Antimicrob Agents Chemother. 2011 Sep 26. [Epub ahead of print]
A novel benzodioxole-containing inhibitor of Toxoplasma gondii growth alters the parasite cell cycle
Kamau E, Meehan T, Lavine MD, Arrizabalaga G, Mustata G, Boyle J.
SourceDepartment of Biological Sciences, University of Pittsburgh, Pittsburgh, PA. 15260.
Abstract
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 chronic cyst stages 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. Out of 17 candidate compounds we identified one with potent anti-parasitic activity. The compound has an IC50 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 are of different abundance after compound treatment. Gene ontology analyses of parasite transcripts with different abundance revealed an enrichment of cell cycle-related genes, suggesting that the compound alters progression of the parasite through the cell cycle. Assaying 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 anti-parasitic activity.
PMID:21947387[PubMed - as supplied by publisher]
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