Second-Generation Novel Liver Stage Active Antimalarials

项目总结/摘要 尽管为消灭疟疾作出了广泛努力，但疟疾的全球影响仍然令人震惊。我们 已经开发了一种新的抗疟疾吖啶酮化学型，其对肝脏阶段和 血液期疟疾，以及单剂治愈能力和预防复发感染的潜力。的能力 对抗感染的多个阶段是一个强大的工具，一个理想的适合实现 随着消灭疟疾工作的开展，严格的优化过程 生产了一系列第二代吖啶酮，在功效，代谢稳定性， 药代动力学和安全性特征。我们的首要目标是开发一种新的抗疟疾药物， 患有G6 PD缺乏症的人，以及最脆弱的人群-孕妇和儿童， 支持在世界范围内消灭这种疾病。该项目的具体目标是引导 优化研究，以生产第二代候选药物，用于全面的临床前评价， 具有广谱特性，并显示出增强的疗效、安全性、溶解度和代谢/药代动力学 调查对选定的吖啶酮候选药物的耐药性倾向，并确定 通过全基因组测序和分析确定分子靶点;并探索这些靶点的作用方式 使用功能测定和生物分析方法的肝阶段活性抗疟吖啶酮。

PROJECT SUMMARY/ABSTRACT The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. We have developed a novel antimalarial acridone chemotype with dual stage efficacy against both liver stage and blood stage malaria, as well as single-dose cure ability and potential to prevent relapsing infection. The ability to combat multiple stages of the infection represents a powerful tool, and one ideally suited to achieve the broadest possible benefit as the malaria eradication effort proceeds. A rigorous optimization process has produced a series of second-generation acridones with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. Our overarching goal is to develop a novel antimalarial that is safe in individuals with G6PD deficiency, and in the most vulnerable populations – pregnant women and children, thus supporting world-wide elimination of the disease. The specific goal of this project is to conduct lead optimization studies to produce second-generation candidates for full preclinical evaluation that retain the broad-spectrum features and demonstrate enhanced efficacy, safety, solubility, and metabolic/pharmacokinetic profiles; to investigate the propensity for drug resistance to selected acridone candidates and identify the molecular target(s) through whole genome sequencing and analysis; and to explore mode(s) of action for these liver stage active antimalarial acridones using functional assays and bioanalytical approaches.