Malaria Topoisomerase inhibitors

 描述(申请人提供)：每年，疟疾导致50万人死亡，超过3亿人感染。很少有酶是已批准的抗疟疾药物的明确靶点，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以DNA拓扑异构酶为靶点。虽然该社区缺乏纯粹和稳定的疟疾拓扑异构酶来研究，但从初步数据中有耐人寻味的线索表明，临床批准的抗疟疾药物，如咯萘啶，可能会抑制疟疾拓扑异构酶。美国国立卫生研究院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，建立了强大的恶性疟原虫拓扑异构酶II和相关酶的分析方法，并获得了疟疾拓扑异构酶II的第一个X射线晶体结构。在目标1中，我们将利用这些资源开始深入探索细胞活性抗疟疾药物，以确定领先的PfTopo II抑制剂进行优化。在目标2和目标3中，迭代药物化学将通过抑制酶和细胞增殖、靶点验证、PK-PD研究、安全性评估和针对不同 寄生虫生命周期的各个阶段，所有这些都有助于提供抗疟疾临床前候选方案。基座 根据我们以前的经验、教训和在疟疾二氢甲酸脱氢酶(DHODH)抑制剂方面的成功，我们有信心有能力开发出针对恶性疟原虫和间日疟原虫拓扑异构酶的具有临床潜力的抗疟疾药物。

 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.