运蛋白系统Xc-（SXc-）。基于其作为专性交换剂的正常操作，SXC-将L-胱氨酸（L-Cys 2）的输入与L-Glu的输出连接起来。L-Cys 2的摄取对谷胱甘肽（GSH）合成和氧化保护至关重要，而L-Glu的流出代表了一个点源，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-与中枢神经系统中的许多重要生理过程有关，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，L-Glu通过SXc-的输出已经引起了相当大的关注，因为它与两个看似不同的病理过程相关（以及治疗干预的潜力）：脑肿瘤生长和药物成瘾。不幸的是，我们对SXc-在这些和其他神经系统疾病以及正常CSN功能中的潜在作用的日益增长的认识，已经迅速超过了用于评估或改变其活性的药理学试剂和探针的可用性。在对SXc进行SAR研究的过程中，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）不仅能被转运蛋白耐受，而且实际上会增加抑制效力。在这个项目中，我们将准备一个探针库，其中荧光团，系链和连接将系统地改变三个证明SXC-抑制剂/底物模板。所提出的化合物和相关的测定条件的优化应产生SXC的荧光探针-在一系列应用中具有相当大的实用性，这些应用的范围从通过高通量测定的药理学筛选到正常和病理组织中的功能成像。 公共卫生关系：系统XC-转运蛋白调节两种重要氨基酸进出脑细胞的运动：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CNS疾病有关，包括：成瘾、肿瘤生长和病毒病理学。该项目将开发系统XC的荧光分子探针，这将促进我们对其在这些疾病中的作用的理解，并促进调节其活性的治疗剂的开发。