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：
7477806
负责人：
DALE F MIERKE
金额：
$ 33.43万
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 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7477806
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，谷氨酸受体信号传导通过 AMPA/红藻氨酸和 NMDA 受体，在药物寻求反应中发挥机械作用，成瘾是谷氨酸的一种形式依赖性可塑性。事实上，最近的研究表明，反复服用可卡因会改变戒断期间红藻氨酸受体的表达水平。 AMPA/红藻氨酸和 NMDA 受体拮抗剂有可能导致与酒精和其他药物成瘾相关的临床综合征。尽管存在多种 AMPA、红藻氨酸和 NMDA 受体亚型，但事实证明很难开发亚型特异性拮抗剂很大程度上是因为它们具有高度同源性。相比之下，谷氨酸受体亚型通过不同的分子支架与不同的细胞内信号级联偶联蛋白质，包括突触相关蛋白 (SAP)、谷氨酸受体相互作用蛋白 (GRIP) 和蛋白质相互作用 C 激酶 (PICK)。这些蛋白质含有PDZ（突触后密度- 95/Discs large/Zona occlusionns-1) 结构域表现出不同程度的受体亚型特异性。 SAP（例如 SAPg0 和 SAP97）由五个独立的域组成：三个 PDZ 域 _DZ1、 PDZ2、PDZ3)、src-同源 3 结构域 (SH3) 和鸟苷激酶样结构域 (GK)。分子内 SAP 不同域之间的相互作用已被证明可以调节功能。在这里我们建议开发肽和肽模拟物，以破坏肽之间和肽内的相互作用这些分子支架蛋白。我们的目标是从结构上描述域间相互作用使用高分辨率 NMR 和计算机模拟的 sAPg0、SAP97、GRIP 和 PICK。纳入将实验确定的结构特征转化为这些支架的详细分子模型蛋白质将允许合理设计这些相互作用的分子抑制剂。这样的分子将有助于更好地理解特定的蛋白质-蛋白质相互作用，并提供治疗毒瘾的新途径。