Chemogenomic Profiling of Plasmodium falciparum Drug Responses and Resistance

恶性疟原虫药物反应和耐药性的化学基因组学分析

基本信息

批准号：
8864956
负责人：
John H Adams
金额：
$ 71.84万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-10 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8864956
关键词：
Animal Model Antimalarials Artemisinins Asia Autophagocytosis Biochemical Biochemical Pathway Calcineurin Cell Cycle Cell Line Cells Chemical Actions Chemicals Clinical Collection Combination Drug Therapy Combined Modality Therapy Containment Critical Pathways Data Development Disease Drug Combinations Drug Compounding Drug Targeting Drug resistance Genes Genetic Genetic Polymorphism Genome Genomics Genotype Inhibitory Concentration 50 Knowledge Lead Libraries Link Malaria Maps Metabolic Metabolic Clearance Rate Metabolic Pathway Molecular Mutation Other Genetics Parasites Pathway interactions Pharmaceutical Preparations Phenotype Physiological Plasmodium falciparum Predisposition Process Property Proteins Public Health Regulatory Pathway Research Resistance Signal Transduction System Therapeutic Yeasts artemisinine base drug discovery drug mechanism drug sensitivity feeding genetic regulatory protein global health improved inhibitor/antagonist molecular marker mutant programs public health relevance resistance mechanism response small molecule success trait

项目摘要

DESCRIPTION (provided by applicant): Malaria is a devastating global health problem that will become much worse if resistance to frontline antimalarial drugs continues to spread. The loss of effective drug treatment of Plasmodium falciparum, especially the loss of artemisinin (ART) combination therapy (ACT), would be a global public health catastrophe. Recently, polymorphism in a regulatory protein, the Kelch "K13-propeller" protein was implicated in the loss of efficacy of ART drugs, but the mechanism of resistance is not understood. Understanding the mechanism of ART drug resistance (ART-R) is important for devising ACTs that inhibit further spread of ART-R and for identifying other molecular markers for surveillance and containment programs. Unfortunately, lack of experimentally validated functional information about most P. falciparum genes remains a strategic hurdle for better understanding ART-R and for development of new anti-malarial therapeutics. Better knowledge of essential metabolic pathways and vulnerabilities in the parasite's physiologic engine are critical for defining mechanisms of action of existing drugs, how resistance develops to these drugs as well molecular strategies for effective combination therapies. We propose to use a chemogenomic systems approach to define critical pathways linked to ART-R, understand mechanisms of action of ART and other antimalarial partner drugs, and predict drug combination therapies with optimal synergistic anti-parasite activity to minimize the emergence of resistance.

描述（由申请人提供）：疟疾是一个毁灭性的全球健康问题，如果对一线抗疟药物的耐药性继续蔓延，恶性疟原虫有效药物治疗的丧失，特别是青蒿素（ART）联合疗法的丧失，该问题将变得更加严重。最近，调节蛋白 Kelch“K13-propeller”蛋白的多态性与 ACT 的功效丧失有关。 ART 药物，但耐药机制尚不清楚。了解 ART 耐药性 (ART-R) 的机制对于设计抑制 ART-R 进一步传播的 ACT 以及识别用于监测和遏制计划的其他分子标记非常重要。大多数恶性疟原虫基因缺乏经过实验验证的功能信息，仍然是更好地了解 ART-R 和开发新的抗疟疾疗法的战略障碍。生理引擎对于定义现有药物的作用机制、这些药物的耐药性如何发展以及有效联合治疗的分子策略至关重要。我们建议使用化学基因组系统方法来定义与 ART-R 相关的关键途径，了解作用机制。 ART 和其他抗疟伙伴药物的研究，并预测具有最佳协同抗寄生虫活性的药物联合疗法，以最大限度地减少耐药性的出现。