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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.

项目概要恶性疟原虫（疟疾死亡率最高的物种）的基因组是预计编码 86-99 个蛋白激酶。其中，36 种激酶在无性细胞中表达寄生虫生命周期的阶段，负责与寄生虫相关的病理学疾病。利用我们专有的 KinaseSeeker 技术，我们最近开发了检测方法对抗 11 种恶性疟原虫激酶，这些激酶在无性阶段表达。筛选小分子激酶抑制剂库揭示了几种化学上易于处理的化学型以亚微摩尔亲和力结合恶性疟原虫激酶。在此应用中，使用基于目标的方法，我们的目标是利用已识别的化学型根据我们的筛选数据，作为开发有效和选择性抗疟药物的起点代理。此外，我们将使用已经商业化的恶性疟原虫激酶测定法来确定潜在激酶抑制剂的靶标，这些抑制剂已被证明在表型中具有活性筛选寄生虫。然后，不同系列的化合物将进一步优化提供新抗疟药和改善人类健康的先导化合物的效力和选择性。