SBIR-STTR Award

Toxoplasmosis is caused by a single-celled apicomplexan, Toxoplasma gondii (T.gondii), which invades host cells through ingestion of uncooked infected meat or contaminated water. T.gondii infects 30% of the world’s population and the current cost of the disease in US itself is estimated to be $3B and rising. Current treatment regimen is effective only against acute infection and has severe side effects. Hence there is an urgent need for new drugs and drug targets. The genome of T.gondii, is predicted to encode 108 active kinases. Kinases have been shown to be involved in every aspect of the life cycle of T.gondii, from invasion of host cells to virulence. However, the lack of commercially available robust kinase assays has hindered T.gondii kinome-directed drug discovery. In this application, we aim to develop and validate assays targeted against the kinases essential to the T.gondii parasite’s life-cycle, which is responsible for transmission and disease pathology. These T.gondii kinase specific assays, based on our three-hybrid split luciferase system, will be further used for high throughput screening of a kinase targeted inhibitor library. These 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.

Public Health Relevance Statement:
Project Narrative Toxoplasma gondii is the causative agent of toxoplasmosis, a debilitating disease in immunocompromised individuals, and current treatments have been shown to have severe side effects. Development of assays against new targets will help advance the discovery of new and effective therapies for this deadly disease. The purpose of our application is to develop low-cost assays for the Toxoplasma gondii kinome.

Project Terms:
acute infection; Antimalarials; assay development; base; Binding; Biological Assay; Biology; Bioluminescence; Birds; Cells; Chemicals; chronic infection; Clinical Research; Collaborations; Collection; contaminated water; cost; Cost of Illness; Data; Development; Disease; drug development; drug discovery; Drug resistance; Drug Targeting; effective therapy; Encephalitis; Genome; Goals; high throughput screening; Human; human disease; Hybrids; Immunocompetent; Immunocompromised Host; Individual; Infection; Ingestion; inhibitor/antagonist; innovation; Intervention; Invaded; Libraries; Life Cycle Stages; Light; Luciferases; Malaria; Mammals; Manuscripts; Meat; mutant; new therapeutic target; novel therapeutics; Parasites; Pathology; Pharmaceutical Preparations; pharmacophore; Phase; Phosphotransferases; Plasmodium falciparum; Population; Pregnant Women; Preparation; prevent; Production; Publications; Pyrimethamine; Reporting; Scaffolding Protein; screening; side effect; Signal Pathway; Sulfadiazine; System; Technology; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; transmission process; Treatment Protocols; uncooked; United States; vector; Vertical Disease Transmission; Virulence; web site; Work

Toxoplasma gondii (T.gondii), the causative agent for toxoplasmosis, invades host cells throughingestion of uncooked infected meat or contaminated water. T.gondii infects 30% of the world'spopulation and the current cost of the disease in US itself is estimated to be $3B and rising.Current treatment regimen is effective only against acute infection and has severe side effects.Hence there is an urgent need for new drugs and drug targets. The genome of T.gondii, ispredicted to encode 108 active kinases. Kinases have been shown to be involved in every aspectof the life cycle of T.gondii, from invasion of host cells to virulence. However, the lack ofcommercially available robust kinase assays has hindered T.gondii kinome-directed drugdiscovery.In this application, we aim to develop and validate assays targeted against the kinases essentialto the T.gondii parasite's life-cycle, which is responsible for transmission and disease pathology.These T.gondii kinase specific assays, based on our three-hybrid split luciferase system, will befurther used for high throughput screening of a kinase targeted inhibitor library. These efforts areboth significant and innovative as the identification of target specific inhibitors will not only providepharmacophores for further drug development but also identify chemical probes for studyingkinase biology and signaling pathways to provide new interventions.

Public Health Relevance Statement:
Project Narrative Toxoplasma gondii is the causative agent of toxoplasmosis, a debilitating disease in immunocompromised individuals, and current treatments have been shown to have severe side effects. Development of assays against new targets will help advance the discovery of new and effective therapies for this deadly disease. The purpose of our application is to develop low-cost assays for the Toxoplasma gondii kinome and chemical probes to inform upon the biology of the parasite.

Project Terms: