MAOI-inspired activity probes to translate epigenetics and genetics into drugs

项目摘要 识别与疾病状态相关的遗传和表观遗传变化可以 让我们深入了解潜在的分子过程，但特别是对于 中枢神经系统(CNS)，将这些信息转化为新的药物疗法仍然是一个 挑战。在这里，我们将利用在精神活性药物中发现的药效团的化学。 研究遗传变异和表观遗传修饰对成瘾的影响。联氨- 包括单胺氧化酶抑制剂(MAOI)在内的基础药物在 治疗中枢神经系统疾病。联氨基团共价灭活几类酶 (例如，氧化物酶、加氧酶、去甲基酶、羟基酶) 转录调控和染色质重塑，从而有助于广泛的 生物学功能和疾病病理学。我之前开发了一种新的化学物质 蛋白质组学发现平台(我称之为`RP-ABPP)通过利用独特的反应性 (反转极性，RP)以创建针对这些酶的无偏探针 按基于活动的蛋白质图谱(ABPP)分类。鉴于联氨的既定能力 药物到达中枢神经系统并操纵其生物化学，该项目将实施第一 使用我们的RP-ABPP平台发现联氨的一类亲核脑穿透探针- 在药物成瘾的临床前模型中，敏感酶被破坏。具体来说，这些探测器 将使用电子设备评估依赖发展过程中大脑的变化 尼古丁递送系统(结束)与一种新建立的小鼠吸入暴露模型。 目标是i)识别尼古丁中不受调控的新的可药物酶靶标 依赖和ii)开发一套选择性探针，可供神经科学家用于 研究药物滥用和其他精神疾病的药理学工具。这个平台是 预计i)创造新的机会来绘制基因突变的功能后果图 和表观遗传修饰在药物依赖中的作用，II)发现新的可药物酶活性 可以通过成像进行空间映射，以及iii)最终为 围绕相对未被开发的化学空间的治疗发展。

Project Abstract Identification of genetic and epigenetic changes associated with disease states can afford deep insight into the underlying molecular processes, but, particularly for diseases of the central nervous system (CNS), translating this information to new drug therapies remains a challenge. Here, we will exploit the chemistry of pharmacophores found in psychoactive drugs to study the impact of genetic variants and epigenetic modifications in addiction. Hydrazine- based drugs including monoamine oxidase inhibitors (MAOI) have a long history of success in treating CNS disorders. The hydrazine group covalently inactivates several classes of enzymes (e.g. oxidases, oxygenases, demethylases, hydroxylases) in the CNS that participate in transcriptional regulation and chromatin remodeling, thereby contributing to a broad range of biological functions and disease pathologies. I previously developed a novel chemical proteomics discovery platform (which I dubbed `RP-ABPP) by exploiting the unique reactivity (reverse polarity, RP) of this pharmacophore to create unbiased probes to target these enzyme classes by activity-based protein profiling (ABPP). Given the established ability of hydrazine drugs to reach the CNS and manipulate its biochemistry, this project will implement first-in- class, nucleophilic brain-penetrating probes using our RP-ABPP platform to discover hydrazine- sensitive enzymes disrupted in preclinical models of drug addiction. Specifically, these probes will evaluate changes to the brain during the development of dependence using electronic nicotine delivery systems (ENDS) with a newly established mouse model of inhalation exposure. The goals are to i) identify novel druggable enzyme targets that are dysregulated in nicotine dependence and ii) develop a suite of selective probes that can be used by neuroscientists as pharmacological tools to study drug abuse and other psychiatric disorders. This platform is expected to i) create new opportunities to map functional consequences of genetic mutations and epigenetic modifications in drug dependence, ii) discover new druggable enzyme activities that can be spatially mapped by imaging, and iii) ultimately create a unique opportunity for therapeutic development around a relatively underexplored chemical space.