Winter, R. W. | bioRxiv Science

bioRxiv2021

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

Targeting conserved metabolic processes that are essential for viability of pathogens, such as Plasmodium and Babesia that cause blood-borne diseases, is an effective strategy to eliminate malaria and babesiosis infections with no recrudescence. One interesting target is the mitochondrial cytochrome bc1 complex, which could be inhibited by drugs such as endochin-like quinolones (ELQ) and atovaquone. We used the tick-transmitted and culturable blood-borne pathogen Babesia duncani to evaluate the structure-activity relationship, safety, efficacy and mode of action of ELQs. We identified a potent and highly selective ELQ prodrug (ELQ-502), which alone or in combination with atovaquone eliminates B. microti and B. duncani infections in vitro and in mouse models of parasitemia and lethal infection. The strong efficacy at low dose, excellent safety, bioavailability and long half-life of this experimental therapy makes it an ideal clinical candidate for the treatment of human infections caused by Babesia and its closely related apicomplexan parasites.

microbiology↗

bioRxiv2020

Orally Bioavailable Endochin-like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts

Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute and latent infection. ELQ-316, in particular, was found to be effective orally against acute toxoplasmosis in mice and highly selective for the T. gondii cytochrome b over the human cytochrome b. Despite oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a six-fold increase in both Cmax (maximum plasma concentration) and AUC (area under the curve) of ELQ-316. The increased bioavailability of ELQ-316, when administered as ELQ-334, resulted in greater efficacy than the equivalent dose of ELQ-316 against acute toxoplasmosis and had similar efficacy against latent toxoplasmosis compared to intraperitoneal administration of ELQ-316. Carbonate ester prodrugs are a successful strategy to overcome the limited oral bioavailability of ELQs for the treatment of toxoplasmosis.

pharmacology and toxicology↗

bioRxiv2019

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

BackgroundThe 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.\n\nMethodsFour 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 [1/2] months after injection.\n\nResultsA single intramuscular injection of ELQ-331 outperformed four other ELQ-300 prodrugs and, at a dose equivalent to 30 mg/kg ELQ-300, protected mice against challenge with P. yoelii sporozoites for at least 4 [1/2] months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (< 6 hours) and sustained (4-5 months) effective plasma ELQ-300 concentration, maximum ELQ-300 concentrations far below the estimated threshold for toxicity, and a distinctive ELQ-300 concentration vs. time profile. Pharmacokinetic modeling indicates a high-capacity, slow-exchange tissue compartment which serves to accumulate and then slowly redistribute ELQ-300 into blood, and this property facilitates an extremely long period during which ELQ-300 concentration is sustained above a minimum fully-protective threshold (60-80 nM).\n\nConclusionsExtrapolation of these results to humans clearly predicts that ELQ-331 should be capable of meeting and far-exceeding currently published duration-of-effect goals for antimalarial LAI-C. Allometric scaling from mice to humans would predict a several-fold enhancement in the relationship between duration-of-effect and dose, and available drug engineering and formulation technologies would be expected to offer significant improvement over the simple powder in sesame oil used here. Furthermore, the distinctive pharmacokinetic profile of ELQ-300 after treatment with ELQ-331 may facilitate durable protection using a variety of delivery and formulation options, and may enable protection for far longer than 3 months. Particularly in light of the favorable pharmacodynamic profile of ELQ-300, ELQ-331 warrants consideration as a leading prototype for LAI-C.

pharmacology and toxicology↗