Curing chronic Toxoplasma infection with novel and potent protease inhibitors

PROJECT SUMMARY Zero effective options exist for treating individuals who are chronically infected with the protozoan parasite Toxoplasma gondii (Tg) as a source of reactivated toxoplasmosis. Reactivated Tg infection in the retina is a leading cause of infectious posterior uveitis, impairing the vision of approximately 3,600 Americans annually. Some individuals experience multiple episodes of reactivated ocular toxoplasmosis, with each bout further eroding their vision. Eliminating Tg tissue cysts could preclude reactivated ocular toxoplasmosis and preserve the vision of at-risk individuals. We have identified a Tg lysosomal protease (TgCPL) that is critical for chronic Tg infection, developed several promising TgCPL-targeted lead compounds based on multiple scaffolds, and established a mouse intravitreal ocular treatment model. Our long-term goal is to provide a safe and effective treatment that eliminates chronic Tg infection from the retina after 2-week administration of a TgCPL inhibitor. As a critical step toward this goal, the proposed studies will: (1) develop a computational structure-to-function model of TgCPL to guide rationale discovery of novel ligands; (2) optimize the potency, pharmacokinetics, and selectivity of our lead TgCPL inhibitors, including derived from novel ligands identified in aim 1; and (3) eradicate chronic Tg infection in a mouse intravitreal ocular treatment model. Completing the proposed studies will result in one or more advanced lead compounds suitable for further progression through the development pipeline, thereby progressing toward a key unmet need for curbing chronic Tg infection. 1