Molecular Pharmacology of the System xc- Glutamate/Cystine Antiporter

xc-谷氨酸/胱氨酸逆向转运蛋白系统的分子药理学

基本信息

批准号：
8771097
负责人：
RICHARD J. BRIDGES
金额：
$ 41.55万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771097
关键词：
2,4-Dinitrophenol Abbreviations Address Allosteric Site Amides Amino Acid Transporter Amino Acids Binding Binding Sites Brain Neoplasms Carboxylic Acids Cations Central Nervous System Diseases Collaborations Cysteine Cystine Data Development Dinitrophenols Drug Addiction Excitatory Amino Acids Glutamate Receptor Glutamates Glutathione Goals Hydrazones Isoxazoles Lead Link Mediating Modeling Molecular Montana Names Neurotransmitters PRTN3 gene Pathology Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Polyamines Process Propionic Acids Relapse Research Series Signal Transduction Specificity Structure Sulfasalazine Synapses Synaptic plasticity System Therapeutic Intervention Tyrosine Universities analog antiporter base chemical property design ibotenate inhibitor/antagonist novel pharmacophore prototype public health relevance quisqualate scaffold small molecule therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to advance the discovery and development of novel inhibitors of the system xc- glutamate/cystine antiporter (Sxc-), specifically targeting a newly identified allosteric site on the transporter. Sxc- is an obligate exchanger that links the import of L-cystine (L-Cys2) with the export of L-glutamate (L-Glu). Sxc- function is particularly critical in the CNS, as it mediates the uptake of a vital sulfu-containing amino acid needed for glutathione (GSH) synthesis and oxidative protection, while simultaneously producing an efflux of an excitatory neurotransmitter well known for its contributions to fast and slow synaptic signaling, synaptic plasticity and excitotoxic pathology. Emerging evidence also indicates that changes in SxC- activity are associated with the underlying pathological mechanisms of a variety of CNS disorders, the most prominent of which are glial brain tumors and drug addiction/relapse. Unfortunately, our growing appreciation for the functional significance of Sxc- in the CNS has rapidly outpaced the availability of potent and selective small molecules with which to modulate transporter activity. Recent synthetic and SAR-based pharmacological studies in our group have identified a novel series of potent noncompetitive inhibitors of Sxc- that we hypothesize are interacting with at least two distinct lipophilic domains adjacent to the substrate binding site on the transporter. Our identification of this new class of noncompetitive inhibitors and, consequently, a previously unrecognized binding site that can allosterically modulate transporter activity, provides an entirely new opportunity for inhibitor development. Using iterative cycles of synthesis and pharmacological assessment, linked by pharmacophore modeling, we propose to build on our lead compounds and optimize the potency and specificity of these Sxc- inhibitors. The proposed synthetic and pharmacological studies address a significant unmet need in the development of small molecules with which to probe the function of Sxc-, as well as its potential as a therapeutic target.

描述（由申请人提供）：该项目的总体目标是提高系统XC-谷氨酸/胱氨酸抗胞菌素（SXC-）的新型抑制剂（SXC-）的发现和开发，该抑制剂专门针对转运蛋白上新鉴定的变构现场。 SXC-是一种强制性交换器，将L-Cystine（L-Cys2）的导入与L-Glutamate（L-GLU）的导出联系起来。 Sxc- function is particularly critical in the CNS, as it mediates the uptake of a vital sulfu-containing amino acid needed for glutathione (GSH) synthesis and oxidative protection, while simultaneously producing an efflux of an excitatory neurotransmitter well known for its contributions to fast and slow synaptic signaling, synaptic plasticity and excitotoxic pathology.新兴的证据还表明，SXC活性的变化与多种中枢神经系统疾病的潜在病理机制有关，其中最突出的是神经胶质脑肿瘤和药物成瘾/复发。不幸的是，我们对中枢神经系统中SXC-的功能意义的越来越多的欣赏迅速超过了有效和选择性的小分子，以调节转运蛋白活性。我们小组中的最新合成和基于SAR的药理研究已经确定了我们假设的一系列新型的SXC的有效非竞争性抑制剂，这些抑制剂与至少两个与转运蛋白上底物结合位点相邻的不同的亲脂性结构域相互作用。我们的身份这类新的非竞争性抑制剂，因此，可以调节转运蛋白活性的先前未识别的结合位点，为抑制剂开发提供了一个全新的机会。我们建议通过药效团建模链接的合成和药理学评估的迭代循环，我们建议建立铅化合物并优化这些SXC-抑制剂的效力和特异性。拟议的合成和药理研究涉及探测SXC-功能的小分子的发展，及其作为治疗靶标的潜力的重要需求。