ACETYLTRANSFERASE INHIBITION AND SELECTIVITY

描述(改编自申请人的摘要)：乙酰转移酶的作用 在不同的过程中发挥重要作用，如昼夜节律和 基因表达的调控。5-羟色胺N-乙酰转移酶负责 动物松果体中褪黑激素的昼夜节律 还有人。组蛋白乙酰转移酶被认为是调节重塑的酶。 通过催化组蛋白上关键的赖氨酸残基的乙酰化作用来控制染色质。他们 也被认为是各种乙酰化反应的催化剂 转录因子。这项提案的主要目标与设计有关， 5-羟色胺N-乙酰转移酶抑制剂的合成与评价 褪黑素节律酶和组蛋白乙酰转移酶(HATS)PCAF和 P300。此外，首席调查员试图更好地定义关键 HAT底物识别的决定因素可能导致发现 新的生物底物。首席调查员试图在最初的基础上 发现双底物类似物可以产生有效和选择性的抑制剂 这些酶中。他将研究一系列修改以增强约束力 亲和力、选择性和细胞渗透性。设计的化合物将进行测试 在体外，将使用X射线晶体结构分析来检测有效的 在可能的情况下使用适当的酶，并在体内各种 不同的系统。HAT底物选择性将使用多肽进行评估 和蛋白质底物，使用经典方法以及组合 图书馆。5-羟色胺N-乙酰转移酶抑制剂将是有用的工具 松果体5-羟色胺和褪黑素在昼夜生理学中的作用 并可能作为情绪和睡眠障碍的先导化合物。有选择性的 HAT酶的抑制剂可能在治疗癌症、艾滋病毒和 其他与基因表达失调有关的疾病。

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.