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.

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

“…An ideal drug against toxoplasmosis should not only be effective against the proliferative stage of the parasite but also exert dual activity against the tissue cyst stage and penetration into cysts (Benmerzouga et al, 2015). Currently, there is no approved therapy that eliminates the tissue cysts responsible for chronic infection (Innes, 2010).…”

Translational Control in the Latency of Apicomplexan Parasites

“…Two selective eIF2 phosphatase inhibitors, salubrinal and guanabenz, have been shown to increase Toxoplasma eIF2 phosphorylation in vitro [51]. These drugs also reduce replication by inducing the conversion of tachyzoites into bradyzoite-containing cysts with abnormal morphology [51,52]. They were also effective against P. falciparum in vitro , indicating that they likely display broad-spectrum anti-apicomplexan activity [52].…”

“…These drugs also reduce replication by inducing the conversion of tachyzoites into bradyzoite-containing cysts with abnormal morphology [51,52]. They were also effective against P. falciparum in vitro , indicating that they likely display broad-spectrum anti-apicomplexan activity [52]. Most interestingly, guanabenz, which is FDA-approved and can cross the blood brain barrier, was effective at reducing the cyst burden in the brains of chronically infected mice [52].…”

“…They were also effective against P. falciparum in vitro , indicating that they likely display broad-spectrum anti-apicomplexan activity [52]. Most interestingly, guanabenz, which is FDA-approved and can cross the blood brain barrier, was effective at reducing the cyst burden in the brains of chronically infected mice [52]. This underscores that the tight control of protein synthesis is critical to maintaining parasite viability in both replicative and latent parasite stages and targeting this translational control mechanism can be a viable drug target to assist in the reduction of latent apicomplexan parasite stages.…”

“…Most importantly, modulating eIF2 phosphorylation status has a direct effect on initiating stage conversion from proliferative to latent stages or on the maintenance of latency. For example, treatment of Toxoplasma with the small molecular inhibitors of eIF2 dephosphorylation, salubrinal or guanabenz, leads to an accumulation of phosphorylated eIF2 in the parasite, an induction of bradyzoite gene expression, and the conversion of tachyzoites into bradyzoites [37,51,52]. In keeping with this theme, salivary gland sporozoites convert prematurely to liver stage parasites when the eIF2 kinase eIK2 (UIS1) is knocked out and conversely, a knockout of the putative eIF2 phosphatase UIS2 impairs the ability of latent sporozoites to convert into liver stage parasites [9,41].…”