Exogenous Chemical Probes of TLR-Mediated Neuroinflammation

TLR 介导的神经炎症的外源化学探针

• 批准号: 8768472
• 负责人: Hang Hubert Yin
• 金额: $ 28.98万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-05 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768472
• 关键词: Absence of pain sensation; Acute; Adverse effects; Analgesics; Animal Model; Animal Testing; Binding; Biochemical; Biological Assay; Blood - brain barrier anatomy; Brain; Cell Line; Cellular Assay; Chemicals; Complex; Dependence; Development; Dimerization; Drug Kinetics; Drug Targeting; Endotoxins; Enzymes; Generations; Goals; Health; Hydrocarbons; Immune; In Vitro; Inflammatory Response; Ligands; Light; Link; Lipopolysaccharides; Literature; Mediating; Membrane; Meperidine; Methadone; Methods; Microglia; Molecular; Molecular Conformation; Morphine; Myelogenous; Neuraxis; Neurobiology; Neuroglia; Neurons; Opiates; Opioid; Outcome; Oxycodone; Pain management; Pathway interactions; Peptides; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Property; Proteins; Radar; Reporting; Research; Resistance; Resolution; Role; Signal Pathway; Signal Transduction; Specificity; Spinal Cord; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic; Vertebral column; Work; Yin; base; clinical efficacy; clinically relevant; computational chemistry; design; drug candidate; drug discovery; improved; in vitro testing; in vivo; inhibitor/antagonist; innovation; insight; interest; macrophage; molecular recognition; multidisciplinary; neglect; neuroinflammation; novel; protein complex; prototype; receptor; receptor function; response; scaffold; small molecule; toll-like receptor 4; tool

DESCRIPTION (provided by applicant): After years of neglect, glial cells are finally registering on drug developers' radar. Evidence has accrued over the last seven years that glia are activated by opioids (e.g. morphine, methadone, meperidine, and oxycodone) and that this opioid-induced glial response suppresses opioid analgesia, resulting in the development of opioid tolerance and dependence. A literature has developed linking opiate efficacy and side effects to their influence on glial cells within the central nervous system (CNS) via the signaling pathway mediated by toll-like receptor 4 (TLR4). In a recent report, the Yin lab has provided the first direct evidence that morphine creates its neuroinflammatory effects by binding to the TLR4 accessory protein, MD-2, and inducing TLR4/MD-2 dimerization and subsequent TLR4 signaling activation in a similar fashion to the classical TLR4 ligand, lipopolysaccharide (LPS; endotoxin). Further, morphine induces neuroinflammation solely through its binding in a specific LPS-binding pocket of MD-2, indicating that disruption of the essential TLR4/MD-2 interactions is sufficient to suppress morphine-induced neuroinflammation. The overall objective of the current proposal is to validate the TLR4/MD-2 complex as a feasible target to suppress morphine-induced neuroinflammation by exogenous chemical probes. Our central hypothesis is that by blocking the formation of the TLR4/MD-2 complex, opioid-induced inflammatory response can also be suppressed and thereby enhance morphine analgesia. The proposed research is significant because it is expected to validate the TLR4/MD-2 complex as a novel target for improving the analgesic efficacy of opioids. The proposed research is innovative because it is the first drug discovery approach attempting to regulate opioid-induced glial activation while almost all previous research focused on neurons. The studies are built on a strong collaborative team with expertise that optimizes its chance to effectively bridge the atomic details of TLR4 activation with the macroscopic pain management inefficiencies of opioid use. Aim 1 and Aim 2 are two independent, parallel approaches that aim to attain highly specific inhibitors of the TLR4/MD-2 interactions. We aim to develop previously identified MD-2 peptides and T5342126 derivatives as potent, selective inhibitors of the TLR4/MD-2 complex with desired PK/PD properties. Aim 3 will test the working hypothesis that by disrupting the TLR4/MD- 2 complex, opioid-induced neuroinflammation can also be blocked, thus enhancing acute opioid analgesia. The optimized inhibitors from Aims 1 and 2 will be tested in vitro using various cell lines, in ex vivo microglia, as well as in animal models. The proposed studies, if successful, are projected to yield significant novel outcome: First, the results will further the understanding of the mechanism of clinically relevant opioid-induced neuroinflammation. Second, the TLR4/MD-2 complex will be validated as a feasible target for developing neuroinflammation suppressant. Third, the stapled peptide and small-molecule antagonists of the TLR4 pathway identified from the proposed research will serve as prototypes for potential drug candidates.

描述（由申请人提供）：经过多年的忽视，神经胶质细胞终于在药物开发人员的雷达上注册。在过去的七年里，越来越多的证据表明，阿片类药物（如吗啡、美沙酮、哌嗪和羟可酮）激活了神经胶质，这种阿片类药物诱导的神经胶质反应抑制了阿片类药物镇痛，导致阿片类药物耐受和依赖的发展。已有文献将阿片类药物的疗效和副作用与它们通过信号传导影响中枢神经系统（CNS）内的胶质细胞联系起来