Chemical Genomics for Antimalarial Targets

描述（由申请人提供）：疟原虫属寄生虫每年导致3 -5亿例人类疟疾病例，并造成约100万人死亡。寻找新的新型抗疟药物依赖于许多方法，包括天然产物、高通量筛选、针对重要途径的小型化学文库，或者只是对先前有效的抗疟药物进行结构修饰。对靶点或途径的了解可能会极大地促进对一种良好的实验性抗疟药的优先排序、优化和推进，使其成为一种临床有用的药物。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，特别是在紧密联系的情况下

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. PUBLIC HEALTH RELEVANCE: Malaria parasites infect over 500 million people and are responsible for over 1 million deaths per year. Cell-based assays and other approaches have revealed thousands of molecules with anti-proliferative activity in culture, but their optimization and advancement to drug-like molecules is often limited by inefficient strategies for target identification and validation. This project will address this need through a multidisciplinary approach combining chemical biology with parasite genetics, and genomics.