Chemical Genomics for Antimalarial Targets

描述(申请人提供)：疟原虫属寄生虫每年造成3亿-5亿人疟疾病例，并导致约100万人死亡。寻找新的抗疟疾药物依赖于许多方法，包括天然产物、高通量筛选、针对重要途径的小化学库，或者只是对先前活性的抗疟疾药物进行结构修饰。对靶点或途径的了解可以极大地促进良好的实验性抗疟疾药物向临床有用药物的优先排序、优化和进展。基于化学和化学生物学的方法可以强大地识别和验证目标，特别是在紧密联系的情况下 到开放式生物工具。我们将研究部分生物活性分子的构效关系(SAR)。对于每一类化合物，我们将(I)建立等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，然后对每一类化合物的等基因菌株进行基因组DNA测序(Ii)开发一种配体结合蛋白质组学方法来识别药物靶标。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，建立有根基的 在一套方案中，我们将首先建立和验证基于基因组序列和蛋白质组学的靶标识别方法，使用来自我们团队的新的抗疟疾药物，具有已证实的靶标。在具体目标2中，我们的全基因组靶标识别方法将扩展到与预期相比作用机制不同和未知的新的抗代谢产物。在目标3中，我们将把基因组工具应用于作用机制完全未知的全新抗疟疾药物。总之，这些精心开发和控制的研究，包括小化学分子和基因组工具，将导致普遍适用的、简化的方法，在良好的抗疟疾药物和它们在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.