Molecular Pathways Targeted by Potent Antimalarial Pyrazole Compounds

有效抗疟吡唑化合物靶向的分子途径

基本信息

批准号：
8605504
负责人：
AKHIL B VAIDYA
金额：
$ 48.87万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605504
关键词：
Abscisic Acid Address Affect Antimalarials Binding Biological Assay Blood Ca(2+)-Transporting ATPase Calcium Cell membrane Clinical Trials Collaborations Computer Simulation Critical Pathways DNA Data Dehydration Development Electrons Event Future Gene Expression Profile Generations Genes Goals Growth Homeostasis Institutes Investigation Knockout Mice Laboratories Lead Light Lipids Malaria Mammalian Cell Mediating Medicine Methods Microscopic Molecular Motor Mutation Myosin ATPase Nature Parasite resistance Parasites Parasitic Diseases Parents Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Phosphoproteins Phosphorylation Physiological Plants Plasmodium falciparum Process Protein phosphatase Proteins Pyrazoles Regulatory Pathway Resistance Series Signal Transduction Staging Structure Structure-Activity Relationship Tertiary Protein Structure Testing Transgenic Organisms Universities Washington Work base calcium-dependent protein kinase cytotoxic deep sequencing design feeding genome sequencing insight interdisciplinary approach killings mutant novel pre-clinical premature receptor response sodium-translocating ATPase steroidogenic acute regulatory protein

项目摘要

DESCRIPTION (provided by applicant): Malaria remains the most important parasitic disease in the world, affecting hundreds of millions of people and killing almost a million every year. Antimalarial drugs are the mainstay of malaria control, but the spread of parasite resistance to most antimalarials is of grave concern. To address this concern, concerted efforts have been directed at discovering and developing new antimalarial drugs, with some encouraging early results. Yet, it is clear that for the foreseeable future we would need to feed the pipeline of antimalarials, because resistance to new drugs is sure to arise. Recently, we have discovered a series of compounds with a pyrazole core that demonstrate highly potent antimalarial activity. These compounds are undergoing the process of development as an antimalarial drug with a novel structure. Our data also suggest that their mode of action is likely to target a vital and a hitherto unknown vulnerable pathway in malaria parasites. By applying a variety of approaches, we propose to uncover the nature of this pathway and its molecular components. The aims we propose here will use both empirical and hypothesis-driven approaches to identify molecular mechanisms underlying this promising series of compounds. We will employ a variety of methods to assess changes occurring in P. falciparum blood stages as they are rapidly being killed by the pyrazole compounds. These will include: phosphoprotein profiling, transcriptome changes, changes in metabolites, calcium homeostasis, and morphological changes at both light and electron microscopic levels. These studies will provide clues, as well as confirmation, regarding the pathways affected by the compounds. Recent studies suggest that pyrazoles and another series of potent antimalarials, spiroindolones, may be working through a common pathway. We will assess common features in mode of action of these two chemically distinct compounds. We will test a hypothesis that the pyrazole compounds are targeting a pathway similar to phosphorylation regulatory mechanisms observed in plants. This hypothesis is based on our initial observation of mutations discovered through whole genome sequencing of resistant parasites that we found to be important in imparting the resistance phenotype. Overall, these studies has the potential not only to understand mechanism of action for promising antimalarials but also to reveal new targets for future investigations.)

描述（由申请人提供）：疟疾仍然是世界上最重要的寄生虫病，每年影响数亿人并导致近百万人死亡。抗疟药物是控制疟疾的支柱，但寄生虫对大多数抗疟药物产生耐药性的蔓延令人严重关切。为了解决这一问题，人们共同努力发现和开发新的抗疟药物，并取得了一些令人鼓舞的早期成果。然而，很明显，在可预见的未来，我们将需要供应抗疟药的管道，因为肯定会出现对新药的耐药性。最近，我们发现了一系列具有吡唑核心的化合物，具有高效的抗疟活性。这些化合物正在作为具有新颖结构的抗疟药物进行开发。我们的数据还表明，它们的作用方式很可能针对疟疾寄生虫中一个重要且迄今未知的脆弱途径。通过应用多种方法，我们建议揭示该途径及其分子成分的本质。我们在此提出的目标将使用经验和假设驱动的方法来确定这一系列有前途的化合物背后的分子机制。我们将采用多种方法来评估恶性疟原虫血液阶段发生的变化，因为它们被吡唑化合物迅速杀死。这些包括：磷蛋白分析、转录组变化、代谢物变化、钙稳态以及光和电子显微镜水平上的形态变化。这些研究将提供有关受化合物影响的途径的线索和确认。最近的研究表明，吡唑类药物和另一系列强效抗疟药螺吲哚酮类药物可能通过共同的途径发挥作用。我们将评估这两种化学上不同的化合物作用模式的共同特征。我们将测试一个假设，即吡唑化合物的靶向途径类似于在植物中观察到的磷酸化调节机制。这一假设基于我们对通过抗性寄生虫全基因组测序发现的突变的初步观察，我们发现这些突变对于赋予抗性表型很重要。总体而言，这些研究不仅有可能了解有前景的抗疟药的作用机制，而且有可能揭示未来研究的新目标。）