Toxoplasma gondii, an Apicomplexan parasite, causes significant morbidity and mortality, including severe disease in immunocompromised hosts and devastating congenital disease, with no effective treatment for the bradyzoite stage. To address this, we used the Tropical Disease Research database, crystallography, molecular modeling, and antisense to identify and characterize a range of potential therapeutic targets for toxoplasmosis. Phosphoglycerate mutase II (PGMII), nucleoside diphosphate kinase (NDK), ribulose phosphate 3-epimerase (RPE), ribose-5-phosphate isomerase (RPI), and ornithine aminotransferase (OAT) were structurally characterized. Crystallography revealed insights into the overall structure, protein oligomeric states and molecular details of active sites important for ligand recognition. Literature and molecular modeling suggested potential inhibitors and druggability. The targets were further studied with vivoPMO to interrupt enzyme synthesis, identifying the targets as potentially important to parasitic replication and, therefore, of therapeutic interest. Targeted vivoPMO resulted in statistically significant perturbation of parasite replication without concomitant host cell toxicity, consistent with a previous CRISPR/Cas9 screen showing PGM, RPE, and RPI contribute to parasite fitness. PGM, RPE, and RPI have the greatest promise for affecting replication in tachyzoites. These targets are shared between other medically important parasites and may have wider therapeutic potential.
Lykins, Joseph D., et al. "CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in <em>Toxoplasma gondii</em>." Frontiers in Cellular and Infection Microbiology, vol. 8, Oct. 2018. https://doi.org/10.3389/fcimb.2018.00352
Lykins, Joseph D., Filippova, Ekaterina V., Halavaty, Andrei S., Minasov, George, Zhou, Ying, Dubrovska, Ievgeniia, Flores, Kristin J., Shuvalova, Ludmilla A., Ruan, Jiapeng, El Bissati, Kamal, Dovgin, Sarah, Roberts, Craig W., Woods, Stuart, Moulton, Jon D., Moulton, Hong, McPhillie, Martin J., Muench, Stephen P., Fishwick, Colin W. G., ... Ngô, Huân M. (2018). CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in <em>Toxoplasma gondii</em>. Frontiers in Cellular and Infection Microbiology, 8. https://doi.org/10.3389/fcimb.2018.00352
Lykins, Joseph D., Filippova, Ekaterina V., Halavaty, Andrei S., et al., "CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in <em>Toxoplasma gondii</em>," Frontiers in Cellular and Infection Microbiology 8 (2018), https://doi.org/10.3389/fcimb.2018.00352
@article{osti_1628035,
author = {Lykins, Joseph D. and Filippova, Ekaterina V. and Halavaty, Andrei S. and Minasov, George and Zhou, Ying and Dubrovska, Ievgeniia and Flores, Kristin J. and Shuvalova, Ludmilla A. and Ruan, Jiapeng and El Bissati, Kamal and others},
title = {CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in <em>Toxoplasma gondii</em>},
annote = {Toxoplasma gondii, an Apicomplexan parasite, causes significant morbidity and mortality, including severe disease in immunocompromised hosts and devastating congenital disease, with no effective treatment for the bradyzoite stage. To address this, we used the Tropical Disease Research database, crystallography, molecular modeling, and antisense to identify and characterize a range of potential therapeutic targets for toxoplasmosis. Phosphoglycerate mutase II (PGMII), nucleoside diphosphate kinase (NDK), ribulose phosphate 3-epimerase (RPE), ribose-5-phosphate isomerase (RPI), and ornithine aminotransferase (OAT) were structurally characterized. Crystallography revealed insights into the overall structure, protein oligomeric states and molecular details of active sites important for ligand recognition. Literature and molecular modeling suggested potential inhibitors and druggability. The targets were further studied with vivoPMO to interrupt enzyme synthesis, identifying the targets as potentially important to parasitic replication and, therefore, of therapeutic interest. Targeted vivoPMO resulted in statistically significant perturbation of parasite replication without concomitant host cell toxicity, consistent with a previous CRISPR/Cas9 screen showing PGM, RPE, and RPI contribute to parasite fitness. PGM, RPE, and RPI have the greatest promise for affecting replication in tachyzoites. These targets are shared between other medically important parasites and may have wider therapeutic potential.},
doi = {10.3389/fcimb.2018.00352},
url = {https://www.osti.gov/biblio/1628035},
journal = {Frontiers in Cellular and Infection Microbiology},
issn = {ISSN 2235-2988},
volume = {8},
place = {United States},
publisher = {Frontiers Research Foundation},
year = {2018},
month = {10}}
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); Michigan Technology Tri-Corridor; U.S. Department of Health and Human Services
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1628035
Alternate ID(s):
OSTI ID: 1767189
Journal Information:
Frontiers in Cellular and Infection Microbiology, Journal Name: Frontiers in Cellular and Infection Microbiology Vol. 8; ISSN 2235-2988