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 对潜在的分子过程有深刻的洞察力，但特别是对于中枢神经系统的疾病 对于神经系统(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)在内的药物在治疗中枢神经系统疾病方面有很长的成功历史 精神错乱。联氨基团共价失活几类酶(例如， 中枢神经系统中参与转录调控的加氧酶、去甲基酶、羟基酶) 和染色质重塑，从而有助于广泛的生物功能和 疾病病理学。我之前开发了一个新的化学蛋白质组发现平台 (我将其命名为‘RP-ABPP)，通过利用其独特的反应性(反极性，RP) 药效团通过基于活性来创建针对这些酶类的无偏探针 蛋白质图谱(ABPP)。鉴于联氨类药物已确定的进入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平台发现联氨敏感酶的穿透性探针 在药物成瘾的临床前模型中被扰乱。具体地说，这些探测器将评估更改 使用电子尼古丁递送系统在依赖发展过程中对大脑的影响 (结束)以一种新建立的吸入暴露的小鼠模型结束。目标是i)确定 在尼古丁依赖中失调的新型可药物酶靶标和ii)开发出一种 一套选择性探针，可被神经科学家用作研究的药理学工具 滥用药物和其他精神疾病。这个平台预计将：i)创造新的 绘制基因突变和表观遗传修饰的功能后果图的机会 在药物依赖方面，二)发现可以空间映射的新的可药物酶活性 通过成像，以及iii)最终创造一个独特的机会，围绕 相对未被开发的化学空间。

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.