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.
Cethromycin was identified by a published quantum model computational analysis for liver- stage malaria drugs. This cethromycin preclinical mouse malaria liver-stage work will build a more solid evidence base for a phase 2, controlled human malaria infection clinical trial. The long-term outcome will be a new safe, effective malaria prophylaxis drug and/or a replacement of primaquine for the dormant liver-stage of P. vivax/ovale.
