Quantum model repurposing of cethromycin for liver stage malaria

赛红霉素治疗肝期疟疾的量子模型

基本信息

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
项目类别：
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

项目摘要

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.

概括在现有分子中确定的基于量子的计算方法新分别针对血液阶段和肝脏阶段的抗疟活性。在肝脏阶段中突出分子与塞红霉素几乎相同，由众所周知的抗疟药物组成喹啉核连接至红霉素支架。在有限的临床前小鼠肝脏阶段子孢子攻击模型中，赛红霉素使用单一低于人体等效剂量。在之前的广泛临床试验中，赛红霉素被证明是等效的现有肺炎药物在 2000 多名细菌性肺炎治疗患者中具有良好的安全性肺炎。假设人类等效的西红霉素剂量对小鼠有疗效肝脏阶段模型，并且庆霉素将在体外证明间日疟原虫催眠活性原代人肝细胞测定。具体目标是： 1. 合成克级临床前级庆霉素 2. 单独或联合使用来表征小鼠肝脏阶段的塞红霉素活性阿奇霉素作为大环内酯类比较药。 3. 与 Medicines for Malaria 合作进行体外 P. vivax 休眠子活性测定人类原代肝细胞的冒险 4. 啮齿动物肝脏、肺和血液水平的药代动力学测量以进行药效学分析。广泛的长期目标是通过每周给药和/或替代伯氨喹治疗休眠的间日疟原虫/卵形肝期寄生虫。这些临床前研究将补充现有的塞红霉素临床前药理学数据，以实现受控人类疟疾感染二期临床试验。这项可量化的临床前工作将验证基于量子的建模方法来识别临床用途的药物再利用。