Quantum model repurposing of cethromycin for liver stage malaria

摘要 一种在现有分子中识别的基于量子的计算方法 分别针对血液和肝脏阶段的抗疟疾活性。在肝期中表现突出 分子与西特罗霉素几乎相同，由众所周知的抗疟疾药物组成。 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 在子孢子攻击模型中，西特罗霉素使用比 人体当量剂量。在之前的大规模临床试验中，西特罗霉素被证明是等同的 在2000多名接受细菌治疗的人中使用具有良好安全性的现有肺炎药物 肺炎。 这个假设是人类等量的西特罗霉素剂量在小鼠身上是有效的。 肝期模型和西特罗霉素将在体外显示间日疟原虫催眠活性 原代人肝细胞检测。 具体目标是： 1.临床前期级头孢霉素克的合成 2.单独或联合使用表征小鼠肝期西特罗霉素的活性 阿奇霉素作为大环内酯类对照药。 3.与治疗疟疾的药物合作进行间日疟原虫催产素活性的体外测定 人原代肝细胞的实验研究 4.鼠肝肺血药动学测定及药效学研究 分析。 广泛的长期目标是安全、有效地预防疟疾，每周给药和/或 替代伯氨喹治疗间日疟原虫/卵圆形肝期寄生虫。这些临床前研究 研究将补充现有的西曲霉素临床前药理学数据，以实现以下目标 控制人类疟疾感染2期临床试验。这项可量化的临床前工作将验证 基于量子的建模方法，以识别临床使用的再用途药物。

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.