Antagonists of CRMP2 Phosphorylation for Chemotherapy-Induced Peripheral Neuropathy

CRMP2 磷酸化拮抗剂治疗化疗引起的周围神经病变

基本信息

批准号：
10505802
负责人：
Rajesh Khanna
金额：
$ 139.49万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10505802
关键词：
Affect Afferent Neurons Analgesics Animal Model Arizona Binding Biochemical Biological Assay Biological Sciences Biology Calcium Calcium Channel Cells Chemicals Chemotherapy-induced peripheral neuropathy Clinical Clinical Trials Cyclin-Dependent Kinase 5 Data Development Disclosure Dorsal Drug Kinetics Economics Effectiveness Electrophysiology (science)Faculty Fentanyl G-Protein-Coupled Receptors Goals Heroin Human In Vitro Industry Ion Channel Knowledge Laboratories Lead Link Marketing Mechanics Modeling Molecular Natural Products Neurons Nociception Nociceptors Opioid Opioid Receptor Paclitaxel Pain Pain management Pathologic Pathway interactions Peripheral nerve injury Pharmaceutical Preparations Pharmacology Phenotype Phosphoproteins Phosphorylation Phosphorylation Site Phosphotransferases Postoperative Pain Productivity Property Public Health Rattus Regulation Research Research Personnel Rewards Rodent Rodent Model Secure Series Site Sodium Sodium Channel Specificity Spinal Spinal Ganglia Stimulus Substantia Gelatinosa Surface Synapses Synaptic Transmission Techniques Technology Testing Translating Tumor Cell Line United States National Institutes of Health Universities Up-Regulation Validation Work addiction addiction liability analog antagonist axon guidance base chronic pain chronic pain management collapsin response mediator protein-2 cytotoxicity design dorsal horn drug development experimental study falls human female in silico in vivo inhibitor injured invention lead series male mechanical allodynia motor impairment mouse model multidisciplinary negative affect nerve injury neurotoxicity neurotransmission neurotransmitter release novel novel strategies opioid epidemic pain processing pain reduction painful neuropathy pre-clinical prescription pain reliever presynaptic programs recruit screening side effect small molecule social spared nerve success synergism synthetic opioid therapeutic development therapeutic target trafficking virtual voltage welfare

项目摘要

SUMMARY Identification of new targets and mechanisms underlying neuropathic pain is critical to developing new target- specific medications for better neuropathic pain management. The misuse of and addiction to opioids—including prescription pain relievers, heroin, and synthetic opioids such as fentanyl—is a serious national crisis that affects public health as well as social and economic welfare. The current opioid crisis requires novel approaches to chronic pain management. Our proposal leverages a unique finding, originating from the laboratory of Dr. Rajesh Khanna (University of Arizona), that peripheral nerve injury-induced upregulation of an axonal guidance phosphoprotein collapsin response mediator protein 2 (CRMP2) and the N-type voltage-gated calcium (CaV2.2) as well as the NaV1.7 voltage-gated sodium channel, correlates with the development of neuropathic pain. Leveraging a pocket on the surface of CRMP2, amenable for in silico screening, the PI’s laboratory performed a virtual screen of nearly 0.3 million compounds (diverse small molecules and natural products). Several of the top 21 ‘hit’ compounds from this screen have been validated in in vitro and in vivo experiments, providing experimental proof of our in-silico predictions. Predicted physico-chemical properties of the hit series fall within ranges of lead- or ‘drug-like’ molecules. We have assembled a diverse multidisciplinary team to test the hypothesis that inhibiting CRMP2 phosphorylation associated with sodium and calcium channel activities to decrease nociceptor activity culminates in reduced pain. Our Specific Aims, guided by quantitative goals, are: (1) to profile CRMP2 phosphorylation antagonists for their ability to: (i) bind CRMP2 and (ii) block its phosphorylation by Cdk5 and (iii) inhibit calcium and sodium currents in sensory neurons using whole-cell electrophysiology with a smaller subset being tested in male/female human DRGs; (2) profile CRMP2 phosphorylation antagonists for ADME pharmacokinetic properties and off-target effects on GPCRs, kinases, ion channels and alternative known pain targets, including opioid receptors; (3) characterize the best CRMP2 phosphorylation antagonists for in vivo efficacy in rodents using a phenotypic screen and spared nerve injury (SNI) model of neuropathic pain and explore the potential of phosphorylated CRMP2 as a marker of target engagement; (4) validate optimized CRMP2 phosphorylation antagonists in a mouse model of chemotherapy- induced peripheral neuropathy (CIPN) and assess potential reward and/or aversion. At the end of our study, we expect to have at least one lead series for optimization with the goal of developing a selective and efficacious CRMP2 phosphorylation inhibitor for neuropathic pain with minimal side effects or addiction potential.

概括确定神经性疼痛的新靶标和机制对于开发新目标至关重要 - 特定药物，用于更好的神经性疼痛管理。对阿片类药物的失误和成瘾 - 包括处方止痛药，海洛因和合成阿片类药物（例如芬太尼）是一场严重的民族危机，会影响公共卫生以及社会和经济福利。当前的阿片类药物危机需要新颖的方法慢性疼痛管理。我们的建议利用了一个独特的发现，起源于拉杰什博士的实验室卡纳（亚利桑那大学），外周神经损伤引起的轴突指导上调磷蛋白倒塌蛋白反应介质蛋白2（CRMP2）和N型电压门控钙（CAV2.2）以及NAV1.7电压门控钠通道，与神经性疼痛的发展相关。利用CRMP2表面的口袋，可以在硅筛选中进行，PI的实验室进行了虚拟筛选近30万种化合物（各种小分子和天然产物）。顶部的几个该屏幕的21个“命中”化合物已在体外和体内实验中得到验证，提供实验证明了我们的内在预测。热门系列的预测物理化学特性属于铅或“药物状”分子的范围。我们已经组建了一个潜水员的多学科团队，以测试假设抑制与钠和钙通道活性相关的CRMP2磷酸化减少伤害感受的活性最终导致疼痛减轻。我们的具体目标在定量目标的指导下是：（1）介绍CRMP2磷酸化拮抗剂的能力：（i）结合CRMP2和（ii）阻止其 CDK5和（III）磷酸化使用全细胞抑制感觉神经元中的钙和钠电流在男性/女性DRG中测试了较小的子集的电生理学；（2）配置文件CRMP2 ADME药代动力学特性的磷酸化拮抗剂和对GPCR，激酶的脱靶作用离子通道和替代已知疼痛靶标，包括阿片类药物受体；（3）表征最好的CRMP2 使用表型筛选并保存神经损伤的磷酸化拮抗剂，用于啮齿动物的体内效率（SNI）神经性疼痛的模型，并探索磷酸化的CRMP2的潜力订婚; （4）在化学疗法的小鼠模型中验证优化的CRMP2辐射拮抗剂 - 诱发周围神经病（CIPN）和评估潜在的奖励和/或厌恶。在研究结束时，我们期望至少有一个铅系列以进行优化，以开发选择性和高效 CRMP2磷酸化抑制剂神经性疼痛具有最小的副作用或成瘾潜力。