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

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4203
Author(s):  
Héloïse Débare ◽  
Nathalie Moiré ◽  
Firmin Baron ◽  
Louis Lantier ◽  
Bruno Héraut ◽  
...  

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.

2013 ◽  
Vol 56 (7) ◽  
pp. 3068-3077 ◽  
Author(s):  
Sebastian Lourido ◽  
Chao Zhang ◽  
Michael S. Lopez ◽  
Keliang Tang ◽  
Jennifer Barks ◽  
...  

2019 ◽  
Author(s):  
Mosleh Kadkhodamohammadi ◽  
Milad Jaberi ◽  
Reza Babaei akerdi ◽  
Masoud Aliyar

AbstractIntroductionThe common treatment for toxoplasmosis was pyrimethamine. In recent years, it has been found that this parasite is getting resistant to this treatment, therefore urgent alternative treatments are needed.Material and MethodsIn this study, by using drug repurposing and in silico methods we tried to make a selective treatment by inhibiting the Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii which doesn’t exist in mammalians. We screened the FDA approved drugs by molecular docking and after ranking them by their binding energies and inspecting the top scored ones, we chose Cefpiramide, Ceftriaxone and Cefotiam as the hit compounds. After that, we used molecular dynamics simulations to test the hit compounds in a much more realistic environment.ResultsBy analyzing the results, we found that all of the hit compounds and good and can bind strongly to the active site of the protein. Therefore, they can be potential candidates for inhibiting Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii.ConclusionMoreover, because the predicted compounds are FDA approved drugs, their toxicity profiles are well known and their newly predicted use can be tested in clinical trials.


2010 ◽  
Vol 17 (5) ◽  
pp. 602-607 ◽  
Author(s):  
Kayode K Ojo ◽  
Eric T Larson ◽  
Katelyn R Keyloun ◽  
Lisa J Castaneda ◽  
Amy E DeRocher ◽  
...  

2018 ◽  
Vol 111 (5) ◽  
pp. 1167-1181 ◽  
Author(s):  
Bethan A. Wallbank ◽  
Caia S. Dominicus ◽  
Malgorzata Broncel ◽  
Nathalie Legrave ◽  
Gavin Kelly ◽  
...  

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