title: Guanabenz repurposed as an antiparasitic with activity against acute and latent toxoplasmosis.
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.
authors: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors: Imaan
authors: I
authors: Benmerzouga
authors: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, USA.
authors: Lisa A
authors: LA
authors: Checkley
authors: Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, USA.
authors: Michael T
authors: MT
authors: Ferdig
authors: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors: Gustavo
authors: G
authors: Arrizabalaga
authors: Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors: Ronald C
authors: RC
authors: Wek
authors: Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA wjsulliv@iu.edu.
authors: William J
authors: WJ
authors: Sullivan
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000627:therapeutic use*; D006143:Guanabenz / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000472:pathogenicity; D014122:Toxoplasma / Q000187:drug effects / Q000472:pathogenicity; D014124:Toxoplasmosis, Animal / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D000977:Antiparasitic Agents; D006143:Guanabenz