Optimizing CDPK1 inhibitors for chronic toxoplasmosis

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PROJECT SUMMARY Toxoplasma gondii is an opportunistic pathogen that causes disease in immunocompromised patients and in infants due to congenital infections. Following a brief acute phase, the parasite differentiates into a semi- dormant form called the bradyzoite, which resides within long-lived tissue cysts that are primarily located in the central nervous system (CNS). Despite a vigorous immune response, tissue cysts are not eliminated and they pose a risk of reactivation when immunity wanes. It is estimated that ~2 billion people worldwide are chronically infected with T. gondii and hence at risk of reactivation should their immune function decline. In many regions of South America, infection can lead to severe and recurrent ocular disease in immunocompetent individuals. Chemotherapy is available for acute toxoplasmosis based on a combination of pyrimethamine and sulfadiazine. However, there are complications due to the toxicity of pyrimethamine and allergic reactions to sulfa drugs. Moreover, this treatment poses risks during pregnancy due to teratogenicity. Current treatment is effective in controlling acute infection, but has minimal effect on chronic tissue cyst stages and hence is not curative. Although a number of new compounds have been shown to inhibit T. gondii growth in vitro, most have little effect on the chronic stage. Hence, there is a major need for new efforts to identify compounds for treating chronic toxoplasmosis. The goal of this project is to identify late stage preclinical leads that show potent inhibition of parasite growth in vitro, eliminate chronic infection in vivo, and that possess appropriate ADME and safety profiles for advancement. We will develop potent and selective inhibitors of TgCDPK1, which is an unique and essential enzyme in T. gondii. In preliminary studies, we have identified several lead compounds that are both highly potent and selective for TgCDPK1 over mammalian kinases. We will design and synthesize new analogs to improve potency, selectivity, CNS penetration, bioavailability, and ADMET-PK properties of these compounds. Specific criteria for potency, selectivity and ADMET properties will be used to advance compounds to in vivo testing. We have developed new quantitative assays for monitoring inhibition of acute and chronic stages of infection and we will employ animal models for monitoring the efficacy of compounds against reactivated toxoplasmosis in the CNS. Successful achievement of these milestones will deliver lead compound(s) for future IND-enabling studies with the eventual goal of curing chronic toxoplasmosis.