Utilizing Novel Scaffolds to Target Cytochrome-B of Toxoplasma gondii Tachyzoites
Session Number
P03
Advisor(s)
Kamal El-Bissati, University of Chicago Farida Esaa, University of Chicago Rima McLeod, University of Chicago Ying Zhou, University of Chicag
Location
B-206 Lecture Hall
Start Date
28-4-2016 8:50 AM
End Date
28-4-2016 9:15 AM
Abstract
Toxoplasma gondii, an apicomplexan parasite affecting one third of the world’s population, causes the disease known as toxoplasmosis. Atovaquone is a current treatment against T.gondii which can partially reduce the number of bradyzoites. However, atovaquone-resistant mutants are rapidly selected during treatment with atovaquone. Atovaquone and related compounds have been developed against cytochrome b, a target within complex III of the parasite’s electron transport chain, hypothesized to be a key component of adenosine triphosphate production within the parasite. A parasite assay determined compounds’ effects upon T. gondii tachyzoites. Human foreskin fibroblasts (HFF) in 96-well plates were utilized as in vitro models. T. gondii tachyzoites invaded HFFs before compound concentrations of 0.03 micromolar (uM) to 10uM were added. A toxicity assay determined the effect of the compound upon HFFs. Varying concentrations of each compound were added to HFFs before WST-1 was added to quantify mitochondrial activity of remaining living HFFs. JAG021 and JAG050 led to significant decreases in parasites at compound concentrations from 0.125uM to 10uM. Additionally, all compounds had minimal levels of toxicity from 1uM- 10uM with exception of HFF toxicity at 15uM. Further studies will be conducted to determine the effects of the compounds within in vivo models to develop the compounds into medicines.
Utilizing Novel Scaffolds to Target Cytochrome-B of Toxoplasma gondii Tachyzoites
B-206 Lecture Hall
Toxoplasma gondii, an apicomplexan parasite affecting one third of the world’s population, causes the disease known as toxoplasmosis. Atovaquone is a current treatment against T.gondii which can partially reduce the number of bradyzoites. However, atovaquone-resistant mutants are rapidly selected during treatment with atovaquone. Atovaquone and related compounds have been developed against cytochrome b, a target within complex III of the parasite’s electron transport chain, hypothesized to be a key component of adenosine triphosphate production within the parasite. A parasite assay determined compounds’ effects upon T. gondii tachyzoites. Human foreskin fibroblasts (HFF) in 96-well plates were utilized as in vitro models. T. gondii tachyzoites invaded HFFs before compound concentrations of 0.03 micromolar (uM) to 10uM were added. A toxicity assay determined the effect of the compound upon HFFs. Varying concentrations of each compound were added to HFFs before WST-1 was added to quantify mitochondrial activity of remaining living HFFs. JAG021 and JAG050 led to significant decreases in parasites at compound concentrations from 0.125uM to 10uM. Additionally, all compounds had minimal levels of toxicity from 1uM- 10uM with exception of HFF toxicity at 15uM. Further studies will be conducted to determine the effects of the compounds within in vivo models to develop the compounds into medicines.