# Novel Therapeutic Strategies for ELQ-422, a preclinical Toxoplasmosis Drug Candidate

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2024 · —

## Abstract

The VA is the largest single provider of HIV care in the United States and cares for a substantial number of
solid organ and bone marrow transplant patients. Toxoplasmosis causes death and severe disability world-
wide and individuals with AIDS are at increased risk of developing toxoplasmosis. First-line antifolate therapy
has a high rate of adverse effects that compromise use for treatment and prophylaxis. Antifolates also fail to
reduce established brain tissue cysts. A safer, more effective therapy for acute toxoplasmosis and prophylaxis
that reduces or eradicates tissue cysts is sorely needed. Endochin-like quinolones (ELQs) are remarkably
potent inhibitors of T. gondii replication that are highly effective in mouse models of acute and latent infection.
ELQ-422, an ELQ-316 prodrug, markedly increased survival in a mouse model of toxoplasmosis. ELQ-316 and
its prodrugs reduced the number of brain tissue cysts in mice, and further reduction occurred with the addition
of pyrimethamine. ELQs bind to either the QO site (ubiquinol oxidation) or the Qi site (ubiquinone reduction) of
the T. gondii cytochrome bc1 complex (cyt bc1). ELQ-316, a Qi site targeting compound, has been selected for
preclinical advancement based on outstanding efficacy and selectivity for the parasite cyt bc1 over the host.
ELQ-422 is a prodrug of ELQ-316 that is rapidly converted to ELQ-316 in vivo resulting in a significant increase
in oral bioavailability. ELQ-422 appears safe based on toxicity testing in rats. Based on this and other
preclinical testing, ELQ-422 stands out as a highly promising lead compound that should be advanced toward
clinical studies. Additionally, despite decades of clinical use and extensive preclinical exploration of cyt bc1
inhibitors as anti-parasitic agents, key questions remain regarding the effect of cyt bc1 inhibition on parasite cell
biology. Answering these questions would provide insight into mechanisms of parasite persistence and
treatment. The aims of this proposal will (1) discover drug targets that are synergistic with cyt bc1 inhibition (2)
carry out a mechanism-based drug screen to identify inhibitors that enhance ELQ-316 efficacy and test lead
compounds in a model of latent toxoplasmosis.

## Key facts

- **NIH application ID:** 10703717
- **Project number:** 2I01BX004522-05A1
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** Joseph Stone Doggett
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2019-04-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10703717

## Citation

> US National Institutes of Health, RePORTER application 10703717, Novel Therapeutic Strategies for ELQ-422, a preclinical Toxoplasmosis Drug Candidate (2I01BX004522-05A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10703717. Licensed CC0.

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