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Published on: June 22, 2017
Guanabenz repurposed as an antiparasitic with activity against acute and latent toxoplasmosis
Imaan Benmerzouga1, Lisa A Checkley2, Michael T Ferdig2
1Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Abstract:
Toxoplasma gondii is a protozoan parasite that persists as a chronic infection. Toxoplasma evades immunity by forming tissue cysts, which reactivate to cause life-threatening disease during immune suppression. There is an urgent need to identify drugs capable of targeting these latent tissue cysts, which tend to form in the brain. We previously showed that translational control is critical during infections with both replicative and latent forms of Toxoplasma. Here we report that guanabenz, an FDA-approved drug that interferes with translational control, has antiparasitic activity against replicative stages of Toxoplasma and the related apicomplexan parasite Plasmodium falciparum (a malaria agent). We also found that inhibition of translational control interfered with tissue cyst biology in vitro. Toxoplasma bradyzoites present in these abnormal cysts were diminished and misconfigured, surrounded by empty space not seen in normal cysts. These findings prompted analysis of the efficacy of guanabenz in vivo by using established mouse models of acute and chronic toxoplasmosis. In addition to protecting mice from lethal doses of Toxoplasma, guanabenz has a remarkable ability to reduce the number of brain cysts in chronically infected mice. Our findings suggest that guanabenz can be repurposed into an effective antiparasitic with a unique ability to reduce tissue cysts in the brain.
Insights
Guanabenz, an FDA-approved drug, shows antiparasitic activity against Toxoplasma gondii and reduces harmful brain cysts in mice. This repurposed drug offers a novel strategy for treating chronic toxoplasmosis.
Area of Science:
- Parasitology
- Drug Repurposing
- Infectious Diseases
Background:
- Toxoplasma gondii causes chronic infections via dormant tissue cysts, posing risks during immune suppression.
- Targeting these latent brain cysts is crucial for effective treatment of toxoplasmosis.
- Translational control is vital for both replicative and latent stages of Toxoplasma.
Purpose of the Study:
- To investigate the antiparasitic potential of guanabenz, an FDA-approved drug targeting translational control.
- To evaluate guanabenz's efficacy against replicative and latent forms of Toxoplasma gondii.
- To assess guanabenz's ability to reduce brain cyst burden in vivo.
Main Methods:
- Assessed guanabenz's activity against replicative Toxoplasma and Plasmodium falciparum in vitro.
- Examined the effect of translational control inhibition on Toxoplasma tissue cyst formation in vitro.
- Evaluated guanabenz's efficacy in mouse models of acute and chronic toxoplasmosis.
Main Results:
- Guanabenz demonstrated antiparasitic activity against replicative Toxoplasma and Plasmodium falciparum.
- Inhibition of translational control disrupted in vitro Toxoplasma tissue cyst development.
- Guanabenz protected mice from lethal Toxoplasma infection and significantly reduced brain cyst numbers in chronic models.
Conclusions:
- Guanabenz exhibits significant antiparasitic properties and effectively reduces Toxoplasma brain cysts.
- Repurposing guanabenz presents a promising therapeutic strategy for chronic toxoplasmosis.
- Targeting translational control offers a novel approach to combat latent parasitic infections.
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