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

项目摘要 鉴定与疾病状态相关的遗传和表观遗传变化可以 提供深入了解潜在的分子过程，但，特别是对疾病的 中枢神经系统（CNS），将这些信息转化为新的药物治疗仍然是一个挑战。 挑战.在这里，我们将探索精神药物中发现的药效团的化学性质 研究遗传变异和表观遗传修饰对成瘾的影响。肼- 包括单胺氧化酶抑制剂（MAOI）在内的基于药物的药物在治疗糖尿病方面有着悠久的成功历史。 治疗CNS疾病。肼基共价地使几类酶失活 (e.g.氧化酶、加氧酶、脱甲基酶、羟化酶），它们参与 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 通过利用独特的反应性，蛋白质组学发现平台（我将其称为“RP-ABPP”） （反极性，RP），以创建无偏探针，以靶向这些酶 基于活性的蛋白质谱（ABPP）。鉴于肼的已知能力 药物到达中枢神经系统和操纵其生物化学，该项目将实施第一次在 类，亲核脑穿透探针使用我们的RP-ABPP平台，以发现肼- 敏感酶在药物成瘾的临床前模型中被破坏。具体来说，这些探针 将评估在依赖性发展过程中大脑的变化， 尼古丁给药系统（ENDS）与新建立的小鼠吸入暴露模型。 目标是i）鉴定尼古丁中失调的新型可药物化酶靶点 依赖和ii）开发一套可供神经科学家使用的选择性探针， 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 和药物依赖的表观遗传修饰，ii）发现新的可药用酶活性 可以通过成像进行空间映射，以及iii）最终为以下方面创造独特的机会： 围绕着一个相对未被探索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.