Plasmodium Protein Kinase Focused Antimalarials Discovery

疟疾仍然困扰着世界上大约一半的人口，导致40多万人死亡，其中大部分是儿童。它是 令人震惊的是，疟疾治疗的选择正变得越来越有限，因为 抗药性。此外，大多数抗疟疾药物只作用于红细胞阶段，治疗疟疾的药物 疟疾的预防和复发是次要的。为了解决疟疾治疗的脆弱性，我们建议 发现和优化作用于未被开发的疟原虫激酶的下一代抗疟疾药物。我们会 利用与药物开发相关的各种化学支架和专有技术的丰富知识 以及对各种人类疾病的基于激酶抑制剂的治疗的耐受性。我们将重点研究II型激酶 通过使用ATP结合位点以及 由非活性构象中的活化环产生的相邻疏水区。尽我们最大努力 据了解，II型抑制剂作为抗疟疾药物仍有待探索。这项提议的前提是 关于我们有希望的初步筛选，已经确定了第二类化合物具有治疗和预防作用 活动。这个项目的目标是检验我们可以设计出有效的第二类化学物质的假设。 作用于寄生虫发育的多个阶段的支架。为达致这个目标，我们建议推行 (1)设计和合成优化的选择性抗疟疾II型化合物，用于体内应用； 抗疟原虫药物将通过以下途径优化，以提高效力、选择性和药理特性 生物和生化活动的迭代模拟设计、合成和评估阶段。(2) 测定先导化合物对小鼠和小鼠的杀伤率、耐药性、阶段敏感性和有效性 人性化的老鼠模型。此外，先导化合物抑制肝期感染和 将对配子体成熟度进行评估。3)我们将利用体外实验确定抗疟疾化学类型的靶点 抗药性的进化之后是全基因组测序。我们将使用有条件的取消和复制 用于靶标验证的阻力决定因素的数量变化。我们将进行磷酸化蛋白质组学 分析以发现被研究中的II型抑制物调制的信号通路。这方面的研究 将通过Debopam实验室之间的多学科合作进行努力 查克拉巴蒂(中佛罗里达大学)、纳撒尼尔·格雷(斯坦福大学)、伊丽莎白·温泽勒 (加州大学圣地亚哥分校)拥有药物化学、激酶化学生物学、 疟疾细胞生物学、抗感染药物发现、目标识别和验证。成功完成 这些目标将导致发现具有治疗和预防潜力的新的化学先导化合物。

Malaria still afflicts about half of the world population causing more than 400,000 deaths, mostly children. It is quite alarming that the options for malaria therapy are increasingly becoming limited because of widespread drug resistance. Furthermore, most of the antimalarials act only on the erythrocytic stages, the drugs for prophylaxis and relapse of malaria are suboptimal. To address the fragility of malaria therapy, we propose to discover and optimize next generation antimalarials acting on underexplored Plasmodium kinases. We will leverage wealth of knowledge on diverse chemical scaffolds and know-how related to the drug development and tolerability of kinase inhibitor-based therapies for various human diseases. We will focus on type II kinase inhibitors that have been designed to overcome selectivity issues by using both the ATP-binding site as well as the adjacent hydrophobic region created by the activation loop in the inactive conformation. To the best of our knowledge, type II inhibitors are yet to be explored as antimalarial agents. Premise for this proposal is based on our promising preliminary screening that has identified type II compounds with therapeutic and prophylactic activities. The goal of this project is to test the hypothesis that we can design effective type II chemical scaffolds that act on multiple stages of parasite development. To achieve this goal, we propose to pursue the following: (1) Design and synthesize optimized selective antimalarial type II compounds for in vivo application; antiplasmodial hits will be optimized to improve potency, selectivity, and pharmacological properties through stages of iterative analog design, synthesis, and evaluation of biological and biochemical activities. (2) Determine rate of killing, resistance profile, stage susceptibility, and efficacy of lead compounds in murine and humanized mouse models. Furthermore, the ability of the lead compounds to inhibit liver stage infection and gametocyte maturation will be assessed. 3) We will identify targets of antimalarial chemotypes using in vitro evolution of resistance followed by whole genome sequencing. We will use conditional knockdown and copy number variation of the resistance determinants for target validation. We will conduct phosphoproteomics analysis to uncover signaling pathways modulated by the type II inhibitors under study. The research in this endeavor will be conducted through a multidisciplinary collaboration between the laboratories of Debopam Chakrabarti (University of Central Florida), Nathanael Gray (Stanford University), Elizabeth Winzeler (University of California San Diego) with combined expertise in medicinal chemistry, kinase chemical biology, malaria cell biology, anti-infective discovery, target identification, and validation. Successful completion of these goal will lead to the discovery of novel chemical leads with therapeutic and prophylactic potential.