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

• 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
• 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

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促进发现和开发XC-谷氨酸/胱氨酸逆向转运体(SXC-)系统的新型抑制剂，特别是针对转运体上新发现的变构位点。SXC-是连接L-胱氨酸(L-Cys2)进口和L-谷氨酸(L-谷氨酸)出口的专有交易所。SXC功能在中枢神经系统中尤其重要，因为它介导了谷胱甘肽(GSH)合成和氧化保护所需的一种重要的含硫氨基酸的摄取，同时产生了一种兴奋性神经递质的外流，该神经递质以其对快慢突触信号、突触可塑性和兴奋性病理的贡献而闻名。新的证据也表明，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，其中最突出的是胶质脑瘤和药物成瘾/复发。不幸的是，我们对SXC-在中枢神经系统中的功能重要性的日益重视，已经迅速超过了用于调节转运蛋白活性的有效和选择性小分子的可用性。我们团队最近的合成和基于SAR的药理学研究已经确定了一系列新的有效的非竞争性SXC抑制剂-我们假设这些抑制剂至少与转运蛋白上底物结合部位附近的两个不同的亲脂结构域相互作用。我们的身份证明 这类新的非竞争性抑制剂，以及由此产生的可以变构调节转运蛋白活性的先前未知的结合位点，为抑制剂的开发提供了一个全新的机会。利用迭代的合成和药理学评估循环，通过药效团建模，我们建议在我们的先导化合物的基础上，优化这些SXC-抑制剂的效力和特异性。拟议的合成和药理学研究解决了小分子开发中一个重要的未得到满足的需求，用来探索SXC-的功能以及它作为治疗靶点的潜力。