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

• 批准号: 10602420
• 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
• 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/10602420
• 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; Cytoplasm; DNA sequencing; Data; Dependence; Development; Disease; Drug Targeting; Drug Tolerance; Drug resistance; Drug usage; Equilibrium; Evolution; Exhibits; Expression Profiling; Fever; Genes; Genetic; Genomic approach; Genomics; Goals; Halofuginone; Homeostasis; Life; Liver; Malaria; Maps; Mass Spectrum Analysis; Mediating; Mediator; Metabolic; Metabolic Pathway; Metabolism; Molecular; Molecular Target; Natural Products; Organism; Parasite resistance; Parasites; Parasitic Diseases; Parasitology; Pathway interactions; Persons; Pharmaceutical Preparations; 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 Efficacy; Treatment Failure; Up-Regulation; Work; amino acid metabolism; analog; applied biomedical research; 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; synergism; targeted treatment

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.

项目总结