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: 8731190
• 负责人: Andrea Grace Hohmann
• 金额: $ 23.4万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731190
• 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）：本申请“作为新型镇痛剂的蛋白质-蛋白质相互作用抑制剂”解决了对没有不良副作用的有效镇痛剂的迫切需要。 NMDA 受体参与慢性疼痛和其他病理性神经元疾病的维持。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 会破坏涉及 NMDA 受体信号转导所需的 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 还可以减轻创伤性神经损伤引起的神经性疼痛大鼠模型中的痛觉过敏。然而，nNOS-PSD95 抑制剂是否抑制伤害感受加工仍不清楚。本申请的目的是验证 nNOS-PSD95 蛋白质-蛋白质相互作用的干扰物作为广谱镇痛药，使用诱发和自发疼痛的动物模型抑制伤害性加工。炎症和中毒性神经性损伤会产生与中枢神经系统敏化相关的持续性疼痛。 IC87201 是第一个小分子蛋白质-蛋白质相互作用干扰剂之一，在多种临床前疼痛模型中显示出功效。这些发现支持了我们的假设，即破坏信号划分代表了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）方面拥有丰富的综合经验，完全有能力开展拟议的工作。我们将根据两个具体目标进行实验：（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镇痛功效； (2) 使用条件性位置偏好方法评估 nNOS-PSD95 小分子抑制剂抑制自发性神经病理性疼痛的功效。该项目的完成预计将验证 nNOS-PSD95 抑制剂作为一类新型广谱镇痛药的用途。这些研究预计将验证信号区室的破坏是一种创新且可行的药物开发方法。开发具有新颖化学结构的有效药物疗法，具有有限的副作用和最小的滥用可能性，预计将降低医疗保健成本并减轻患者的痛苦。