Chemical Genomics for Antimalarial Targets

描述（由申请人提供）：疟原虫属寄生虫导致 300-5 亿人类疟疾病例，每年造成约 100 万人死亡。寻找新型抗疟药依赖于多种方法，包括天然产物、高通量筛选、针对重要途径的小型化学库，或者只是对先前活性抗疟药进行结构修饰。通过了解靶点或途径，可以极大地促进将良好的实验性抗疟药物优先化、优化和升级为临床有用的药物。基于化学和化学生物学的方法对于目标识别和验证非常有效，尤其是在紧密联系的情况下 开放式生物工具。我们将研究选定生物活性分子的结构活性关系 (SAR)。对于每个化合物类别，我们将 (i) 建立同基因敏感和耐药菌株，以帮助建立对化学-生物学联系的信心，然后对每个化学类别的同基因菌株进行基因组 DNA 测序 (ii) 分别开发配体结合蛋白质组学方法来识别药物靶点。为了获得对我们方法的信心，我们将在我们的具体目标中使用不断升级的挑战。在具体目标 1 中，建立基础良好的 根据一套协议，我们将首先使用我们团队的新抗疟化学品和经过验证的目标，建立并验证基于基因组序列和蛋白质组学的目标识别方法。在具体目标 2 中，我们的全基因组靶标识别方法将扩展到新的抗代谢药物，其作用机制与预期不同且未知。在目标 3 中，我们将把基因组工具应用于其作用机制完全未知的全新抗疟药。总之，这些精心开发和控制的研究，涉及小化学分子和基因组工具，将产生普遍适用的、简化的方法，在良好的抗疟药和寄生虫中的高价值靶标之间建立联系。

DESCRIPTION (provided by applicant): Parasites of the genus Plasmodium are responsible for 300-500 million cases of human malaria and cause about one million deaths every year. The search for new novel antimalarials relies on a number of approaches including natural products, high-throughput screens, small chemical libraries directed at important pathways, or just structural modification of previously active antimalarials. Prioritization, optimization, and advancement of a good experimental antimalarial to a clinically useful drug may be greatly facilitated by knowledge of the target or the pathway. Chemistry and Chemical Biology based approaches can be powerful for target identification and validation, especially when tightly linked to open-ended biological tools. We will study the Structure Activity Relationships (SAR) of select bioactive molecules. For each compound class, we will (i) establishment isogenic sensitive and resistant strains to help develop confidence in the chemistry-biology links, before genomic DNA sequencing on the isogenic strains for each chemical classes (ii) separately, develop a ligand-binding proteomics approach to identify drug targets. To gain confidence in our approach, we will use escalating challenge in our specific aims. In Specific Aim 1, to establish a well-grounded set of protocols, we will first establish and validate genome-sequence and proteomics- based approaches for target identification, using new antimalarial chemicals from our team with proven targets. In Specific Aim 2, our genome-wide target identification approaches will be expanded to new anti-metabolites where the mechanisms of action are different and unknown, compared to what was expected. In Aim 3, we will apply the genomic tools to completely new antimalarials whose mechanisms of action are completely unknown. Together, these carefully developed and controlled studies, involving small chemical molecules and genomic tools, will lead to generally applicable, streamlined approaches for establishing connections between good antimalarials and their high-value targets in the parasite.