Proline homeostasis: a novel mediator of drug tolerance in Plasmodium falciparum

脯氨酸稳态：恶性疟原虫耐药性的新型介质

基本信息

批准号：
10374013
负责人：
Ralph Mazitschek
金额：
$ 69.96万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374013
关键词：
Address Amino Acyl-tRNA Synthetases Antimalarials Artemisinins Binding Biochemical Biology Cell Line Cell physiology Cellular Stress Cessation of life Chinese Traditional Medicine Combined Modality Therapy DNA sequencing Data Dependence Development Disease Drug Targeting Drug Tolerance Drug resistance Drug usage Equilibrium Evolution Exhibits Expression Profiling Fever Genes Genetic Genomics Goals Halofuginone Homeostasis Life Liver Malaria Maps Mass Spectrum Analysis Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Molecular Molecular Target Natural Products Organism Parasite resistance Parasites Parasitic Diseases Parasitology Pathway interactions Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacology Physiological Plasmodium Plasmodium falciparum Point Mutation Prevention Process Proline Protein Isoforms Proteome Proteomics Publishing Regulation Reporting Research Research Project Grants Resistance Signal Transduction Source Synthesis Chemistry Technology Transfer RNA Treatment Failure Up-Regulation Work amino acid metabolism analog applied biomedical research base chemotherapy febrifugine genome-wide in vivo inhibitor insight metabolomics new therapeutic target next generation non-genetic novel novel therapeutics prevent proline-tRNA resistance mechanism response targeted treatment treatment strategy

Address Amino Acyl-tRNA Synthetases Antimalarials Artemisinins Binding Biochemical Biology Cell Line Cell physiology Cellular Stress Cessation of life Chinese Traditional Medicine Combined Modality Therapy DNA sequencing Data Dependence Development Disease Drug Targeting Drug Tolerance Drug resistance Drug usage Equilibrium Evolution Exhibits Expression Profiling Fever Genes Genetic Genomics Goals Halofuginone Homeostasis Life Liver Malaria Maps Mass Spectrum Analysis Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Molecular Molecular Target Natural Products Organism Parasite resistance Parasites Parasitic Diseases Parasitology Pathway interactions Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacology Physiological Plasmodium Plasmodium falciparum Point Mutation Prevention Process Proline Protein Isoforms Proteome Proteomics Publishing Regulation Reporting Research Research Project Grants Resistance Signal Transduction Source Synthesis Chemistry Technology Transfer RNA Treatment Failure Up-Regulation Work amino acid metabolism analog applied biomedical research base chemotherapy febrifugine genome-wide in vivo inhibitor insight metabolomics new therapeutic target next generation non-genetic novel novel therapeutics prevent proline-tRNA resistance mechanism response targeted treatment treatment strategy

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项目摘要

PROJECT SUMMARY Sustained availability of efficacious drugs is essential for worldwide efforts to eradicate malaria. The emergence and spread of drug resistance to current antimalarial therapies remains a pressing concern with reports of artemisinin-based treatment failures escalating the need for novel antimalarial chemotherapies. Thus the discovery of new druggable targets and pathways, including those that are critical for multiple life stages, is a major challenge for the development of next-generation therapeutics. Using an integrated chemogenomic approach, we have identified the cytoplasmic prolyl tRNA synthetase in Plasmodium falciparum (PfcPRS) as the long-sought biochemical target of halofuginone. Furthermore, we uncovered an unprecedented mechanism of drug-tolerance in the parasite by modulation of proline homeostasis. In this proposal, we seek to understand the molecular basis of the parasite’s ability to sense and evolve resistance to halofuginone via the Adaptive Proline Response (APR). We bring an integrated approach combining our expertise in molecular parasitology, metabolomics, genetics, and synthetic chemistry to probe these aspects of aminoacyl tRNA synthetase biology and inhibition in the parasite. We will investigate a non-genetic mechanism of resistance to the PfcPRS inhibitor, halofuginone. We identify the primary source of increased intracellular proline in response to halofuginone treatment and strategies to circumvent this process. We will determine if increased proline levels in parasites exhibiting the APR are mediated by changes in key metabolic pathways at the genomic or proteomic level, using high-coverage DNA sequencing and quantitative mass spectrometry-based proteomic technologies. We will explore APR-independent mechanisms of aaRS inhibition in the parasite, evaluating PRS inhibitors with differing binding modes.

项目摘要持续的有效药物可用性对于全球放射性疟疾的努力至关重要。出现耐药性对当前抗疟疾疗法的传播仍然是一个紧迫的关注点基于青蒿素的治疗失败逐渐增加了对新型抗疟疾化学疗法的需求。就是这样发现新的可吸毒目标和途径，包括对多个生命阶段至关重要的靶标的，是一个下一代疗法发展的主要挑战。使用整合化学生成方法，我们已经确定恶性疟原虫（PFCPRS）是halofuginone的长期生化靶标。此外，我们通过调节脯氨酸稳态，发现了寄生虫中耐药的前所未有的机制。在此提案中，我们试图了解寄生虫感知和发展能力的分子基础通过自适应脯氨酸反应（APR）对卤素酮的抗性。我们带来综合方法结合我们在分子寄生虫学，代谢组学，遗传学和合成化学方面的专业知识以证明寄生虫中氨基酰基TRNA合成酶生物学和抑制的这些方面。我们将研究一种对PFCPRS抑制剂Halofuginone的抗性机制。我们确定响应晕枪酮治疗和策略的细胞内脯氨酸增加的主要来源绕过这个过程。我们将确定表现出APR的寄生虫中的脯氨酸水平是否增加是由变化的变化介导的使用高覆盖的DNA测序和基因组或蛋白质组学水平的关键代谢途径基于定量质谱的蛋白质组学技术。我们将探索寄生虫中AARS抑制的APR无关机制，评估PRS抑制剂具有不同的绑定模式。