ACETYLTRANSFERASE INHIBITION AND SELECTIVITY

描述（改编自申请人的摘要）：乙酰转移酶发挥作用 在诸如昼夜节律等不同过程中的重要作用， 基因表达的调控。血清素N-乙酰转移酶负责 动物松果体褪黑激素产生的昼夜节律 和人民组蛋白乙酰转移酶被认为是调节重塑的重要因素 通过催化组蛋白上关键的赖氨酸残基的乙酰化作用，他们 也被认为是作为催化剂用于乙酰化各种 转录因子本提案的主要目标涉及设计， 5-羟色胺N-乙酰转移酶抑制剂的合成和评价 褪黑激素节律酶和组蛋白乙酰转移酶（HAT）PCAF和 p300。此外，首席研究员寻求更好地定义关键 HAT底物识别的决定因素，这可能导致发现 新的生物基质。首席研究员寻求建立在最初的基础上， 发现双底物类似物可以产生有效的选择性抑制剂 这些酶。他将研究一系列的修改，以增强约束力 亲和力、选择性和细胞渗透性。设计的化合物将被测试 在体外，将使用X射线晶体结构分析来检查有效的化合物 在可能的情况下用适当的酶，并在体内在各种 不同的系统。将使用肽评价HAT底物选择性 和蛋白质底物，使用经典的方法以及组合 图书馆. 5-羟色胺N-乙酰转移酶抑制剂将是有用的工具 评价松果体5-羟色胺和褪黑素在昼夜生理中的作用 并可能作为治疗情绪和睡眠障碍的先导化合物。选择性 HAT酶的抑制剂可用于治疗癌症、HIV和 与基因表达失调有关的其他疾病。

DESCRIPTION (adapted from applicant's abstract): Acetyltransferases play important roles in such diverse processes as circadian rhythm and the regulation of gene expression. Serotonin N-acetyltransferase is responsible for the circadian pattern of melatonin production in the pineal gland of animals and people. Histone acetyltransferases are proposed to modulate the remodeling of chromatin by catalyzing acetylation of key lysine residues on histones. They are also thought to serve as catalysts for the acetylation of a variety of transcription factors. The principal goals of this proposal concern the design, synthesis, and evaluation of inhibitors of serotonin N-acetyltransferase, the melatonin rhythm enzyme, and the histone acetyltransferases (HATs) PCAF and p300. In addition, the principal investigator seeks to better define the key determinants for HAT substrate recognition which may lead to the discovery of new biological substrates. The principal investigator seeks to build on initial findings that bi-substrate analogs can lead to potent and selective inhibitors of these enzymes. He will examine a range of modifications to enhance binding affinity, selectivity, and cell permeability. Designed compounds will be tested in vitro, potent ones will be examined using X-ray crystal structure analysis with the appropriate enzyme where possible, and in vivo in a variety of different systems. HAT substrate selectivity will be evaluated using peptide and protein substrates, using classical approaches as well as combinatorial libraries. Inhibitors of serotonin N-acetyltransferase will be useful as tools to evaluate the role of pineal serotonin and melatonin in circadian physiology and potentially as lead compounds for mood and sleep disorders. Selective inhibitors of HAT enzymes may be useful in the treatment of cancer, HIV, and other diseases related to the dysregulation of gene expression.