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：
10396619
负责人：
Robert J DeVita
金额：
$ 16.9万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396619
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 Chippewa 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 Oxidoreductase Patients Permeability Persons 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 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.

项目摘要 /摘要在这个项目中，研究人员建议开发一种新型谷氨酸酸尿1型的治疗选择（GA1; MIM 231670）。 GA1是赖氨酸，羟基胺和色氨酸的常染色体隐性先天误差降解。患者可以出现脑畸形，并可能由于急性脑病危机后的纹状体损伤。该疾病是由谷胱甘肽-COA缺乏引起的脱氢酶（GCDH），导致神经毒性谷氨酸和3-羟基谷物的积累酸。 GA1被认为是可治疗障碍，因此在许多人中包括在新生儿筛查计划中国家。但是，当前的治疗包括饮食干预，补充肉碱和紧急护理。这种治疗范式需要照顾者和患者的巨大努力。一定是精心维护，但在某些患者中，神经疾病可能仍会发展。这些限制证明需要提高效率和便利性的新型热选择。调查人员假设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中的谷氨酸和3-羟基氯丁酸可以转移到更耐受的代谢物中。它一直表明高质量血症是一种具有临床意义的生化表型。它是由突变引起的编码2-氨基丙二醇半甲醛合酶（AASS）的AASS，它是GCDH上游的酶赖氨酸降解途径。研究人员获得了初步数据，表明删除AASS/AASS 限制GA1的细胞和小鼠模型中的代谢物积累。这表明AASS是合适的，并且可能安全的GA1治疗目标。这是该提议的总体目标是确定新颖赖氨酸 - 氧基戊二酸还原酶（LOR）AASS的小分子抑制剂适合将来药物化学优化。在AIM 1中，调查人员将通过小分子高通量屏幕（HTS）和计算（虚拟）筛选都获得2.2ÅLOR晶体结构。然后，使用基于结构的药物设计，药物化学方法和共结晶，他们将发展初步的结构活性关系，以验证新的命中类似物作为类似毒品的脚手架。 HTS和虚拟筛选的所有主动命中均在AIM 2中进一步评估为了生成具有良好医学化学特性的商业化合物的优先级清单。目标 3个选定的经过验证的HIT分子将通过监测已建立的GA1的细胞模型进行体外测试生物标志物抑制LOR和疾病。结合在一起，这三个目标不仅会高度产生经过验证的LOR的命中抑制剂，可以进一步开发用于治疗GA1的抑制剂，但也很重要有关赖氨酸降解的生物化学和生理学的数据。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1.

人赖氨酸-2-氧化戊二酸还原酶结构域的表征和结构，这是治疗 1 型戊二酸尿症的新治疗靶点。

DOI：
10.1098/rsob.220179
发表时间：
2022-09
期刊：
Open biology
影响因子：
5.8
作者：
通讯作者：

A case of hyperlysinemia identified by urine newborn screening.

DOI：
10.1002/jmd2.12399
发表时间：
2023-11
期刊：
JIMD reports
影响因子：
0
作者：
Yeganeh M;Auray-Blais C;Maranda B;Sabovic A;DeVita RJ;Lazarus MB;Houten SM
通讯作者：
Houten SM

Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1.

人琥珀酰辅酶 A：戊二酸辅酶 A 转移酶（1 型戊二酸尿症的遗传修饰剂）的表征、结构和抑制。

DOI：
10.1101/2024.02.07.578422
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Khamrui,Susmita;Dodatko,Tetyana;Wu,Ruoxi;Leandro,João;Sabovic,Amanda;Violante,Sara;Cross,JustinR;Marsan,Eric;Kumar,Kunal;DeVita,RobertJ;Lazarus,MichaelB;Houten,SanderM
通讯作者：
Houten,SanderM