Chemical Genomics for Antimalarial Targets

抗疟靶点的化学基因组学

基本信息

批准号：
9057427
负责人：
PRADIPSINH K. RATHOD
金额：
$ 50.29万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057427
关键词：
Accountability Address Algorithms Antimalarials Antimetabolites Asia Basic Science Biochemical Biological Biological Assay Biological Process Biology Businesses Cells Cessation of life Chemicals Chemistry Controlled Study DNA Sequence Detection Development Dihydroorotate dehydrogenase Disadvantaged Drug Kinetics Drug Targeting Drug resistance Drug toxicity Effectiveness Event Folic Acid Antagonists Future Genetic Genetic Polymorphism Genomic DNA Genomic approach Genomics Goals Grant Human Individual Intervention Kinetics Knowledge Lead Ligand Binding Link Malaria Modification Natural Products 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 gene product genome sequencing genome-wide genomic tools high throughput screening improved inhibitor/antagonist interdisciplinary approach microbial novel pathogen protein farnesyltransferase resistant strain response scaffold small molecule small molecule libraries tool whole genome

项目摘要

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.

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) 建立同基因敏感和抗性菌株，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确定药物靶点的方法。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。