Kinase Targeted Antimalarial Agents

项目摘要 恶性疟原虫是导致疟疾死亡最多的物种，其基因组是 预测编码86-99个蛋白激酶。其中，36个激酶在无性系中表达 寄生虫生命周期的阶段，这是与 疾病。使用我们专有的KinaseSeeker技术，我们最近开发了分析方法 针对11个恶性疟原虫蛋白激酶，它们在无性阶段表达。筛选 一个小分子激酶抑制剂库已经发现了几种化学上易处理的化学类型 它以亚微摩尔亲和力结合恶性疟原虫的蛋白激酶。 在本应用程序中，使用基于目标的方法，我们的目标是利用识别的化学类型 从我们的筛查数据来看，作为开发有效和选择性抗疟疾药物的起点 探员们。此外，我们将使用已经商业化的恶性疟原虫激酶检测，以 确定已被证明具有表型活性的潜在激酶抑制剂的靶点 对寄生虫进行筛选。然后，将进一步优化不同系列的化合物 效力和选择性，为新的抗疟疾药物提供线索，并改善人类健康。

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.