A Novel Calcium-Dependent Protein Kinase 1 Inhibitor Potently Prevents Toxoplasma gondii Transmission to Foetuses in
Héloïse Débare1, Nathalie Moiré1, Firmin Baron1
1Infectiologie et Santé Publique, National Research Institute for Agriculture, Food and the Environment, Université de Tours, 37000 Tours, France.
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.
Insights
A new drug, SP230, effectively prevents congenital toxoplasmosis transmission in mice. Targeting Toxoplasma gondii, SP230 significantly reduced parasite burden in dams and fetuses, offering a promising alternative therapy.
Area of Science:
- Parasitology
- Pharmacology
- Immunology
Background:
- Current treatments for congenital toxoplasmosis lack specificity and cause severe side effects.
- Toxoplasma gondii infection during pregnancy poses significant risks to fetal development.
Purpose of the Study:
- To evaluate the efficacy of SP230, a novel drug targeting Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1), in preventing congenital toxoplasmosis.
- To assess SP230's safety and effectiveness in a mouse model of congenital toxoplasmosis.
Main Methods:
- Congenital toxoplasmosis was induced in pregnant Swiss mice infected with the ME49 strain of T. gondii.
- Mice were treated with SP230 (50 mg/kg) via intraperitoneal or oral routes for 5 days.
- Parasite burden in dams and fetuses was quantified using qPCR.
Main Results:
- Intraperitoneal SP230 reduced parasite burden by over 97% in dams' brains and lungs and 66% in fetuses.
- Oral SP230 administration achieved a 97% reduction in fetal parasite burden.
- SP230 treatment did not adversely affect offspring number or weight.
Conclusions:
- SP230 demonstrates significant efficacy in reducing fetal transmission of T. gondii in a mouse model.
- SP230 is a promising candidate for developing safer and more specific therapeutic options for pregnant women with toxoplasmosis.
