Protein-protein interaction inhibitors as novel analgesics

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”满足了对无不良副作用的有效镇痛剂的迫切需求。NMDA受体参与慢性疼痛和其他病理性神经元疾病的维持。赖博士是该项目的联合首席研究员，他首先表明，小分子抑制剂IC87201破坏了涉及PDZ结构域(神经元型一氧化氮合酶，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，这是NMDA受体信号传递所必需的。IC87201还减轻了由创伤性神经损伤产生的神经病理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性加工仍不清楚。这项应用的目的是验证nNOS-PSD95蛋白质-蛋白质相互作用的干扰物作为广谱止痛剂，通过诱发和自发疼痛的动物模型抑制伤害性处理。与中枢神经系统敏化相关的持续性疼痛将通过炎性和毒性神经病理性侮辱而产生。IC87201是最早的小分子蛋白质-蛋白质相互作用干扰物之一，在几个临床前疼痛模型中显示出有效性。这些发现支持我们的假设，即信号区隔的中断代表着一种开发副作用更少的新型止痛药的创新方法。研究人员在药物发现(LAI)和开发新的疼痛模型(Hohmann)方面拥有广泛的结合经验，能够很好地开展拟议的工作。我们将在两个特定目标下进行实验：(1)评价nNOS-PSD95小分子抑制剂对炎症诱导的行为超敏反应和神经元激活的抗伤害效应；(2)采用条件性位置偏爱方法评价nNOS-PSD95小分子抑制剂抑制自发性神经病理性疼痛的有效性。该项目的完成有望验证nNOS-PSD95抑制剂作为一类新的广谱止痛药的使用。这些研究有望验证信号区隔的中断是药物开发的一种创新和可行的方法。开发具有新的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倾向，有望降低医疗保健成本，减轻患者的痛苦。

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.