DESIGNING SELECTIVE INHIBITORS OF CALCIUM-DEPENDENT KINASES IN PARASITES

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DESCRIPTION (provided by applicant): Toxoplasma gondii and Cryptosporidium parvum are important opportunistic pathogens that cause devastating disease in immunocompromised humans. Both are capable of causing food or waterborne infections and hence are also a threat to healthy individuals. Severe infections with T. gondii typically occur in immunocompromised patients, including HIV infection, cancer chemotherapy, organ transplant, or infants infected in utero. Additionally, new studies indicate that severe ocular disease can also occur in healthy adults. Cryptosporidium also causes severe diarrheal disease in immunocompromised patients and treatment is hampered by the lack of effective therapy. Cryptosporidium has also been known to cause widespread outbreaks of debilitating illness in healthy individuals due to contaminated domestic water supplies. Treatment of infections caused by these parasites is complicated by lack of effective medicines and/or intolerance to currently available drugs. Hence, there is a need to develop new therapeutic agents to treat infections with these parasites. The goal of our project is to develop small molecule inhibitors of parasite-specific kinases belonging to the calcium-dependent protein kinase (CDPK) family. CDPKs are plant-like protein kinases that are not found in animal cells, yet they are expanded in apicomplexan parasites. Our recent studies using molecular genetic and chemical biology approaches reveal that CDPK1 is essential for parasite growth. We have also demonstrated that CDPK1 is specifically and potently inhibited by bulky ATP analogs, which have limited activity against host kinases. We will pursue identification of improved inhibitors with greater potency for selective inhibition of CDPK1 from T. gondii and C. parvum using a combination of biochemical, molecular genetic, chemical biology and medicinal chemistry approaches. We will also design, synthesize, and test new inhibitors with improved pharmacological properties for in vivo treatment. Selective inhibitors will be evaluated for their ability to prevent acute and chronic infection in a rodent model for toxoplasmosis.