lykins, JD, Filippova, E, Halavaty, AS et al. (21 more authors) (2018) CSGID Identifies Phenotypes and Solves Structures for Five Enzymes in Toxoplasma gondii. Frontiers in cellular and infection microbiology, 8. ARTN352. ISSN 2235-2988
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © Lykins, Filippova, Halavaty, Minasov, Zhou, Dubrovska, Flores, Shuvalova, Ruan, El Bissati, Dovgin, Roberts, Woods, Moulton, Moulton, McPhillie, Muench, Fishwick, Sabini, Shanmugam, Roos, McLeod, Anderson and Ngô. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. (https://creativecommons.org/licenses/by/4.0/) |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 08 Oct 2018 10:22 |
Last Modified: | 25 Jun 2023 21:32 |
Status: | Published |
Publisher: | Frontiers Media S.A. |
Identification Number: | 10.3389/fcimb.2018.00352 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:136789 |