Malaria Topoisomerase inhibitors

疟疾拓扑异构酶抑制剂

基本信息

批准号：
9203608
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/9203608
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 Clinical Data Communities Complex Crystallization DHODH gene DNA DNA Topoisomerases Development Dihydroorotate dehydrogenase 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 Learning Life Cycle Stages Liver Malaria Metabolic Metabolism Modernization Monitor Nuclear Parasites Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Plasmodium Plasmodium falciparum Plasmodium vivax Plastids Property Prophylactic treatment Research Research Personnel Resources Rodent Roentgen Rays SCID Mice Safety Secure Series Solubility Streptococcus Structure Structure-Activity Relationship Suggestion Testing Topoisomerase Topoisomerase II Topoisomerase Inhibitors United States National Institutes of Health Validation Work antimicrobial drug base cell killing clinical candidate 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 scaffold success targeted agent 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（由适用提供）：每年，疟疾杀死50万人，并感染了3亿多人。很少有酶是认可的抗疟药的明确靶标，因此需要新的高价值代谢靶标及其抑制剂。许多临床批准的抗菌和抗癌剂靶向DNA拓扑酶。尽管社区缺乏纯粹和稳定的疟疾拓扑异构酶，但初步数据的提示令人着迷，即临床批准的抗疟药（例如吡inar虫）可能会抑制疟疾拓扑异构酶。一项为期三年的NIH资助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，以设置对恶性疟原虫拓扑异构酶II和相关酶的强大暗杀，并获得首个疟疾拓扑异构酶II的X射线晶体结构。有了这些资源，在AIM 1中，我们将开始对细胞活性抗疟药的彻底探索，以鉴定优化的前跑者Pftopoii抑制剂。在目标2和3中，迭代药物化学将通过抑制酶和细胞增殖，靶标验证，PK-PD研究，安全评估以及针对不同不同的活动来指导。寄生虫生命周期的阶段，所有这些都有助于提供抗菌临床前候选者。基于在我们以前的经验，学习和成功的糖二氢甲酸脱氢酶（DHODH）抑制剂方面，我们对开发针对恶性疟原虫和维瓦克斯P. topoisomerases的抗疟药的能力充满信心，这些能力具有临床潜力。