The complete absence of treatment options for chronic Toxoplasma gondii (Tg) infection renders ~2 billion people at risk for reactivated toxoplasmosis. Congenitally infected individuals or those with weakened immune systems are particularly vulnerable to reactivated toxoplasmosis manifested as fatal encephalitis, myocarditis or loss of vision. As the leading cause of infectious posterior uveitis and second leading cause of foodborne deaths in the USA, reactivated toxoplasmosis could be substantially reduced in high-risk individuals by eliminating Tg tissue cysts. We used new genetic tools to identify an essential role for a cathepsin protease L (CPL) activity during chronic Tg infection, creating an exciting opportunity to exploit a new target for combatting reactivated toxoplasmosis. To begin addressing this key unmet need, we identified an initial lead dipeptide nitrile CPL inhibitor based on its potential for CNS penetrance and conducted primary SAR studies against Tg and human cathepsin L, demonstrating that we could achieve over 100-fold improvement in selectivity for the Tg enzyme in under 20 analogs. In the R21 phase we will use structure-based design to further optimize potency and selectivity along with improving stability and permeability in in vitro models, delivering one or more potent, selective, stable, and cell-permeable leads. In the R33 phase we will evaluate and further refine PK and CNS penetrance in mice before measuring maximum tolerated dose and efficacy in an established murine treatment model for chronic Tg infection. Both phases will feature first-of-their-kind assays for cyst viability developed for the studies. Upon successful completion, this project will yield one or more Tg CPL inhibitors effective for reducing or eliminating tissue cysts, thereby advancing a potential new solution for chronic Tg infection. 1
People who are chronically infected with the single-celled parasite Toxoplasma gondii are at risk of impaired vision or loss of life due to fatal brain or heart disease. To advance a new experimental treatment for chronic T. gondii infection, this project will identify and validate novel inhibitors targeting a parasite cathepsin protease required for chronic infection. Upon successful completion, this work will yield one or more inhibitors that establish cathepsin protease as a viable target for reducing or eliminating chronic T. gondii infection, thereby delivering a new potential treatment option. 1
| Zwicker, Jeffery D; Diaz, Nicolas A; Guerra, Alfredo J et al. (2018) Optimization of dipeptidic inhibitors of cathepsin L for improved Toxoplasma gondii selectivity and CNS permeability. Bioorg Med Chem Lett 28:1972-1980 |
