Novel Treatment Options for Glutaric Aciduria

项目总结/摘要 在这个项目中，研究人员提出开发新的治疗选择谷氨酸尿症1型 (GA1; MIM 231670）。GA 1是赖氨酸、羟赖氨酸和色氨酸的常染色体隐性遗传病 降解患者可表现为脑萎缩和大头畸形，急性脑梗死后可发展为肌张力障碍。 由导致纹状体退化的儿童期并发感染引发的脑病危象。的 疾病是由戊二酰辅酶A脱氢酶（GCDH）的缺陷引起的，由于GCDH中的突变， 神经毒性谷氨酸和3-羟基谷氨酸的积累。GA 1被认为是一种可治疗的疾病 并因此被纳入许多国家的新生儿筛查项目中。目前的治疗包括 饮食干预、补充肉毒碱和紧急治疗。这种治疗模式需要 照顾者和病人都付出了巨大努力。它必须严格维持，因为发生严重危机的风险 始终存在。这些局限性表明需要具有改善疗效的新型治疗选择 与品质研究人员假设，通过在赖氨酸降解的上游使用抑制剂， 通过这种途径，神经毒性谷氨酸和3-羟基谷氨酸在GA 1中的积累可以被转移到更多的 耐受代谢物。已表明，β-氨基己二酸和β-酮己二酸尿症是一种生化 表型无临床意义。它是由DHTKD 1基因突变引起的，DHTKD 1基因编码E1亚基， 酮己二酸脱氢酶，其是GCDH上游的酶。因此，研究人员建议， DHTKD 1是治疗GA 1的极好靶点。因此，本建议的总体目标是 鉴定适用于未来药物化学优化DHTKD 1的新型小分子抑制剂先导物。在 研究人员将通过小分子高通量鉴定候选酶抑制剂AIM 1 使用DHTKD 1蛋白质结构的分子模型进行HTS筛选和计算（虚拟）筛选。 HTS的验证命中将用于改进模型，然后使用计算和 药物化学方法，更大的化学空间，以寻找类似物的结构-活性关系或新的 像药物一样的支架。所有来自HTS和虚拟筛选的有效命中将在AIM 2中进一步评估， 以生成具有良好药物化学性质的商业化合物的优先级列表。在AIM 3中 通过监测已建立的生物标志物，将在GA 1细胞模型中对选定的先导分子进行体外测试 用于抑制DHTKD 1和疾病。结合这三个目标将不仅产生铅抑制剂， DHTKD 1，可以进一步开发用于治疗GA 1，但也有重要的额外数据， 赖氨酸降解的生物化学和生理学。

Project Summary / Abstract In this project, the investigators propose to develop novel treatment options for glutaric aciduria type 1 (GA1; MIM 231670). GA1 is an autosomal recessive inborn error of lysine, hydroxylysine and tryptophan degradation. Patients can present with brain atrophy and macrocephaly and may develop dystonia after acute encephalopathic crises triggered by intercurrent childhood infections that lead to striatal degeneration. The disorder is caused by a defect of glutaryl-CoA dehydrogenase (GCDH) due to mutations in GCDH, leading to the accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid. GA1 is considered a treatable disorder and therefore included in newborn screening programs in many countries. However, current treatment consists of dietary intervention, carnitine supplementation, and emergency treatment. This treatment paradigm requires intense efforts from both caregiver and patient. It must be strictly maintained because the risk of an acute crisis is always present. These limitations demonstrate the need for novel therapeutic options with improved efficacy and convenience. The investigators hypothesize that by using inhibitors upstream in the lysine degradation pathway, accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid in GA1 can be diverted into more tolerable metabolites. It has been shown that -aminoadipic and -ketoadipic aciduria is a biochemical phenotype without clinical significance. It is caused by mutations in DHTKD1 encoding the E1 subunit of - ketoadipic acid dehydrogenase, which is an enzyme upstream of GCDH. Therefore, the investigators propose that DHTKD1 is an excellent target for treatment of GA1. Thus the overall objective of this proposal is to identify novel small-molecule inhibitor leads for DHTKD1 suitable for future medicinal chemistry optimization. In AIM 1, the investigators will identify enzyme inhibitor candidates through a small molecule high-throughput screen (HTS) and computational (virtual) screening using a molecular model of the DHTKD1 protein structure. The verified hits from the HTS will be used to improve the model then to explore, using computational and medicinal chemistry methods, a larger chemical space to find analogs for structure-activity relationships or new drug-like scaffolds. All active hits from the HTS and virtual screening will be further evaluated in AIM 2 in order to generate a prioritized list of commercial compounds with good medicinal chemistry properties. In AIM 3 selected lead molecules will be tested in vitro in a cellular model of GA1 by monitoring established biomarkers for the inhibition of DHTKD1 and the disease. Combined these three aims will yield not only lead inhibitors of DHTKD1 that can be further developed for treatment of GA1, but also important additional data on the biochemistry and physiology of lysine degradation.