Second-Generation Novel Liver Stage Active Antimalarials

项目摘要/摘要 尽管为根除疟疾作出了广泛努力，但疟疾对全球的影响仍然令人震惊。我们 已经开发出一种新的抗疟疾阿克利酮化疗类型，对肝期和慢性疟疾具有双重疗效 血液期疟疾，以及单剂治疗预防复发感染的能力和潜力。一种能力 与感染的多个阶段作斗争是一个强大的工具，也是实现 随着根除疟疾工作的进行，最大可能的好处是。严格的优化过程具有 生产了一系列第二代吖啶酮类药物，在疗效、代谢稳定性、 药代动力学和安全性。我们的首要目标是开发一种新的抗疟疾药物，这种药物在 G6PD缺乏症患者和最脆弱的人群--孕妇和儿童，因此 支持在世界范围内消除这种疾病。这个项目的具体目标是进行领导 优化研究，以产生第二代候选药物进行全面的临床前评估，保留 广谱特征，并表现出增强的有效性、安全性、溶解性和代谢/药代动力学 调查对某些吖啶酮类候选药物的耐药性倾向，并确定 通过全基因组测序和分析，寻找分子靶点(S)，并探索其作用模式(S) 使用功能分析和生物分析方法的肝期活性抗疟疾吖啶酮类药物。

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.