ELQ-331 as a prototype for extremely durable chemoprotection against malaria

Abstract

Background:The potential benefits of long-acting injectable chemoprotection (LAI-C) against malaria have been recently recognized, prompting a call for suitable candidate drugs to help meet this need. On the basis of its known pharmacodynamic and pharmacokinetic profiles after oral dosing, ELQ-331, a prodrug of the parasite mitochondrial electron transport inhibitor ELQ-300, was selected for study of pharmacokinetics and efficacy as LAI-C in mice.Methods: Four trials were conducted in which mice were injected with a single intramuscular dose of ELQ-331 or other ELQ-300 prodrugs in sesame oil with 1.2% benzyl alcohol; the ELQ-300 content of the doses ranged from 2.5 to 30 mg/kg. Initial blood stage challenges with Plasmodium yoelii were used to establish the model, but the definitive study measure of efficacy was outcome after sporozoite challenge with a luciferase-expressing P.yoelii, assessed by whole-body live animal imaging. Snapshot determinations of plasma ELQ-300 concentration ([ELQ-300]) were made after all prodrug injections;after the highest dose of ELQ-331 (equivalent to 30 mg/kg ELQ-300), both [ELQ-331] and [ELQ-300] were measured at a series of timepoints from 6 hours to 5 ½ months after injection.

Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection

“…ELQs have been shown to target the Qi site or the Qo site of the cytochrome b of multiple apicomplexan parasites such as Plasmodium spp. (15,16,(19)(20)(21), Toxoplasma gondii (11) and Babesia microti (10). Whereas the ability to maintain P. falciparum and T. gondii in culture made it possible to conduct structure-activity relationship studies to identify inhibitors suitable for each pathogen, detailed structureactivity relationship evaluation could not be conducted in B. microti due to the lack of an in vitro culture system.…”