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. 2021 Jul 10;26(14):4203.
doi: 10.3390/molecules26144203.

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

Héloïse Débare  1 , Nathalie Moiré  1 , Firmin Baron  1 , Louis Lantier  1 , Bruno Héraut  1 , Nathalie Van Langendonck  2 , Caroline Denevault-Sabourin  3 , Isabelle Dimier-Poisson  1 , Françoise Debierre-Grockiego  1
Affiliations

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

Héloïse Débare et al. Molecules. .

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.

Keywords: Toxoplasma gondii; congenital toxoplasmosis; imidazoazines; treatment.

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Conflict of interest statement

The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. F.D.G. was invited to present part of these results at the Antibiotic Resistance Mechanisms Meeting for BSAC grant holders held on December 2017 in Birmingham, UK. All other authors: none to declare.

Figures

Figure 1
Figure 1
Mice were infected at mid-gestation by tachyzoites (intraperitoneal route, i.p.) or cysts (oral route) of the ME49 strain of T. gondii. Mice received PBS or SP230 (50 mg/kg) by the same routes for 5 days. The number of T. gondii parasites was evaluated by qPCR at day 17 of gestation in brain (a) and lungs (b) of dams (n = 5 to 7) or in foetuses ((c), n = 90 [PBS i.p., 5 dams], 47 [SP230 i.p., 3 dams], 86 [PBS oral, 6 dams] and 53 [SP230 oral, 3 dams]). NS: not significant, * p < 0.05, ** p < 0.01, **** p < 0.0001 (Dunn’s multiple comparison test).
See this image and copyright information in PMC

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