Investigating the role of uptake and metabolism in the mechanism of action of the drug N-acetyl-leucine

研究摄取和代谢在药物 N-乙酰亮氨酸作用机制中的作用

• 批准号: 2879189
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2879189
• 关键词: Investigating; role; uptake; metabolism; mechanism

N-acetyl-leucine (NAL) is an acetylated form of the amino acid leucine. Originally used as a treatment for acute vertigo, there is now intense interest in repurposing this drug for other neurological disorders with unmet medical needs. Potential applications include the lysosomal storage disorder Niemann-Pick disease Type C (NPC), for which a successful phase III clinical trial was completed in 2023 (NCT05163288). NAL is a chiral molecule, existing as L and D enantiomers. The L form is of primary interest for clinical development, although the D form can elicit certain therapeutic effects (Kaya et al, 2021). Despite its therapeutic promise, the mechanism of action of NAL remains incompletely understood. This project aims to contribute to our mechanistic understanding of NAL, thereby providing a rational framework to expand its use in rare and common neurological disorders and potentially informing the development of new drugs. The working hypothesis is that NAL is a prodrug of leucine, acting via leucine or its metabolites. A broad outcome of NAL treatment may be to normalise cellular energy production, which has been shown to be dysregulated in NPC (Kennedy et al, 2013). Experimental data also indicate that cellular uptake of NAL utilises a monocarboxylate transporter (MCT) rather than the L-type amino acid transporter (LAT1) used by leucine (Churchill et al, 2021). This may have important mechanistic implications: for example, MCT kinetics could enhance the relative flux through ordinarily minor pathways of leucine metabolism. We will test several independent but interrelated hypotheses regarding the mechanism of NAL. Central aims of the project are as follows:1. To test the role of uptake by a transporter in the mechanism of action of NAL2. To determine the metabolic fate of NAL3. To test the role of metabolism in the mechanism of action of NALExperimental techniques will include molecular and cell biology methods, the use of pharmacological inhibitors, flow cytometry, imaging/microscopy, liquid chromatography and mass spectrometry. Areas of skill development will include quantitative skills such as statistical analysis, development of scientific communication skills, and training for in vivo work if required.

N-乙酰胶氨酸（NAL）是氨基酸亮氨酸的乙酰化形式。最初用作急性眩晕的治疗方法，现在对将这种药物重新利用为其他未满足医疗需求的神经系统疾病引起了浓厚的兴趣。潜在的应用包括溶酶体储存障碍Niemann-Pick型C型（NPC），该疾病在2023年成功完成了III期临床试验（NCT05163288）。 NAL是一种手性分子，以L和D对映异构体存在。尽管D形式可以引起某些治疗作用，但L形式是临床发育的主要兴趣（Kaya等，2021）。尽管具有治疗性的希望，但NAL的作用机理仍然不完全理解。该项目旨在为我们对NAL的机械理解做出贡献，从而提供了一个合理的框架，以扩大其在罕见和常见的神经系统疾病中的使用，并有可能告知新药的发展。工作假设是NAL是亮氨酸的前药，它通过亮氨酸或其代谢产物作用。 NAL治疗的广泛结果可能是使细胞能量产生归一化，在NPC中已显示出失调（Kennedy等，2013）。实验数据还表明，NAL的细胞摄取利用单羧酸酯转运蛋白（MCT），而不是亮氨酸使用的L型氨基酸转运蛋白（LAT1）（Churchill等，2021）。这可能具有重要的机械含义：例如，MCT动力学可以通过亮氨酸代谢的通常较小的途径来增强相对通量。我们将测试有关NAL机制的几个独立但相互关联的假设。该项目的中心目的如下：1。测试转运蛋白在NAL2作用机理中摄取的作用。确定Nal3的代谢命运。为了测试代谢在Nalexpermentiment技术作用机理中的作用，包括分子和细胞生物学方法，使用药理学抑制剂，流式细胞仪，成像/显微镜，液相色谱和质谱法。技能开发领域将包括定量技能，例如统计分析，科学沟通技巧的发展以及如果需要的（如果需要）培训。