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

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.
项目总结/摘要 在这个项目中,研究人员建议开发一种新的治疗方案,用于丙酸障碍 代谢,如丙酸血症(PA)。PA患者可能出现急性代谢失代偿 高氨血症,并可能发展为多系统疾病或心肌病。这种紊乱是由 由于PCCA或PCCB中的双等位基因突变导致的丙酰辅酶A羧化酶(PCC)缺乏。PCC缺陷 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,所有这些都旨在减少丙酸 前体,但PA的结果仍然是不利的,因为许多患者有长期并发症, 影响多个器官系统此外,饮食管理可能会导致营养缺乏症的基本 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结果。研究人员假设,通过在促丙酸酶上游使用抑制剂, 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, 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(ACAD 8)参与BCAA异亮氨酸和缬氨酸的降解, 分别缺陷型SBCAD和ACAD 8被认为是没有临床意义的生化表型。 意义已发表的和初步的数据表明,SBCAD和ACAD 8的抑制限制了代谢物 在PA的细胞系模型中的累积。这表明SBCAD和ACAD 8是合适的, 治疗PA的安全靶点。因此,本提案的总体目标是确定和验证新的 适用于未来药物化学优化的小分子SBCAD和ACAD 8抑制剂 分子。在AIM 1中,研究人员将优化筛选SBCAD和ACAD 8的酶测定法。 使用重组蛋白的抑制剂候选物。酶抑制剂候选物将在AIM 2中通过 使用报道的人SBCAD和ACAD 8的晶体结构进行计算(虚拟)筛选。所有命中 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,将检测选定的经验证的命中分子 通过监测用于抑制SBCAD的已建立生物标志物,在PA的基于细胞的体外模型中, ACAD 8和疾病。结合起来,这四个目标将不仅产生SBCAD的有效抑制剂, ACAD 8可以进一步优化PA的治疗,但也是对生物化学和 丙酰辅酶A生产的生理学。

项目成果

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Robert J DeVita其他文献

Robert J DeVita的其他文献

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{{ truncateString('Robert J DeVita', 18)}}的其他基金

Allosteric regulation of lysine degradation as a novel pathophysiological mechanism in glutaric aciduria type 1
赖氨酸降解的变构调节作为 1 型戊二酸尿症的一种新的病理生理机制
  • 批准号:
    10720740
  • 财政年份:
    2023
  • 资助金额:
    $ 8.46万
  • 项目类别:
Preclinical Validation of Novel Gut-Restricted LRRK2 Inhibitors as Therapeutic Leads for IBD
新型肠道限制性 LRRK2 抑制剂作为 IBD 治疗先导药物的临床前验证
  • 批准号:
    10706472
  • 财政年份:
    2022
  • 资助金额:
    $ 8.46万
  • 项目类别:
Preclinical Validation of Novel Gut-Restricted LRRK2 Inhibitors as Therapeutic Leads for IBD
新型肠道限制性 LRRK2 抑制剂作为 IBD 治疗先导药物的临床前验证
  • 批准号:
    10450467
  • 财政年份:
    2022
  • 资助金额:
    $ 8.46万
  • 项目类别:
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
  • 批准号:
    10396619
  • 财政年份:
    2021
  • 资助金额:
    $ 8.46万
  • 项目类别:
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
  • 批准号:
    10216580
  • 财政年份:
    2021
  • 资助金额:
    $ 8.46万
  • 项目类别:
Biological and Medicinal Chemistry Approaches to Human Beta Cell Regeneration
人类 β 细胞再生的生物和药物化学方法
  • 批准号:
    10025889
  • 财政年份:
    2020
  • 资助金额:
    $ 8.46万
  • 项目类别:
Modulate Cullin-RING E3 ubiquitin ligases by small molecule agents
通过小分子试剂调节 Cullin-RING E3 泛素连接酶
  • 批准号:
    10434891
  • 财政年份:
    2020
  • 资助金额:
    $ 8.46万
  • 项目类别:
Biological and Medicinal Chemistry Approaches to Human Beta Cell Regeneration
人类 β 细胞再生的生物和药物化学方法
  • 批准号:
    10363716
  • 财政年份:
    2020
  • 资助金额:
    $ 8.46万
  • 项目类别:
Modulate Cullin-RING E3 ubiquitin ligases by small molecule agents
通过小分子试剂调节 Cullin-RING E3 泛素连接酶
  • 批准号:
    10030712
  • 财政年份:
    2020
  • 资助金额:
    $ 8.46万
  • 项目类别:
Modulate Cullin-RING E3 ubiquitin ligases by small molecule agents
通过小分子试剂调节 Cullin-RING E3 泛素连接酶
  • 批准号:
    10668982
  • 财政年份:
    2020
  • 资助金额:
    $ 8.46万
  • 项目类别:

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