A novel treatment option for disorders of propionate metabolism

丙酸代谢紊乱的新治疗选择

基本信息

批准号：
10284208
负责人：
Robert J DeVita
金额：
$ 8.46万
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：
2021-09-22 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284208
关键词：
Acute Affect Amish Antibiotic Therapy Binding Biochemical Biochemical Genetics Biochemistry Biological Assay Biological Markers Biotin Branched-Chain Amino Acids Cardiomyopathies Cardiovascular system Cell Line Cells Chemicals Childhood Chronic Clinical Management Communities Country Crystallization Data Degradation Pathway Diagnosis Diet Disease Early Intervention Enzyme Inhibitor Drugs Enzymes Evaluation Fasting Future Goals Greenland Hematology Hereditary Disease Human Hyperammonemia Immune In Vitro Inborn Errors of Metabolism Inherited Intake Intervention Inuits Isoleucine Kidney Lead Malnutrition Medical Metabolic Metabolic Diseases Metabolism Methods Modeling Monitor Mutation Neonatal Screening Ophthalmology Outcome Oxidoreductase Patients Permeability Pharmaceutical Chemistry Pharmacologic Substance Pharmacology Pharmacology Study Phenotype Physiology Population Production Property Propionates Publishing Rare Diseases Recombinant Proteins Reporting Research Research Personnel Structure Supplementation Synthesis Chemistry Validation Valine Work acyl-CoA dehydrogenase base body system carnitine supplementation clinically significant dietary drug discovery efficacy testing experimental study follow-up gastrointestinal high throughput screening improved improved outcome in vitro testing inhibitor/antagonist insight isobutyryl-coenzyme A ketotic hyperglycinemia lead optimization liver transplantation medical food mortality neonatal period neurobehavioral novel novel therapeutics organic acid programs propionyl-coenzyme A screening screening program skeletal small molecule treatment optimization validation studies virtual screening

项目摘要

Project Summary / Abstract In this project, the investigators propose to develop a novel treatment option for disorders of propionate metabolism such as propionic acidemia (PA). PA patients may present with acute metabolic decompensation with hyperammonemia, and can develop a multisystem disorder or cardiomyopathy. The disorder is caused by propionyl-CoA carboxylase (PCC) deficiency due to biallelic mutations in PCCA or PCCB. PCC deficiency leads to the accumulation of propionyl-CoA and several organic acids, which are thought to be toxic. PA patients benefit from early intervention and the disorder has been included in newborn screening programs in many countries. Current treatments include acute and chronic interventions all aiming to reduce propiogenic precursors, but the outcome of PA is still unfavorable as many patients have long-term complications that can affect multiple organ systems. In addition, dietary management may lead to nutritional deficiencies in essential branched-chain amino acids (BCAAs). This illustrates the need for new therapeutic options that can further improve outcome in PA. The investigators hypothesize that by using inhibitors upstream in the propiogenic isoleucine and valine degradation pathways, accumulation of toxic propionyl-CoA and its derivatives can be diverted into more tolerable metabolites. Short/branched-chain acyl-CoA dehydrogenase (SBCAD) and isobutyryl-CoA dehydrogenase (ACAD8) are involved in the degradation of the BCAAs isoleucine and valine, respectively. Deficiencies SBCAD and ACAD8 are thought to be biochemical phenotypes without clinical significance. Published and preliminary data show that inhibition of SBCAD and ACAD8 limits metabolite accumulation in cell line models for PA. This suggests that SBCAD and ACAD8 are suitable and potentially safe targets for treatment of PA. Thus, the overall objective of this proposal is to identify and validate novel small-molecule SBCAD and ACAD8 inhibitors suitable for future medicinal chemistry optimization to candidate molecules. In AIM 1, the investigators will optimize enzyme assays for the screening of SBCAD and ACAD8 inhibitor candidates using recombinant proteins. Enzyme inhibitor candidates will be identified in AIM 2 through a computational (virtual) screening using reported crystal structures for human SBCAD and ACAD8. All hits from the virtual screening will be further evaluated in AIM 3 in order to generate a prioritized list of commercial compounds with good medicinal chemistry properties. In AIM 4 selected validated hit molecules will be tested in vitro in cell-based models of PA by monitoring established biomarkers for the inhibition of SBCAD and ACAD8, and the disease. Combined, these four aims will yield not only validated hit inhibitors of SBCAD and ACAD8 that can be further optimized for treatment of PA, but also important insights into the biochemistry and physiology of propionyl-CoA production.

项目概要/摘要在这个项目中，研究人员建议开发一种新的丙酸盐疾病治疗方案代谢，如丙酸血症（PA）。 PA 患者可能出现急性代谢失代偿患有高氨血症，并可能发展为多系统疾病或心肌病。该病症是由于由于 PCCA 或 PCCB 的双等位基因突变导致丙酰辅酶 A 羧化酶 (PCC) 缺乏。 PCC缺乏症导致丙酰辅酶A和几种有机酸的积累，这些有机酸被认为是有毒的。 PA 患者受益于早期干预，该疾病已被纳入新生儿筛查计划许多国家。目前的治疗方法包括急性和慢性干预措施，均旨在减少丙酸原但 PA 的结果仍然不利，因为许多患者有长期并发症，可能会导致影响多个器官系统。此外，饮食管理可能会导致必需营养素的营养缺乏。支链氨基酸 (BCAA)。这说明需要新的治疗选择，可以进一步改善 PA 的结果。研究人员假设，通过在促生素上游使用抑制剂异亮氨酸和缬氨酸降解途径，有毒的丙酰辅酶A及其衍生物的积累可以转化为更容易耐受的代谢物。短/支链酰基辅酶A脱氢酶（SBCAD）和异丁酰辅酶 A 脱氢酶 (ACAD8) 参与支链氨基酸异亮氨酸和缬氨酸的降解，分别。 SBCAD 和 ACAD8 缺陷被认为是生化表型，没有临床证据。意义。已发表的初步数据表明，抑制 SBCAD 和 ACAD8 可限制代谢物 PA 细胞系模型中的积累。这表明 SBCAD 和 ACAD8 是合适的并且有潜力 PA 治疗的安全目标。因此，该提案的总体目标是识别和验证新颖的适用于未来药物化学优化的小分子 SBCAD 和 ACAD8 抑制剂分子。在 AIM 1 中，研究人员将优化用于筛选 SBCAD 和 ACAD8 的酶测定使用重组蛋白的候选抑制剂。 AIM 2 中将通过以下方式确定候选酶抑制剂使用报告的人类 SBCAD 和 ACAD8 晶体结构进行计算（虚拟）筛选。所有点击虚拟筛选结果将在 AIM 3 中进一步评估，以生成商业广告的优先列表具有良好药物化学性质的化合物。在 AIM 4 中，将测试选定的经过验证的命中分子通过监测已建立的抑制 SBCAD 的生物标志物，在基于 PA 的细胞模型中进行体外实验 ACAD8，和疾病。结合起来，这四个目标不仅会产生经过验证的 SBCAD 命中抑制剂， ACAD8 可以进一步优化 PA 的治疗，而且对生物化学和丙酰辅酶A产生的生理学。