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

被引:4
作者
Debare, Heloise [1 ,4 ]
Moire, Nathalie [1 ]
Baron, Firmin [1 ]
Lantier, Louis [1 ]
Heraut, Bruno [1 ]
Van Langendonck, Nathalie [2 ]
Denevault-Sabourin, Caroline [3 ]
Dimier-Poisson, Isabelle [1 ]
Debierre-Grockiego, Francoise [1 ]
机构
[1] Univ Tours, Natl Res Inst Agr Food & Environm, Infectiol & Sante Publ, F-37000 Tours, France
[2] Ctr Hosp Reg Univ Tours, Serv Parasitol Mycol Med Trop, F-37000 Tours, France
[3] Univ Tours, Grp Innovat & Ciblage Cellulaire EA7501, F-37200 Tours, France
[4] Natl Res Inst Agr Food & Environm, Anim Genet & Innovat Biol, F-78352 Jouy En Josas, France
关键词
Toxoplasma gondii; congenital toxoplasmosis; treatment; imidazoazines; CONGENITAL TOXOPLASMOSIS; PREGNANCY;
D O I
10.3390/molecules26144203
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:7
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