Document Detail


A novel benzodioxole-containing inhibitor of Toxoplasma gondii growth alters the parasite cell cycle.
MedLine Citation:
PMID:  21947387     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Toxoplasma gondii is an obligate intracellular parasite that can cause disease in the developing fetus and in immunocompromised humans. Infections can last for the life of the individual, and to date there are no drugs that eliminate the chronic cyst stages that are characteristic of this parasite. In an effort to identify new chemical scaffolds that could form the basis for new therapeutics, we carried out a chemoinformatic screen for compounds that had the potential to interact with members of a superfamily of parasite-secreted kinases and assayed them for growth inhibition in vitro. Of 17 candidate compounds, we identified one with potent antiparasitic activity. The compound has a 50% inhibitory concentration (IC(50)) of ~2 nM, and structure-function analyses implicate the benzodioxole moiety in its action. The compound does not appear to be cytotoxic to host cells. Using microarray analyses of both parasites and host cells treated with the compound, we found that the levels of very few host cell transcripts are altered by the compound, while a large number of parasite transcripts have a different abundance after compound treatment. Gene ontology analyses of parasite transcripts with a different abundance revealed an enrichment of cell cycle-related genes, suggesting that the compound alters progression of the parasite through the cell cycle. Assaying the nuclear content of treated parasites demonstrated that compound treatment significantly increased the percentage of parasites in the S/M phase of the cell cycle compared to controls. This compound and its analogs represent a novel scaffold with antiparasitic activity.
Authors:
Edwin Kamau; Tracy Meehan; Mark D Lavine; Gustavo Arrizabalaga; Gabriela Mustata Wilson; Jon Boyle
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-26
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  55     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-14     Completed Date:  2012-03-29     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5438-51     Citation Subset:  IM    
Affiliation:
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Antiparasitic Agents / chemistry*,  metabolism,  pharmacology*
Benzodioxoles / chemistry,  metabolism,  pharmacology*
Cell Cycle / drug effects*
Cells, Cultured
Computational Biology / methods
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry,  metabolism,  pharmacology*
Fibroblasts / parasitology
Humans
Inhibitory Concentration 50
Molecular Sequence Data
Oligonucleotide Array Sequence Analysis
Parasitic Sensitivity Tests
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  chemistry,  genetics
Sequence Alignment
Toxoplasma / drug effects*,  genetics,  growth & development,  metabolism
Grant Support
ID/Acronym/Agency:
K22AI080977/AI/NIAID NIH HHS; UL1 RR024153/RR/NCRR NIH HHS; UL1 TR000005/TR/NCATS NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Antiparasitic Agents; 0/Benzodioxoles; 0/Enzyme Inhibitors; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ROP18 protein, Toxoplasma gondii
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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