Drug Design: Glutamate Receptor Signaling

药物设计：谷氨酸受体信号传导

• 批准号: 6928977
• 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/6928977
• 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，谷氨酸受体信号，通过AMPA/红藻氨酸和NMDA受体，在药物寻求反应中起着机械作用，成瘾是谷氨酸依赖性可塑性的一种形式。事实上，最近的研究表明，重复给予可卡因会改变戒断过程中红藻氨酸受体的表达水平。AMPA/红藻氨酸盐和NMDA受体拮抗剂具有治疗与酒精和其他药物成瘾相关的临床综合征的潜力。尽管存在AMPA、红藻氨酸盐和NMDA受体的许多亚型，但已证明很难开发亚型特异性拮抗剂，这主要是因为它们的高度同源性。相比之下，谷氨酸受体亚型通过不同的分子支架蛋白（包括突触相关蛋白（SAP），谷氨酸受体相互作用蛋白（GRIPs）和蛋白质相互作用C激酶（PICK））与不同的细胞内信号级联反应偶联。这些蛋白质含有PDZ（突触后密度-95/椎间盘大/闭合带-1）结构域，显示不同程度的受体亚型特异性。SAP（例如，SAP 90和SAP 97）由五个独立的结构域组成：三个PDZ结构域（PDZ 1、PDZ 2、PDZ 3）、src同源3结构域（SH 3）和鸟苷激酶样结构域（GK）。SAP的不同结构域之间的分子内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，将破坏这些分子支架蛋白的相互作用和内部。我们的目标是使用高分辨率NMR和计算机模拟来结构表征sAP 90、SAP 97、GRIP和PICK的结构域间相互作用。将实验确定的结构特征转化为这些支架蛋白的详细分子模型将允许这些相互作用的分子抑制剂的合理设计。这些分子将允许更好地理解特定的蛋白质-蛋白质相互作用，并为药物成瘾的治疗提供新的途径。