Drug Design: Glutamate Receptor Signaling

药物设计：谷氨酸受体信号传导

基本信息

批准号：
7556423
负责人：
DALE F MIERKE
金额：
$ 33.07万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7556423
关键词：
AMPA Receptors Affinity Binding Binding Sites Biological Assay Chromosome Pairing Clinical Cocaine Computer Simulation Crystallography Cyclic Peptides DLG1 gene DLG4 gene Development Drug Addiction Drug Delivery Systems Drug Design Fluorescence GluR6 kainate receptor Glutamate Receptor Glutamates Guanylate kinase Herpes zoster disease Individual Informal Social Control Intracellular Signaling Proteins Kainic Acid Receptors Lead Ligand Binding Mediating Methods Molecular Mutation N-Methyl-D-Aspartate Receptors NCOA2 gene NMDA receptor antagonist Nitric Oxide Synthase Peptides Pharmaceutical Preparations Phosphotransferases Physiological Play Proline Property Protein Kinase C Proteins Receptor Signaling Regulation Research Research Personnel Resolution Role Route SAP90 protein Scaffolding Protein Signal Transduction Specificity Structure Surface Synapses Syndrome System Therapeutic Agents Withdrawal addiction alcohol and other drug base brain-enriched GKAP desensitization design glutamate receptor interacting protein inhibitor/antagonist insight kainate molecular modeling novel peptidomimetics polyproline presynaptic density protein 95 programs protein protein interaction receptor receptor function response scaffold src Homology Domains trafficking

项目摘要

Growing evidence indicates that glutamate receptor signaling, via both AMPA/kainate and NMDA receptors, plays a mechanistic role in drug seeking responses and that addiction is a form of glutamate- dependent plasticity. Indeed, it was recently shown that repeated administration of cocaine alters the expression levels of kainate receptors during withdrawal. AMPA/kainate and NMDA receptor antagonists have potential for clinical syndromes associated with addiction to alcohol and other drugs. Although numerous subtypes of AMPA, kainate, and NMDA receptors exist, it has proven difficult to develop subtype specific antagonists largely because of their high homology. In contrast, glutamate receptor subtypes couple to different intracellular signaling cascades via different molecular scaffolding proteins, including the synaptic associated proteins (SAPs), glutamate receptor-interacting proteins (GRIPs), and proteins interacts C kinases (PICK). These proteins contain PDZ (postsynaptic density- 95/Discs large/Zona occludens-1) domains displaying various extents of receptor subtype specificity. The SAPs (e.g., SAPg0 and SAP97) are made up of five separate domains: three PDZ domains _DZ1, PDZ2, PDZ3), a src-homology 3 domain (SH3), and a guanyl kinase-like domain (GK). Intra-molecular interactions between the different domains of the SAPs have been shown to regulate function. Here we propose to develop peptides and peptidomimetics that will disrupt the inter- and intra-interactions of these molecular scaffolding proteins. We aim to structurally characterize the inter-domain interactions of sAPg0, SAP97, GRIP, and PICK using high-resolution NMR and computer simulations. Incorporating the experimentally determined structural features into detailed molecular models of these scaffolding proteins will allow for the rational design of molecular inhibitors of these interactions. Such molecules will allow for a greater understanding of the specific protein-protein interactions as well as provide a novel route for the treatment of drug addiction.

越来越多的证据表明，通过AMPA/Kainate和NMDA，谷氨酸受体信号传导受体，在寻求反应的药物中起着机械作用，成瘾是谷氨酸的一种形式依赖性可塑性。确实，最近显示可卡因的重复给药改变了戒断过程中海藻酸盐受体的表达水平。 AMPA/Kainate和NMDA受体拮抗剂具有与酒精和其他药物成瘾有关的临床综合征的潜力。尽管存在许多AMPA，海藻酸盐和NMDA受体的亚型，但事实证明它很难发展亚型特定的拮抗剂很大程度上是因为它们的同源性很高。相反，谷氨酸受体亚型通过不同的分子脚手架到不同的细胞内信号传导级联蛋白质，包括突触相关蛋白（SAP），谷氨酸受体相互作用蛋白（握把），蛋白质相互作用C激酶（挑选）。这些蛋白质含有PDZ（突触后密度 - 95/圆盘大/zona occludens-1）域显示了受体亚型特异性的各种范围。 SAPS（例如SAPG0和SAP97）由五个单独的域组成：三个PDZ域_dz1， PDZ2，PDZ3），SRC-同源3结构域（SH3）和一个类激酶样域（GK）。分子内 SAP的不同域之间的相互作用已显示以调节函数。我们在这里提议开发肽和肽仪，以破坏这些分子支架蛋白。我们的目的是在结构上表征使用高分辨率NMR和计算机模拟，SAPG0，SAP97，抓地力和选择。合并这些脚手架的详细分子模型的实验确定的结构特征蛋白质将允许对这些相互作用的分子抑制剂进行合理设计。这样的分子将允许对特定蛋白质蛋白质相互作用有更深入的了解，并提供治疗吸毒的新途径。