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 h to 5½ months after injection. Results A 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 4½ months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (< 6 h) 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 versus 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). Conclusions Extrapolation of these results to humans predicts that ELQ-331 should be capable of meeting and far-exceeding currently published duration-of-effect goals for anti-malarial LAI-C. Furthermore, the distinctive pharmacokinetic profile of ELQ-300 after treatment with ELQ-331 may facilitate durable protection and enable protection for far longer than 3 months. These findings suggest that ELQ-331 warrants consideration as a leading prototype for LAI-C.

The cytochrome bc1 complex as an antipathogenic target

“…ELQ‐331, an alkoxycarbonate ester of ELQ‐300, is currently the lead prodrug that is reported to have significantly increased ELQ‐300 exposure after oral dosing [140]. ELQ‐331 is currently advancing preclinical development as an oral formulation and is also being progressed as a long‐acting injectable chemoprotection agent [141].…”

Treatment of Human Babesiosis: Then and Now

“…A novel class of compounds, endochin-like quinolones (ELQs) has recently been reported with high potency against B. microti and B. duncani [11,57]. Previously reported for their high potency against other apicomplexan parasites such as Plasmodium [115][116][117][118][119][120][121][122][123][124][125], Toxoplasma [126,127] and Leishmania [128], ELQs have been shown to target the cytochrome bc 1 complex of the parasites (Figure 3) [117,120,122,[128][129][130]. In 2016, Lawres et al demonstrated potency of ELQ-271 and ELQ-316 in the short-term ex vivo culture system of B. microti as well as in the in vivo SCID model of B. microti infection.…”

Efforts Made to Eliminate Drug-Resistant Malaria and Its Challenges

“…ELQ-300 is also another drug being developed as a long-acting injectable chemo-protective agent. This parasiticidal drug is reported to inhibit cytochrome bc 1 complex of Plasmodium parasites and bypass resistant mutations to atovaquone [ 79 , 80 ].…”