CSGID solves structures and identifies phenotypes for five enzymes in Toxoplasma gondii

Joseph D. Lykins, Ekaterina V. Filippova, Andrei S. Halavaty, George Minasova, 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

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Abstract

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
Article number352
Number of pages21
JournalFrontiers in Cellular and Infection Microbiology : Parasite and Host
Volume8
DOIs
Publication statusPublished - 5 Oct 2018

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Keywords

  • Toxoplasma gondii
  • phyophoglycerate mutase
  • nucleoside diphoshate kinase

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