Malaria Topoisomerase inhibitors

疟疾拓扑异构酶抑制剂

基本信息

批准号：
9029062
负责人：
PRADIPSINH K. RATHOD
金额：
$ 43.11万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029062
关键词：
Aminacrine Anti-Bacterial Agents Antimalarials Antineoplastic Agents Artemisinins Binding Proteins Biological Biological Assay Budgets Cell Proliferation Cells Cessation of life Chemicals Clinical Communities Complex DNA DNA Topoisomerases Data Decision Making Development Dihydroorotate Dehydrogenase Inhibitor Distant Drug Kinetics Drug Targeting Drug resistance Effectiveness Enzyme Inhibition Enzymes Evaluation Funding Future Genetic Transcription Genome Grant Review Human In Vitro Individual Intervention Ion Channel Laboratories Lead Life Cycle Stages Liver Malaria Metabolic Metabolism Monitor Nuclear Parasites Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Plasmodium Plasmodium falciparum Plasmodium vivax Plastids Property Prophylactic treatment Research Research Personnel Resources Rodent SCID Mice Safety Secure Series Solubility Staging Streptococcus Structure Structure-Activity Relationship Suggestion Testing Topoisomerase Topoisomerase II Topoisomerase Inhibitors Topoisomerase-II Inhibitor United States National Institutes of Health Validation Work antimicrobial drug artemisinine base cell killing drug development drug discovery enzyme activity experience improved inhibitor/antagonist killings knowledge base mitochondrial genome mouse model nanomolar new therapeutic target novel pathogen pre-clinical programs protein structure public health relevance pyronaridine repaired resistance frequency response safety study scaffold success tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Yearly, malaria kills 0.5 million people and infects over 300 million individuals. Few enzymes are unambiguous targets of approved antimalarials, so new high-value metabolic targets and their inhibitors are needed. Many clinically approved antibacterial and anticancer agents target DNA topoisomerases. While the community has lacked pure and stable malarial topoisomerases to work with, there are intriguing hints from preliminary data that clinically-approved antimalarials, such as pyronaridine, may inhibit malaria topoisomerases. A three-year NIH-funded research program has allowed our team to express large quantities of stable malaria topoisomerases, to setup robust assays for Plasmodium falciparum topoisomerase II and related enzymes, and to obtain the first x-ray crystal structure of a malarial topoisomerase II. With these resources, in Aim 1, we will start a thorough exploration of cell-active antimalarials to identify front-runner PfTopoII inhibitors for optimizaton. In Aims 2 and 3, iterative medicinal chemistry will be guided by inhibition of enzyme and cell proliferation, target validation, PK-PD studies, safety evaluations, and activity against different stages of the parasite life-cycle, all to help deliver an antimalarial preclinical candidate. Based on our previous experiences, learnings, and success with malarial dihydroorotate dehydrogenase (DHODH) inhibitors, we are confident in our ability to develop antimalarials directed at P. falciparum and P. vivax topoisomerases that have clinical potential.

描述（由申请人提供）：疟疾每年导致 50 万人死亡并感染超过 3 亿人。很少有酶是已批准的抗疟药的明确靶点，因此需要新的高价值代谢靶点及其抑制剂。许多临床批准的抗菌和抗癌药物。虽然社区缺乏可使用的纯且稳定的疟疾拓扑异构酶，但初步的研究发现了一些有趣的线索。临床批准的抗疟药（例如吡咯烷）可能抑制疟疾拓扑异构酶的数据表明，由 NIH 资助的一项为期三年的研究计划使我们的团队能够表达大量稳定的疟疾拓扑异构酶，从而建立针对恶性疟原虫拓扑异构酶 II 和相关酶的可靠检测方法。，并获得疟疾拓扑异构酶 II 的第一个 X 射线晶体结构。利用这些资源，我们将实现目标 1。开始对细胞活性抗疟药进行彻底探索，以确定用于优化的领跑者 PfTopoII 抑制剂。在目标 2 和 3 中，迭代药物化学将以抑制酶和细胞增殖、靶点验证、PK-PD 研究、安全性评估为指导。和针对不同的活动寄生虫生命周期的各个阶段，所有这些都是为了帮助提供基于抗疟疾的临床前候选药物。根据我们之前在疟疾二氢乳清酸脱氢酶 (DHODH) 抑制剂方面的经验、学习和成功，我们对开发针对恶性疟和间日疟拓扑异构酶且具有临床潜力的抗疟药物的能力充满信心。