Molecular Pathways Targeted by Potent Antimalarial Pyrazole Compounds

描述(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100万人死亡。抗疟疾药物是控制疟疾的主要药物，但对大多数抗疟疾药物的寄生虫耐药性的传播令人严重关切。为解决这一关切，已作出协调一致的努力，以发现和开发新的抗疟疾药物，并取得了一些令人鼓舞的初步成果。然而，很明显，在可预见的未来，我们将需要供应抗疟疾药物，因为新药肯定会产生抗药性。最近，我们发现了一系列以吡唑为核心的化合物，它们具有很强的抗疟疾活性。这些化合物正在开发成为一种具有新结构的抗疟疾药物。我们的数据还表明，他们的行动模式可能针对疟疾寄生虫中一条至关重要且迄今未知的脆弱途径。通过应用各种方法，我们建议揭示这一途径的性质及其分子组成。我们在这里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希望的化合物背后的分子机制。我们将使用各种方法来评估恶性疟原虫血液阶段发生的变化，因为它们正在被吡唑化合物迅速杀死。这些将包括：磷蛋白图谱，转录组变化，代谢物变化，钙稳态，以及光镜和电子显微镜下的形态变化。这些研究将提供关于受化合物影响的途径的线索和确认。最近的研究表明，吡唑和另一系列有效的抗疟疾药物螺吲哚可能通过一个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在作用模式上的共同特征。我们将检验一种假设，即吡唑类化合物的靶向途径类似于植物中观察到的磷酸化调节机制。这一假设是基于我们对通过耐药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赋予耐药表型很重要。总体而言，这些研究不仅有可能了解有希望的抗疟疾药物的作用机制，而且还可能为未来的研究揭示新的靶点。)

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.)