Chemical Genomics for Antimalarial Targets

抗疟靶点的化学基因组学

• 批准号: 8284154
• 负责人: PRADIPSINH K. RATHOD
• 金额: $ 51.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284154
• 关键词: Accountability; Address; Algorithms; Antimalarials; Antimetabolites; Asia; Basic Science; Biochemical; Biological; Biological Assay; Biological Factors; Biological Process; Biology; Businesses; Cells; Cessation of life; Chemicals; Chemistry; Controlled Study; DNA Sequence; Detection; Development; Dihydroorotate dehydrogenase; Disadvantaged; Drug Delivery Systems; Drug Kinetics; Drug resistance; Drug toxicity; Effectiveness; Event; Folic Acid Antagonists; Future; Genetic; Genetic Polymorphism; Genomics; Goals; Grant; Human; Individual; Intervention; Kinetics; Knowledge; Lead; Ligand Binding; Link; Malaria; Modification; Parasites; Pathway interactions; Pharmaceutical Preparations; Plasmodium; Plasmodium falciparum; Property; Proteins; Proteomics; Protocols documentation; Request for Applications; Research; Research Design; Resistance; Running; Staging; Structure; Structure-Activity Relationship; System; Testing; Thymidylate Synthase; Toxic effect; Translational Research; Validation; Writing; base; candidate validation; drug candidate; drug metabolism; fluoropyrimidine; genome sequencing; genome-wide; high throughput screening; improved; inhibitor/antagonist; interdisciplinary approach; microbial; novel; pathogen; protein farnesyltransferase; resistant strain; response; scaffold; small molecule; small molecule libraries; tool

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.

描述（由申请人提供）：疟原虫属的寄生虫造成3 - 5亿例人类疟疾病例，每年造成约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，或仅对先前活性抗疟药物进行结构修饰。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优先化、优化和发展为临床有用的药物。基于化学和化学生物学的方法对于目标识别和验证是强大的，特别是当紧密相连时 开放式的生物工具。我们将研究选择的生物活性分子的结构活性关系（SAR）。对于每种化合物类别，我们将（i）建立等基因敏感和耐药菌株，以帮助建立化学-生物学联系的信心，然后对每种化学类别的等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以识别药物靶标。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逐步升级的挑战。在具体目标1中，建立一个基础良好的 在一系列协议中，我们将首先建立和验证基于基因组序列和蛋白质组学的目标识别方法，使用我们团队的新抗疟化学品，并证明目标。在特定目标2中，我们的全基因组靶标鉴定方法将扩展到新的抗代谢物，与预期相比，其作用机制是不同的和未知的。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，将导致普遍适用的，简化的方法，建立良好的抗疟药物和寄生虫中的高价值目标之间的联系。 疟疾寄生虫感染超过5亿人，每年造成100多万人死亡。基于细胞的测定和其他方法已经揭示了数千种在培养中具有抗增殖活性的分子，但是它们的优化是不可能的。 并且向药物样分子的进展通常受到用于靶点鉴定和验证的低效策略的限制。该项目将通过将化学生物学与寄生虫遗传学和基因组学相结合的多学科方法来解决这一需求。