Activity of the Histone Deacetylase Inhibitor FR235222 on Toxoplasma gondii : Inhibition of Stage Conversion of the Parasite Cyst Form and Study of New Derivative Compounds

Abstract

Bradyzoite-to-tachyzoite conversion plays a role in the pathogenesis of recrudescence of ocular toxoplasmosis and disease in immunocompromised persons. The currently available medicines are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. A previous study showed that the histone deacetylase inhibitor FR235222 has a dramatic effect on tachyzoite growth and induces tachyzoite-to-bradyzoite conversion in vitro. The present study shows that FR235222 can target in vitro-converted cysts and bradyzoites. Moreover, the compound is active on ex vivo T. gondii cysts. Free bradyzoites isolated after lysis of the cell wall did not proliferate in vitro when the cyst was treated with FR235222. The results imply that this compound is able to cross the T. gondii cystic cell wall. Fluorescent labeling shows that the compound impairs the capacity of the bradyzoites to convert without damaging the cyst wall integrity. In vivo inoculation of formerly treated cysts fails to infect mice when these cysts were treated with FR235222. We used our structural knowledge of FR235222 and its target, T. gondii HDAC3, to synthesize new FR235222 derivative compounds. We identified two new molecules that are highly active against tachyzoites. They harbor a better selectivity index that is more suitable for a future in vivo approach. These results identify FR235222 and its derivatives as new lead compounds in the range of therapeutics available for acute and chronic toxoplasmosis.Toxoplasma gondii is the causative agent of toxoplasmosis and is considered one of the most common parasitic diseases, given its worldwide distribution and its broad range of intermediate hosts (18). T. gondii is an intracellular parasite that belongs to the Apicomplexa family, like Plasmodium species, with which it shares major biologic and genetic similarities (4,35). Its life cycle is complex and is characterized by the interconversion phenomenon, which is the ability of the parasite to differentiate from a tachyzoite form to a cystic structure (containing the bradyzoite form) and vice versa. Cysts, which are responsible for the chronic form of toxoplasmosis, are believed to not cause symptoms in healthy people, but if they are reactivated, they can be potentially life-threatening in immunocompromised patients. Treatments of acute toxoplasmosis are currently based on the combination of pyrimethamine (PYR) and sulfadiazine, which can be associated with cytopenia and allergic skin reactions, respectively, as possible side effects. The antibiotics cotrimoxazole and clindamycin have been used as second-line treatments (14). In addition, medicines used so far in the clinical setting target the tachyzoite form, while the tissue cysts remain unaffected. Despite the highly active research on this parasite and the description of dozens of potential new molecular targets, no candidates presenting an anticystic activity have been identified, therefore providing no grounds for a treatment able to eliminate T. gondii from infected patients. Discovering...

Garcinol Inhibits GCN5-Mediated Lysine Acetyltransferase Activity and Prevents Replication of the Parasite Toxoplasma gondii

“…The target of the antiparasitic compound apicidin was found to be a parasite KDAC homologue (3). FR23522 and its derivatives also display potent activity against Toxoplasma by targeting a KDAC called TgHDAC3 (4,5). In contrast, there are no reports to date of a Toxoplasma KAT inhibitor despite genetic studies showing that KATs are essential for parasite viability (6)(7)(8)(9)(10)(11)(12)(13).…”

Nanoparticles show potential to retard bradyzoites in vitro formation of Toxoplasma gondii

“…The cysts are sequestered in tissues and upon reactivation, can be life-threatening particularly for the immunocompromised patients. Many potential new molecular targets have been identified (Maubon et al 2010), but, no drug candidate with anti-cystic activity has been reported to date. Therefore, the discovery of new therapeutic agents that are effective on cysts is an important challenge in toxoplasmosis control.…”

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

“…We may be able to add infections caused by protozoan parasites to this list, as genetic studies have shown that most parasite bromodomain proteins are crucial for viability and virulence. Some studies have already begun to examine the effects of bromodomain inhibitors against these protozoan parasites, and these complement previous work showing the antiparasitic activities of KAT and KDAC inhibitors (55)(56)(57)(58)(59)(60)(61)(62)(63).…”