Kinase Targeted Antimalarial Agents

激酶靶向抗疟药

基本信息

批准号：
9918203
负责人：
REENA ZUTSHI
金额：
$ 95.77万
依托单位：
LUCEOME BIOTECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-16 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918203
关键词：
Affect Affinity Anopheles Genus Antimalarials Artemisinins Binding Biological Assay Biology CSNK1A1 gene Cessation of life Chemicals Clinical Collection Combined Modality Therapy Communities Country Culicidae Data Development Disease Drug Targeting Drug resistance Erythrocytes Goals Health Human Human Bites Incidence Infection Investments Lead Libraries Life Cycle Stages Luciferases Malaria Maps Medicine Morbidity - disease rate Parasites Pathology Pharmaceutical Preparations Phase Phenotype Phosphotransferases Plasmodium Plasmodium falciparum Plasmodium falciparum genome Plasmodium vivax Private Sector Protein Kinase Public Sector Publishing Reporting Research Resistance Series Technology Trees asexual base candidate selection clinical candidate combat design disorder control drug development genome sequencing improved in vivo inhibitor/antagonist kinase inhibitor knockout gene member mortality next generation novel novel therapeutics open source phosphoproteomics programs protein kinase inhibitor scaffold screening small molecule tool

项目摘要

Project Summary The genome of Plasmodium falciparum, the species responsible for most mortality in malaria, is predicted to encode 86-99 protein kinases. Of these, 36 kinases are expressed in the asexual stage of the parasite’s life-cycle, which is responsible for the pathology associated with the disease. Using our proprietary KinaseSeeker technology, we have recently developed assays against 11 Plasmodium falciparum kinases, which are expressed in the asexual stage. Screening a small-molecule kinase inhibitor library has revealed several chemically tractable chemotypes that bind P. falciparum kinases with sub-micromolar affinity. In this application, using a target-based approach, we aim to utilize the chemotypes identified from our screening data, as starting points for development of potent and selective antimalarial agents. In addition, we will use the already commercialized P. falciparum kinase assays, to identify targets for potential kinase inhibitors that have been shown to be active in phenotypic screens against the parasite. The different series of compounds will then be further optimized for potency and selectivity to deliver leads for new antimalarials and improve human health.

项目摘要恶性疟原虫的基因组是疟疾大多数死亡率的物种，是预测编码86-99蛋白激酶。其中，在无性恋中表达了36种激酶寄生虫生命周期的阶段，该阶段负责与之相关的病理疾病。使用我们的专有Kinaseseeker技术，我们最近开发了测定法针对11个在无性阶段表达的恶性疟原虫激酶。筛选小分子激酶抑制剂库已揭示了几种可化学处理的化学型将恶性疟原虫激酶与亚微摩尔亲和力结合。在此应用中，使用基于目标的方法，我们旨在利用所识别的化学型从我们的筛选数据中，作为发展潜力和选择性抗疟疾的起点代理商。此外，我们将使用已经商业化的恶性疟原虫激酶测定法识别已显示在表型中活跃的潜在激酶抑制剂的靶标针对寄生虫的屏幕。然后，不同的化合物系列将进一步优化为新抗疟药提供潜在客户并改善人类健康的能力和选择性。