Drug Design: Glutamate Receptor Signaling

药物设计：谷氨酸受体信号传导

• 批准号: 6830660
• 负责人: DALE F MIERKE
• 金额: $ 34.88万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 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/6830660
• 关键词: AMPA receptors; biological signal transduction; drug design /synthesis /production; glutamate receptor; inhibitor /antagonist; molecular site; nuclear magnetic resonance spectroscopy; protein protein interaction; protein sequence; protein structure function; receptor expression; structural biology; transcription factor

DESCRIPTION (provided by applicant): 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 glutamatedependent 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., SAP90 and SAP97) are made up of five separate domains: three PDZ domains (PDZ1, 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 sAP90, 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.

描述（由申请人提供）： 越来越多的证据表明，通过AMPA/Kainate和NMDA受体，谷氨酸受体信号传导在寻求药物反应中起着机理作用，而成瘾是一种依赖谷氨酸的可塑性的形式。实际上，最近显示可卡因的重复给药会改变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，很难开发特定的特定拮抗剂，这在很大程度上是由于它们的高同源性。相反，谷氨酸受体亚型通过不同的分子支架蛋白（包括突触相关蛋白（SAPS），谷氨酸受体相互作用蛋白（GRIPS），谷氨酸受体亚型夫妇伴随不同的细胞内信号传导级联。这些蛋白质包含PDZ（突触后密度-95/椎间盘较大/Zona occludens-1）域显示了受体亚型特异性各种范围的域。 SAPS（例如SAP90和SAP97）由五个独立的域组成：三个PDZ域（PDZ1，PDZ2，PDZ3），SRC-同源3域（SH3）和一个鸟甘基激酶样域（GK）。 SAP的不同结构域之间的分子内相互作用已显示以调节功能。在这里，我们建议开发肽和肽仪，以破坏这些分子支架蛋白的间隔和内部相互作用。我们旨在在结构上表征SAP90，SAP97，GRIP的域间相互作用，并使用高分辨率NMR和计算机模拟进行选择。将实验确定的结构特征纳入这些脚手架蛋白的详细分子模型中，将允许对这些相互作用的分子抑制剂进行合理设计。这样的分子将使对特定蛋白质蛋白质相互作用的了解，并为药物成瘾的治疗提供新的途径。