Canavan disease (CD) is a fatal leukodystrophy caused by mutations in the aspA gene coding for the enzyme aspartoacylase. Insufficient catalytic activity by this enzyme leads to the accumulation of its substrate, N-acetyl-l-aspartate (NAA), and diminished production of acetate in brain oligodendrocytes of patients with CD. There is growing evidence that this accumulation of NAA is the cause of many of the developmental defects observed in these patients. NAA is produced in the brain by a transacetylation reaction catalyzed by aspartate N-acetyltransferase (ANAT), and this membrane-associated enzyme has recently been purified as a soluble maltose binding protein fusion. Designing selective inhibitors against ANAT has the potential to slow the accumulation of NAA and moderate these developmental defects, and this is the goal of this project. Several bisubstrate analog inhibitors of ANAT have been synthesized that have achieved nanomolar level binding affinities against this enzyme. Truncated versions and fragments of these bisubstrate analog inhibitors have identified the essential structural elements needed for high binding affinity. More drug-like versions of these inhibitors can now be built, based on these essential core structures.

中文翻译：

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天冬氨酸N-乙酰基转移酶（一种关键的脑酶）的双底物类似物抑制剂的开发。

Canavan病（CD）是一种致命的白细胞营养不良，是由编码天冬氨酸酰化酶的aspA基因突变引起的。该酶的催化活性不足会导致其底物N-乙酰基-1-天冬氨酸（NAA）积累，并减少CD患者脑少突胶质细胞中乙酸的产生。越来越多的证据表明，NAA的这种积累是这些患者中观察到的许多发育缺陷的原因。NAA是由天冬氨酸N-乙酰基转移酶（ANAT）催化的转乙酰反应在大脑中产生的，这种与膜相关的酶最近已被纯化为可溶性麦芽糖结合蛋白融合体。设计针对ANAT的选择性抑制剂有可能减慢NAA的积累并缓解这些发育缺陷，这是该项目的目标。已合成了几种ANAT双底物类似物抑制剂，它们对这种酶已达到纳摩尔水平的结合亲和力。这些双底物类似物抑制剂的截短形式和片段已经确定了高结合亲和力所需的基本结构元件。基于这些基本的核心结构，现在可以构建这些抑制剂的更多类似药物的形式。