Quantum model repurposing of cethromycin for liver stage malaria

总结 一种基于量子的计算方法，在现有分子中发现了新的 抗疟活性分别为血液和肝脏阶段。在肝脏阶段突出 分子是一个几乎相同的匹配赛红霉素，包括众所周知的抗疟疾 喹啉核连接到红霉素支架上。在有限的临床前小鼠肝脏阶段， 子孢子攻击模型，赛红霉素减少疟疾寄生虫负荷使用一个低于 人体等效剂量。在以前的广泛的临床试验中，赛红霉素被证明是等效的 在2000多名接受细菌性肺炎治疗的患者中， 肺炎 假设人类等效的头孢霉素剂量将在小鼠中具有治愈性 在体外实验中，赛红霉素将证明间日疟原虫催眠子活性 原代人肝细胞测定。 具体目标是： 1.合成克量临床前级赛红霉素 2.使用以下方法表征小鼠肝脏阶段赛红霉素单独或联合给药的活性 阿奇霉素作为大环内酯类对照药物。 3.与疟疾药物合作进行体外间日疟原虫催眠子活性测定 Venture人原代肝细胞 4.啮齿动物肝脏、肺和血液水平的药代动力学测量，用于药效学 分析. 广泛的长期目标是每周一次给药和/或每周一次给药， 替代伯氨喹治疗休眠间日疟原虫/卵形肝期寄生虫。这些临床前 研究将补充现有的赛红霉素临床前药理学数据， 控制人类疟疾感染的第二阶段临床试验。这项可量化的临床前工作将验证 基于量子的建模方法来识别临床使用的再利用药物。

Summary A quantum based computational approach identified amongst existing molecules new antimalarial activity separately for both blood and liver-stages. Prominent amongst the liver-stage molecules was a near identical match to cethromycin, comprised of the well known antimalarial quinoline nucleus joined to the erythromycin scaffold. In a limited preclinical mouse liver-stage sporozoite challenge model, cethromycin reduced the malaria parasite load using a single lower than human-equivalent dose. In previous extensive clinical trials cethromycin was shown to be equivalent to existing pneumonia drugs with a good safety profile in more than 2000 persons treated for bacterial pneumonia. The hypothesis is that human equivalent cethromycin dosing will be curative in the mouse liver-stage models and that cethromycin will demonstrate P. vivax hypnozoite activity in the in vitro primary human hepatocyte assay. The specific aims are: 1. Synthesize gram quantities of preclinical grade cethromycin 2. Characterize mouse liver-stage cethromycin activity alone or in combination using azithromycin as macrolide class comparator. 3. Perform in vitro P. vivax hypnozoite activity assays in collaboration with Medicines for Malaria Venture on human primary hepatocytes 4. Pharmacokinetic measurements on rodent liver, lung and blood levels for pharmacodynamics analysis. The broad long-term objective is a safe, effective malaria prophylaxis with weekly dosing and/or replacement of primaquine for cure of dormant P. vivax/ovale liver-stage parasites. These preclinical studies will supplement existing cethromycin preclinical pharmacologic data for the goal of a controlled human malaria infection phase 2 clinical trial. This quantifiable preclinical work will validate the quantum based modeling approach to identify repurposing drugs for clinical use.