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"解决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。Lai博士是该项目的共同主要研究者，他首先发现小分子抑制剂IC87201破坏了NMDA受体信号传导所需的功能性蛋白质-蛋白质相互作用，包括PDZ结构域（神经元一氧化氮合酶，nNOS和突触后密度蛋白95，PSD 95）。IC87201还在由创伤性神经损伤产生的神经性疼痛的大鼠模型中减弱痛觉过敏。然而，nNOS-PSD95抑制剂是否抑制伤害性加工仍然未知。本申请的目的是使用诱发性和自发性疼痛的动物模型验证nNOS-PSD 95蛋白-蛋白相互作用的干扰物作为抑制伤害性处理的广谱镇痛剂。与中枢神经系统致敏相关的持续性疼痛将使用炎症和毒性神经性损伤产生。IC87201是第一个小分子蛋白质-蛋白质相互作用破坏剂之一，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，即信号区室化的破坏代表了开发副作用较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（Hohmann）的开发方面具有丰富的综合经验，能够很好地开展拟议的工作。我们将根据两个具体目的进行实验：（1）评估nNOS-PSD95的小分子抑制剂对炎症诱发的行为超敏反应和神经元活化的抗伤害感受功效;（2）使用条件性位置偏好方法评估nNOS-PSD95的小分子抑制剂在抑制自发性神经性疼痛中的功效。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用途。这些研究预计将验证信号区室的破坏作为药物开发的创新和可行的方法。开发具有新的化学结构、副作用有限、滥用可能性最小的有效药物疗法，预计将降低医疗保健成本，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.