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提供 深入了解潜在的分子过程，但是，特别是对于中枢神经系统疾病， 神经系统（CNS）的疾病，将这些信息转化为新的药物治疗仍然是一个挑战。 在这里，我们将利用精神活性药物中发现的药效团的化学性质来研究 遗传变异和表观遗传修饰对成瘾的影响。肼类药物 包括单胺氧化酶抑制剂（MAOI）在治疗CNS方面具有长期的成功历史 紊乱肼基团共价地使几类酶（例如氧化酶， 加氧酶、脱甲基酶、羟化酶），其参与转录调节 和染色质重塑，从而有助于广泛的生物学功能， 疾病病理学我之前开发了一个新的化学蛋白质组学发现平台 （我称之为“RP-ABPP”）通过利用这种独特的反应性（反极性，RP）， 药效团，以创建无偏倚的探针，通过基于活性的 蛋白质谱分析（ABPP）。考虑到肼类药物到达中枢神经系统的能力， 操纵它的生物化学，这个项目将实现一流的，亲核的大脑- 使用我们的RP-ABPP平台的穿透探针来发现肼敏感酶 在药物成瘾的临床前模型中被破坏。具体来说，这些探测器将评估 在依赖性发展过程中使用电子尼古丁输送系统 （ENDS）与新建立的小鼠吸入暴露模型。目标是：i）确定 在尼古丁依赖中失调的新的可药物化的酶靶点，和ii）开发一种 一套选择性探针，可用于神经科学家作为药理学工具， 药物滥用和其他精神疾病。该平台有望i）创造新的 绘制基因突变和表观遗传修饰的功能后果的机会 在药物依赖中，ii）发现可以空间映射新的可药物化的酶活性 通过成像，和iii）最终为围绕一个特定的治疗方法的治疗开发创造一个独特的机会。 相对而言，化学空间尚未被充分利用。

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.