A Novel Calcium-Dependent Protein Kinase 1 Inhibitor Potently Prevents Toxoplasma gondii Transmission to Foetuses in Mouse.

Héloïse Débare,Caroline Denevault-Sabourin,Bruno Héraut,Nathalie Van Langendonck,Isabelle Dimier-Poisson,Firmin Baron,Nathalie Moiré,Françoise Debierre-Grockiego,Louis Lantier

doi:10.3390/molecules26144203

Héloïse Débare, Caroline Denevault-Sabourin + Show 7 more

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https://doi.org/10.3390/molecules26144203

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Abstract

Treatments currently used to prevent congenital toxoplasmosis are non-specific of Toxoplasma gondii and have grievous side effects. To develop a more specific and less toxic drug, we have designed SP230, an imidazo[1,2-b]pyridazine salt targeting the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) and active against acute toxoplasmosis in mice. Efficiency of SP230 to inhibit foetal transmission of the parasite was evaluated in a mouse model of congenital toxoplasmosis. Swiss mice were infected at mid-pregnancy with tachyzoites or cysts of the ME49 strain of T. gondii by intraperitoneal and oral route, respectively, and treated with SP230 at 50 mg/kg for 5 days by the same routes. Parasite burden in organs of dams and in foetuses was measured by quantitative PCR. Intraperitoneal administration of SP230 drastically reduced the number of parasites (more than 97% of reduction) in the brain and lungs of dams, and led to a reduction of 66% of parasite burden in foetuses. Oral administration of SP230 was particularly efficient with 97% of reduction of parasite burdens in foetuses. SP230 did not impact number and weight of offspring in our conditions. This inhibitor of TgCDPK1 is a promising candidate for the development of alternative therapeutics to treat infected pregnant women.

Highlights

Human beings are at risk of infection with the apicomplexan parasite Toxoplasma gondii mainly by ingestion of cysts present in undercooked meat
We have previously demonstrated the outstanding efficacy of the imidazo[1,2-b]pyridazine salt SP230, a T. gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitor that strongly reduced parasite burdens in the brain and lungs of non-pregnant infected mice [7]
The batch of SP230 synthesized for this study had similar therapeutic index than in our previous work [7], with a CE50 of 0.080 μM on T. gondii tachyzoites in vitro and a CC50 of more than 30 μM on the human foreskin fibroblasts used as host cells for tachyzoite growth in vitro (CC50/CE50 > 350)

Summary

Introduction

Human beings are at risk of infection with the apicomplexan parasite Toxoplasma gondii mainly by ingestion of cysts present in undercooked meat. Tachyzoites can cross the placental barrier and infect the foetus resulting in congenital toxoplasmosis. The macrolide antibiotic spiramycin is often used to inhibit transmission of infection to the foetus but is inefficient when foetal contamination is confirmed, because it cannot cross the placental barrier [3]. At this stage, the therapeutic option widely used is an association of pyrimethamine with a sulphonamide drug, targeting the T. gondii folate pathway, characterized by a modest efficacy, long periods of treatment and significant side effects [4,5].

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