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）：疟原虫属的寄生虫造成300-5亿例人类疟疾病例，每年造成约100万人死亡。寻找新的新型抗疟药依赖于多种方法，包括天然产物，高通量屏幕，针对重要途径的小型化学文库，或仅仅对以前有效的抗疟药的结构修饰。通过了解目标或途径的知识，可以极大地促进对临床有用药物的良好实验性抗疟药的优先级，优化和进步。化学和基于化学生物学的方法对于目标识别和验证可能很强大，尤其是在紧密相连的情况下开放式生物学工具。我们将研究精选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）建立等生敏感和抗性菌株，以帮助建立对化学生物学联系的信心，然后在基因组DNA测序对每个化学类别（ii）分别开发出一种配体结合蛋白质组学方法以识别药物靶标的基因组DNA测序。为了对我们的方法充满信心，我们将在我们的特定目标中使用不断提高的挑战。在特定目标1中，建立一个良好的基础一组协议，我们将使用具有良好靶标的团队的新抗疟药化学品，首先建立并验证基于蛋白质组学的基因组序列和基于蛋白质组学的方法来识别目标识别。在特定的目标2中，我们全基因组靶标识别方法将扩展到新的抗代谢物，在这些抗代谢物中，与预期相比，作用机理不同且未知。在AIM 3中，我们将将基因组工具应用于全新的抗疟药，其作用机理是完全未知的。这些精心开发和对照研究的研究涉及小型化学分子和基因组工具，将导致通常适用，简化的方法，用于在寄生虫中建立良好的抗菌素及其高价值靶标之间的连接。