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

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.