Quantum model repurposing of cethromycin for liver stage malaria

赛红霉素治疗肝期疟疾的量子模型

• 批准号: 9205554
• 负责人: DAVID Joseph SULLIVAN
• 金额: $ 32.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205554
• 关键词: Adverse effects; Antimalarials; Azithromycin; Bacterial Pneumonia; Biological Assay; Blood; Boxing; Carbon; Cell Nucleus; Chemicals; Chemoprophylaxis; Chloroguanide; Clinical; Clinical Trials; Collaborations; Computer Analysis; Data; Data Set; Dose; Drug Kinetics; Enzyme Tests; Erythromycin; Glucosephosphate Dehydrogenase Deficiency; Goals; Hemolysis; Hepatocyte; Human; Hybrids; In Vitro; Life; Liver; Lung; Macrolides; Malaria; Measurement; Medicine; Mefloquine; Modeling; Mus; Outcome; Parasites; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Photosensitivity; Plasmodium vivax; Pneumonia; Primaquine; Prophylactic treatment; Publishing; Regimen; Rodent; Safety; Schedule; Solid; Sporozoites; Staging; Tetracyclines; Training; Vaginitis; Work; atovaquone; base; evidence base; gastrointestinal; improved; in vitro activity; malaria infection; neuropsychiatry; novel; pre-clinical; preclinical study; quantum; quinoline; scaffold

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.

概括 现有分子之间确定的基于量子的计算方法 血液和肝脏分别分别用于抗疟疾。肝脏中突出 分子与肝霉素几乎相同，由众所周知的抗疟药组成 喹啉核与红霉素支架相连。在有限的临床前小鼠肝脏中 Sporozoite挑战模型，肝霉素使用单个低于 人类等效剂量。在先前的广泛临床试验中，素霉素被证明是等效的 在2000多人接受细菌治疗的人中，现有的肺炎药物具有良好的安全性。 肺炎。 假设是人类当量的肌霉素的剂量将在小鼠中治愈 肝脏阶段模型和肝霉素将在体外表现出肝假发症状的活性 主要人肝细胞测定法。 具体目的是： 1。合成的革兰氏数量 2。单独或使用使用的小鼠肝级肝霉素活性或使用 阿奇霉素作为大环内酯类类比较剂。 3。与疟疾药物合作进行体外P. Vivax Hypnozoite活性测定 人类原发性肝细胞 4。药物动力学的药代动力学测量 分析。 广泛的长期目标是每周剂量和/或 替代primaquine用于治愈休眠疟原虫/椭圆形肝阶段寄生虫。这些临床前 研究将补充现有的肌霉素临床前药理数据，以实现 受控的人类疟疾感染阶段2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，用于识别重新利用临床用途的药物。