Protein-protein interaction inhibitors as novel analgesics

蛋白质-蛋白质相互作用抑制剂作为新型镇痛药

• 批准号: 8459637
• 负责人: Andrea Grace Hohmann
• 金额: $ 19.5万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459637
• 关键词: Address; Adverse effects; Affect; American; Analgesics; Animal Model; Animals; Area; Attenuated; Behavior assessment; Behavioral; Biochemical Markers; Biological; Chemical Structure; Clinical; Complex; Development; Disease; Dose; Excision; Formalin; Goals; Health Care Costs; Human; Hyperalgesia; Hypersensitivity; Inflammation; Inflammatory; Knowledge; Maintenance; Measures; Mediating; Medical; Methodology; Modeling; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neuraxis; Neurons; Neuropathy; Nitric Oxide Synthase Type I; Nociception; Pain; Patients; Persistent pain; Pharmacotherapy; Positioning Attribute; Pre-Clinical Model; Principal Investigator; Process; Productivity; Rattus; Receptor Activation; Receptor Signaling; Research; Research Personnel; Rodent Model; Role; Scaffolding Protein; Sedation procedure; Signal Pathway; Signal Transduction; Stimulus; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Traumatic Nerve Injury; Work; analog; central sensitization; chronic pain; clinical efficacy; cost; density; drug development; drug discovery; expectation; experience; in vivo; inhibitor/antagonist; innovation; mental state; nerve injury; novel; novel strategies; novel therapeutics; pain behavior; painful neuropathy; postsynaptic; postsynaptic density protein; pre-clinical; preference; presynaptic density protein 95; protein protein interaction; public health relevance; research study; small molecule; socioeconomics; spontaneous pain

DESCRIPTION (provided by applicant): The present application "Protein-protein interaction inhibitors as novel analgesics" addresses the critical need for efficacious analgesics lacking adverse side-effects. The NMDA receptor is involved in the maintenance of chronic pain and other pathological neuronal diseases. Dr. Lai, a co-principal investigator for this project, first showed that the small molecule inhibitor IC87201 disrupts the functional protein-protein interaction involving PDZ domains (neuronal nitric oxide synthase, nNOS and postsynaptic density protein 95, PSD95) required for NMDA receptor signaling. IC87201 also attenuated hyperalgesia in a rat model of neuropathic pain produced by traumatic nerve injury. However, whether nNOS-PSD95 inhibitors suppress nociceptive processing remains unknown. The objective of this application is to validate disruptors of nNOS-PSD95 protein-protein interactions as broad spectrum analgesics that suppress nociceptive processing using animal models of evoked and spontaneous pain. Persistent pain associated with central nervous system sensitization will be produced using inflammatory and toxic neuropathic insults. IC87201, one of the first small molecule protein-protein interaction disruptors, shows efficacy in several preclinical pain models. These findings support our hypothesis that disruption of signal compartmentalization represents an innovative approach to develop novel analgesics with fewer side-effects. The investigators, with extensive combined experience in drug discovery (Lai) and development of novel pain models (Hohmann) are well-positioned to conduct the proposed work. We will conduct experiments proposed under two Specific Aims: (1) To evaluate antinociceptive efficacy of small molecule inhibitors of nNOS-PSD95 on both inflammation-evoked behavioral hypersensitivities and neuronal activation; (2) To assess the efficacy of small molecule inhibitors of nNOS-PSD95 in suppressing spontaneous neuropathic pain using a conditioned place preference approach. Completion of this project is expected to validate the use of nNOS-PSD95 inhibitors as a new class of broad-spectrum analgesics. These studies are expected to validate the disruption of signal compartmentation as an innovative and feasible approach to drug development. The development of effective pharmacotherapies with novel chemical structures that possess limited side-effect profiles and minimal abuse liability is expected to drive down health care costs and alleviate suffering in patients.

描述（由申请人提供）：目前的申请“蛋白质-蛋白质相互作用抑制剂作为新型镇痛药”解决了对无不良副作用的有效镇痛药的迫切需求。NMDA受体参与慢性疼痛和其他病理性神经疾病的维持。该项目的联合首席研究员Lai博士首先表明，小分子抑制剂IC87201破坏了NMDA受体信号传导所需的PDZ结构域（神经元一氧化氮合酶，nNOS和突触后密度蛋白95，PSD95）的功能性蛋白质-蛋白质相互作用。IC87201还能减轻创伤性神经损伤引起的神经性疼痛大鼠模型的痛觉过敏。然而，nNOS-PSD95抑制剂是否抑制伤害性加工仍然未知。本应用的目的是通过诱发性和自发性疼痛的动物模型验证nNOS-PSD95蛋白-蛋白相互作用的干扰物作为广谱镇痛药抑制伤害性加工。与中枢神经系统致敏相关的持续性疼痛将通过炎症和毒性神经性损伤产生。IC87201是首批小分子蛋白-蛋白相互作用干扰物之一，在几种临床前疼痛模型中显示出疗效。这些发现支持了我们的假设，即信号区隔化的破坏代表了一种开发副作用更少的新型镇痛药的创新方法。研究人员在药物发现（Lai）和新型疼痛模型开发（Hohmann）方面具有丰富的综合经验，可以很好地开展拟议的工作。我们将在两个特定目的下进行实验：(1)评估nNOS-PSD95小分子抑制剂对炎症诱发的行为超敏反应和神经元激活的抗伤害感受作用；(2)采用条件位置偏好法评价nNOS-PSD95小分子抑制剂对自发性神经性疼痛的抑制作用。该项目的完成有望验证nNOS-PSD95抑制剂作为一类新的广谱镇痛药的使用。这些研究有望验证信号区隔的破坏是一种创新和可行的药物开发方法。开发具有新化学结构、副作用有限、滥用责任最小的有效药物疗法，有望降低医疗保健费用，减轻患者的痛苦。