Optimizing the Clinical Efficacy of Opioids by TLR4 Blockade

通过 TLR4 阻断优化阿片类药物的临床疗效

• 批准号: 7707898
• 负责人: Hang Hubert Yin
• 金额: $ 13.6万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707898
• 关键词: Absence of pain sensation; Address; Adverse effects; Animal Model; Arts; Binding; Biological Assay; Biology; Blood - brain barrier anatomy; Cellular Assay; Chemicals; Clinical; Complex; Dependence; Development; Drug Addiction; Generations; Goals; In Vitro; Length; Ligands; Light; Link; Lymphocyte Antigen 96; Maintenance; Mediating; Membrane; Meperidine; Methadone; Molecular Conformation; Morphine; Neurobiology; Neuroglia; Neurons; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Outcome; Oxycodone; Pain; Pain management; Peptide Synthesis; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Proteins; Protocols documentation; Receptor Activation; Regulation; Research; Rewards; Role; Services; Signal Pathway; Signal Transduction; Structural Protein; Structure; Syndrome; Technology; Testing; Therapeutic; Work; assay development; chronic pain; clinical application; clinical efficacy; clinically relevant; design; drug development; drug discovery; high reward; high risk; improved; in vivo; inhibitor/antagonist; innovation; insight; molecular recognition; new therapeutic target; next generation; novel; novel therapeutics; opioid abuse; painful neuropathy; peptidomimetics; prevent; protein complex; protein protein interaction; prototype; public health relevance; receptor; receptor function; scaffold; small molecule; toll-like receptor 4; tool

DESCRIPTION (provided by applicant): Opioid-induced glial activation, which compromises pain treatment and contributes to the development of drug addiction and abuse, is regulated via a signaling pathway downstream of toll-like receptor-4 (TLR4), a membrane spanning receptor that functions in complex with its accessory protein MD-2. As current opioid pharmacotherapeutics have failed to control pain while avoiding the negative consequences, there is an urgent need to understand opioid dysregulation via TLR4. The central hypothesis of the current proposal is that disruption of the TLR-4/MD-2 complex formation can inhibit opioid-induced glial activation, thereby enhancing analgesia and reducing opioid tolerance and dependence. The rationale underlying the proposed research is that the identified inhibitors, which selectively block the critical protein-protein interactions between TLR4 and MD-2, will provide a useful tool for investigating the role of the TLR4-mediated signaling pathway in glial activation. The proposed research is innovative because it is the first drug discovery approach attempting to regulate opioid-induced glial activation. The proposed high risk/high reward approach, if successful, is projected to yield significant novel outcomes. First, the results will shed light on the mechanism of the clinically relevant opioid-induced glial activation. Second, if successful, the peptide and peptidomimetic antagonists of the TLR4/MD-2 interactions identified in the proposed research can serve as prototypes for more drug-like small-molecule inhibitors. These inhibitors may eventually find application in the development of novel therapeutics to enhance the clinical efficacy of opioid analgesics and to treat opioid addiction and abuse, as well as other clinically relevant indications. The proposed studies are built on a strong collaborative team with expertise that optimizes its chance to effectively bridge between atomic detail of the TLR4/MD-2 interaction and its macroscopic effect, namely pain management and avoiding negative consequences of opoid use. In Aim 1, antagonists of TLR4 or MD-2 that block the TLR4/MD-2 complex formation will be developed using a cutting-edge computational technology. The working hypothesis here is that conformationally strained peptides derived from the binding region can compete with the full-length protein and thereby inhibit the TLR4/MD-2 interaction. These peptides can serve as starting points for the computational design of stronger inhibitors. In Aim 2, the second working hypothesis, that the inhibitors of the TLR4/MD-2 interactions can non-competitively prevent opioids from inducing TLR4-mediated glial activation, will be tested. Cellular assays and animal models will be used to evaluate the inhibition of glial activation by the TLR4 antagonists both in vitro and in vivo. The proposed research is significant because it is expected to establish the TLR4/MD-2 protein-protein complex as a novel therapeutic target for optimizing opioid analgesia while preventing and treating opioid abuse. Regarding its positive impact on scientific advancements, this work will (1) improve scientific understanding of drug dependence and pain suppression and (2) allow the development of a new generation of therapeutics. PUBLIC HEALTH RELEVANCE: The proposed research aims to unravel the mechanism of opioid-induced glial activation that both hinders the ability of opioids to effectively control pain and also importantly contributes to the development of drug addiction and abuse. State-of-the-art technologies will be employed to define, design, create, and test new chemical entities predicted to prevent opioid induced glial activation, thereby optimizing opioid analgesia while preventing negative consequences of clinical opioid use.

