Quantum model repurposing of cethromycin for liver stage malaria
Quantum model repurposing of cethromycin for liver stage malaria
批准号:
9205554
负责人:
DAVID Joseph SULLIVAN
金额:
$32.62万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-01 至 2018-07-31
关键词:
Adverse effectsAntimalarialsAzithromycinBacterial PneumoniaBiological AssayBloodBoxingCarbonCell NucleusChemicalsChemoprophylaxisChloroguanideClinicalClinical TrialsCollaborationsComputer AnalysisDataData SetDoseDrug KineticsEnzyme TestsErythromycinGlucosephosphate Dehydrogenase DeficiencyGoalsHemolysisHepatocyteHumanHybridsIn VitroLifeLiverLungMacrolidesMalariaMeasurementMedicineMefloquineModelingMusOutcomeParasitesPatientsPersonsPharmaceutical PreparationsPharmacodynamicsPhasePhase II Clinical TrialsPhotosensitivityPlasmodium vivaxPneumoniaPrimaquineProphylactic treatmentPublishingRegimenRodentSafetyScheduleSolidSporozoitesStagingTetracyclinesTrainingVaginitisWorkatovaquonebaseevidence basegastrointestinalimprovedin vitro activitymalaria infectionneuropsychiatrynovelpre-clinicalpreclinical studyquantumquinolinescaffold
中文摘要
总结
英文摘要
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.
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海外基金