Enabling Toxoplasma gondii Kinome Directed Drug Discovery

Project Summary Toxoplasmosis is caused by a single celled apicomplexanToxoplasma gondiiT gondiiwhich invades host cells through ingestion of uncooked infected meat or contaminated waterT gondii infectsof the world s population and the current cost of the disease in US itself is estimated to be $ B and risingCurrent treatment regimen is effective only against acute infection and has severe side effectsHence there is an urgent need for new drugs and drug targetsThe genome of T gondiiis predicted to encodeactive kinasesKinases have been shown to be involved in every aspect of the life cycle of T gondiifrom invasion of host cells to virulenceHoweverthe lack of commercially available robust kinase assays has hindered T gondii kinome directed drug discoveryIn this applicationwe aim to develop and validate assays targeted against the kinases essential to the T gondii parasite s life cyclewhich is responsible for transmission and disease pathologyThese T gondii kinase specific assaysbased on our three hybrid split luciferase systemwill be further used for high throughput screening of a kinase targeted inhibitor libraryThese efforts are both significant and innovative as the identification of target specific inhibitors will not only provide pharmacophores for further drug development but also identify chemical probes for studying kinase biology and signaling pathways to provide new interventions Project Narrative Toxoplasma gondii is the causative agent of toxoplasmosisa debilitating disease in immunocompromised individualsand current treatments have been shown to have severe side effectsDevelopment of assays against new targets will help advance the discovery of new and effective therapies for this deadly diseaseThe purpose of our application is to develop low cost assays for the Toxoplasma gondii kinome