描述（由申请人提供）：阿片类药物诱导的神经胶质细胞激活会影响疼痛治疗并导致药物成瘾和滥用，该激活是通过 Toll 样受体 4 (TLR4) 下游的信号通路进行调节的，TLR4 是一种跨膜受体，与其辅助蛋白 MD-2 复合发挥作用。由于目前的阿片类药物治疗无法在控制疼痛的同时避免负面后果，因此迫切需要通过 TLR4 了解阿片类药物的失调。目前提议的中心假设是，破坏 TLR-4/MD-2 复合物的形成可以抑制阿片类药物诱导的神经胶质细胞活化，从而增强镇痛作用并降低阿片类药物的耐受性和依赖性。这项研究的基本原理是，所确定的抑制剂可以选择性地阻断 TLR4 和 MD-2 之间关键的蛋白质-蛋白质相互作用，将为研究 TLR4 介导的信号通路在神经胶质细胞激活中的作用提供有用的工具。拟议的研究具有创新性，因为它是第一个尝试调节阿片类药物诱导的神经胶质细胞激活的药物发现方法。所提出的高风险/高回报方法如果成功，预计将产生重大的新颖成果。首先，结果将揭示临床相关的阿片类药物诱导的神经胶质细胞激活的机制。其次，如果成功的话，拟议研究中确定的 TLR4/MD-2 相互作用的肽和拟肽拮抗剂可以作为更多药物样小分子抑制剂的原型。这些抑制剂最终可能应用于开发新疗法，以增强阿片类镇痛药的临床疗效，治疗阿片类药物成瘾和滥用，以及其他临床相关适应症。拟议的研究建立在一个强大的协作团队的基础上，该团队拥有专业知识，可以优化有效连接 TLR4/MD-2 相互作用的原子细节与其宏观效应（即疼痛管理和避免阿片类药物使用的负面后果）之间的机会。在目标 1 中，将使用尖端计算技术开发阻断 TLR4/MD-2 复合物形成的 TLR4 或 MD-2 拮抗剂。这里的工作假设是，源自结合区域的构象应变肽可以与全长蛋白质竞争，从而抑制 TLR4/MD-2 相互作用。这些肽可以作为更强抑制剂的计算设计的起点。在目标 2 中，将测试第二个工作假设，即 TLR4/MD-2 相互作用的抑制剂可以非竞争性地阻止阿片类药物诱导 TLR4 介导的神经胶质激活。细胞测定和动物模型将用于评估 TLR4 拮抗剂在体外和体内对神经胶质活化的抑制作用。拟议的研究意义重大，因为预计将 TLR4/MD-2 蛋白-蛋白复合物建立为优化阿片类镇痛同时预防和治疗阿片类药物滥用的新治疗靶点。就其对科学进步的积极影响而言，这项工作将（1）提高对药物依赖和疼痛抑制的科学认识；（2）促进新一代疗法的开发。公共健康相关性：拟议的研究旨在揭示阿片类药物诱导的神经胶质激活机制，该机制既阻碍阿片类药物有效控制疼痛的能力，又重要地促进药物成瘾和滥用的发展。将采用最先进的技术来定义、设计、创建和测试预计可防止阿片类药物诱导的神经胶质激活的新化学实体，从而优化阿片类药物镇痛，同时防止临床阿片类药物使用的负面后果。