Abstract
Toxoplasmosis is a zoonosis of worldwide distribution. Currently, two drugs, pyrimethamine and sulfadiazine, are used as a reference in the treatment of toxoplasmosis, but the resistance of Toxoplasma gondii appears as a relevant public health problem. In order to identify new drugs to toxoplasmosis treatment, we performed a molecular docking of raltitrexed to T. gondii thymidylate synthase-dihydrofolate reductase (TS-DHFR) and also evaluated its efficacy in infected mice. Initially, raltitrexed was docked on the crystallographic structures of TS-DHFR from T. gondii and Mus musculus. Then, 48 h after infection with the T. gondii RH strain, different groups of mice received an oral dose of raltitrexed (0.15, 0.75, and 1.5 mg kg−1). Two days after treatments, raltitrexed was able to prevent mortality and reduce the number of tachyzoites in the peritoneal fluid and liver imprints from infected mice. The results showed that raltitrexed has important protective activities against the T. gondii RH strain. Molecular docking still suggests that the effects against the parasite may be dependent on the inhibition of T. gondii thymidylate synthase. This study opens new perspectives for the use of raltitrexed in patients infected with T. gondii, especially when conventional treatments do not exhibit the expected efficacy.
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Acknowledgements
This work was supported by grants from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil), Diretoria Executiva de Gestão da Pesquisa e Pós-Graduação (DEGPP/UNIPAR, Brazil), Fundação de Amparo a Pesquisa do Estado do Paraná (Fundação Araucária, Brazil, grant number 147/14), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil), and Laboratório Nacional de Computação Científica (LNCC, Brazil).
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All procedures were previously approved by the Institutional Ethics Committee of Universidade Paranaense (Brazil; protocol number 25452/2014) and conducted in accordance with Guidelines for the Care and Use of Laboratory Animals as adopted and promulgated by the US National Health Institute.
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de Paula Reis, M., de Lima, D.A., Pauli, K.B. et al. Molecular docking to Toxoplasma gondii thymidylate synthase-dihydrofolate reductase and efficacy of raltitrexed in infected mice. Parasitol Res 117, 1465–1471 (2018). https://doi.org/10.1007/s00436-018-5835-5
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DOI: https://doi.org/10.1007/s00436-018-5835-5