Substrate reduction as a novel therapeutic strategy for Glutaric Aciduria Type 1

减少底物作为 1 型戊二酸尿症的新型治疗策略

基本信息

批准号：
10216580
负责人：
Robert J DeVita
金额：
$ 29.64万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216580
关键词：
Acids Acute Address Amish Animal Model Binding Biochemical Biochemical Genetics Biochemistry Biological Biological Assay Biological Markers Caregivers Cell Line Cell model Cells Chemicals Childhood Communities Complex Corpus striatum structure Country Crystallization Data Defect Diagnosis Dietary Intervention Disease Diversity Library Drug Design Drug Kinetics Drug Targeting Dystonia Emergency Care Emergency treatment Enzyme Inhibitor Drugs Enzymes Ethnic group Excretory function Future Genetic Diseases Glutaryl-CoA dehydrogenase Goals Hereditary Disease Hydroxylysine Hyperlysinemias In Vitro Indigenous Injury Intervention Lead Lumbee tribe Lysine Lysine Degradation Pathway Macrocephaly Metabolism Methods Modality Modeling Monitor Movement Disorders Mutation Neonatal Screening Ojibwe Oxidoreductase Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Study Phase Phenotype Physiology Process Property Rare Diseases Research Research Personnel Source South African Structure Structure-Activity Relationship Synthesis Chemistry Therapeutic Tryptophan Validation absorption amino acid metabolism analog base carnitine supplementation clinically significant drug discovery efficacy testing experimental study follow-up glutaric acid glutaric acidemia glutaryl coA high throughput screening improved in vitro testing inhibitor/antagonist mouse model nervous system disorder neurotoxic novel novel therapeutic intervention novel therapeutics pharmacophore pre-clinical programs scaffold screening program small molecule small molecule inhibitor structural biology virtual screening

项目摘要

Project Summary / Abstract In this project, the investigators propose to develop a novel treatment option 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 macrocephaly and may develop a complex movement disorder due to striatal injury after an acute encephalopathic crisis. The disorder is caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH), which leads 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 care. This treatment paradigm requires intense efforts from both caregiver and patient. It must be meticulously maintained, but in some patients neurological disease may still develop. 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 hyperlysinemia is a biochemical phenotype without clinical significance. It is caused by mutations in AASS encoding 2-aminoadipic semialdehyde synthase (AASS), which is an enzyme upstream of GCDH in the lysine degradation pathway. The investigators obtained preliminary data showing that deletion of AASS/Aass limits metabolite accumulation in cell and mouse models for GA1. This suggests that AASS is a suitable and potentially safe target for treatment of GA1. Thus, the overall objective of this proposal is to identify novel small-molecule inhibitors of the lysine-oxoglutarate reductase (LOR) domain of AASS suitable for future medicinal chemistry optimization. In AIM 1, the investigators will identify enzyme inhibitor candidates through both a small molecule high-throughput screen (HTS) and computational (virtual) screening using their recently obtained 2.2Å LOR crystal structure. Then, using structure-based drug design, medicinal chemistry methods and co-crystallization, they will develop preliminary structure-activity relationships to validate new hit analogs as 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 validated hit molecules will be tested in vitro in cell-based models of GA1 by monitoring established biomarkers for the inhibition of LOR and the disease. Combined, these three aims will yield not only highly validated hit inhibitors of LOR that can be further developed for treatment of GA1, but also important additional data on the biochemistry and physiology of lysine degradation.

项目概要/摘要在该项目中，研究人员提议开发一种针对 1 型戊二酸尿症的新治疗方案（GA1；MIM 231670） GA1 是赖氨酸、羟赖氨酸和色氨酸的常染色体隐性先天性错误。患者可能会出现大头畸形，并可能因以下原因出现复杂的运动障碍。急性脑病危象后的纹状体损伤是由戊二酰辅酶A缺乏引起的。脱氢酶（GCDH），导致神经毒性戊二酸和 3-羟基戊二酸的积累 GA1 被认为是一种可治疗的疾病，因此被纳入许多新生儿筛查计划中。然而，目前的治疗包括饮食干预、肉碱补充和这种治疗模式需要护理人员和患者的共同努力。精心维护，但某些患者仍可能出现神经系统疾病。证明需要具有更高功效和便利性的新型治疗选择。研究发现，通过在赖氨酸降解途径上游使用抑制剂，神经毒性的积累 GA1中的戊二酸和3-羟基戊二酸可以转化为更耐受的代谢物。研究表明，高赖氨酸血症是一种没有临床意义的生化表型，它是由基因突变引起的。 AASS 编码 2-氨基己二酸半醛合酶 (AASS)，它是 GCDH 上游的酶研究人员获得的初步数据表明，AASS/Aass 的缺失。限制 GA1 细胞和小鼠模型中的代谢物积累，这表明 AASS 是一种合适且有效的方法。因此，该提案的总体目标是确定新的 GA1 治疗靶点。适合未来的 AASS 赖氨酸氧化戊二酸还原酶 (LOR) 结构域的小分子抑制剂在 AIM 1 中，研究人员将通过以下方式识别酶抑制剂候选物。小分子高通量筛选（HTS）和计算（虚拟）筛选都使用他们最近的技术然后，利用基于结构的药物设计、药物化学方法获得了2.2Å LOR晶体结构。和共结晶，他们将开发初步的结构-活性关系来验证新的热门类似物作为类药物支架，来自 HTS 和虚拟筛选的所有活性命中将在 AIM 2 中进一步评估。为了在 AIM 中生成具有良好药物化学特性的商业化合物的优先列表。将通过监测已建立的 GA1 细胞模型对 3 个选定的经过验证的命中分子进行体外测试结合起来，这三个目标将不仅产生抑制 LOR 和疾病的生物标志物。经过验证的 LOR 命中抑制剂，可以进一步开发用于治疗 GA1，但也是重要的附加功能赖氨酸降解的生物化学和生理学数据。