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

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.; Sabini, Elisabetta; Shanmugam, Dhanasekaran; Roos, David S.; McLeod, Rima; Anderson, Wayne F.; Ngô, Huân M.

doi:10.3389/fcimb.2018.00352

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

Journal Article · Fri Oct 05 00:00:00 EDT 2018 · Frontiers in Cellular and Infection Microbiology

DOI:https://doi.org/10.3389/fcimb.2018.00352· OSTI ID:1628035

Lykins, Joseph D. ^[1]; Filippova, Ekaterina V. ^[2]; Halavaty, Andrei S. ^[2]; Minasov, George ^[2]; Zhou, Ying ^[1]; Dubrovska, Ievgeniia ^[2]; Flores, Kristin J. ^[2]; Shuvalova, Ludmilla A. ^[2]; Ruan, Jiapeng ^[2]; El Bissati, Kamal ^[1]; Dovgin, Sarah ^[3]; Roberts, Craig W. ^[4]; Woods, Stuart ^[4]; Moulton, Jon D. ^[5]; Moulton, Hong ^[6]; McPhillie, Martin J. ^[7]; Muench, Stephen P. ^[8]; Fishwick, Colin W. G. ^[8]; Sabini, Elisabetta ^[2]; Shanmugam, Dhanasekaran ^[9] more »

Univ. of Chicago, IL (United States)
Northwestern Univ., Evanston, IL (United States)
Illinois Math and Science Academy, Aurora, IL (United States)
Univ. of Strathclyde, Glasgow (United Kingdom)
Gene Tools, LLC, Philomath, OR (United States)
Oregon State Univ., Corvallis, OR (United States)
Univ. of Sheffield (United Kingdom)
Univ. of Leeds, Leeds (United Kingdom)
CSIR National Chemical Lab., Pune (India)
Univ. of Pennsylvania, Philadelphia, PA (United States)
Northwestern Univ., Evanston, IL (United States); BrainMicro LLC, New Haven, CT (United States)

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.

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Research Organization:: Argonne National Laboratory (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; 2T35DK062719-27; 085P1000817; HHSN272200700058C; HHSN272201200026C; HHSN272201700060C

OSTI ID:: 1628035

Journal Information:: Frontiers in Cellular and Infection Microbiology, Vol. 8; ISSN 2235-2988

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 9 works

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