CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in Toxoplasma gondii

Joseph D. Lykins, Ekaterina V. Filippova, Andrei S. Halavaty, George Minasov, Ying Zhou, Ievgeniia Dubrovska, Kristin J. Flores, Ludmilla A. Shuvalova, Jiapeng Ruan, Kamal El Bissati, Sarah Dovgin, Craig W. Roberts, Stuart Woods, Jon D. Moulton, Hong Moulton, Martin J. McPhillie, Stephen P. Muench, Colin W.G. Fishwick, Elisabetta Sabini, Dhanasekaran ShanmugamDavid S. Roos, Rima McLeod, Wayne F. Anderson*, Huân M. Ngô

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Article number352
JournalFrontiers in Cellular and Infection Microbiology
StatePublished - Oct 5 2018


  • PPMO
  • Toxoplasma gondii
  • crystallography
  • nucleoside diphoshate kinase
  • ornithine aminotransferase
  • phosphoglycerate mutase
  • ribose-5-phosphate isomerase
  • ribulose-3-phosphate epimerase

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases
  • Microbiology
  • Immunology


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