Avaliação da atividade dos inibidores virais Lopinavir e Pritelivir contra os protozoários Toxoplasma gondii e Trypanosoma cruzi.

Abstract

Despite the progress in basic knowledge about Trypanosoma cruzi and Toxoplasma gondii, as well as the discovery of several compounds with activity for these protozoa, Chagas' disease and Toxoplasmosis still portray high morbidity and in some of its manifestations, high mortality. Due to the lack of drugs that act in the chronic phase of these diseases, as well as the high adverse effects caused by current treatments. The pharmaceutical industry's lack of interest in developing treatments for tropical diseases is mainly because it does not offer sufficient financial returns. It is mainly due to their lack of financial returns. Drug repositioning is a strategy in which drugs developed and in use for a given disease can be re­evaluated for use in another indication, thus reducing the time and cost of research and with known safety. Therefore, this work evaluated the activity of two antivirals, Lopinavir and Pritelivir, against tachyzoites of the RH strains, TgCTBr8 and TgCTBR5 of T. gondii and Y strain of T. cruzi. Therefore, the in vitro capacity of antivirals to interrupt the proliferation of these parasites was analyzed, and in addition, for T. gondii, the capacity to inhibit invasion with pretreated tachyzoites, the proliferative activity of the combination of Lopinavir with sulfadiazine (SDZ) and pyrimethamine (PYR) and analysis of the cystogenic potential caused by the treatment were also evaluated. For the in vivo analysis, the efficacy of treatment in acute and chronic infection models was evaluated for T. gondii. Lopinavir was able to inhibit 78% of the proliferation of TgCTBr8 and TgCTBr5 strains with 7 and 15 μM, respectively, and was also able to inhibit by 56% the invasion of tachyzoites with 7 μM in the TgCTBr8 strain and 35% with 15 μM in the TgCTBr5 strain. Regarding the standard treatment for toxoplasmosis (SDZ+PYR), the TgCTBr5 strain was more susceptible than the TgCTBr8 strain, while the association of this treatment with Lopinavir presented antagonism, increasing the proliferation of the TgCTBr5 strain. The cystogenesis assay demonstrated that the TgCTBr8 strain has a greater spontaneous or induced cystogenic capacity by Lopinavir. In the acute phase in vivo trials, the combined treatment of antivirals and antifolates did not affect animal survival, but was able to reduce the burden of brain cysts, when compared to the group treated only with antifolates. On the other hand, the isolated treatment with Lopinavir in a chronic trial of the disease showed a moderate decrease in brain cysts. About Pritelivir, a reduction in the proliferation of T. gondii and T. cruzi of 77% and 80%, respectively, was obtained with the use of 60 μg/mL in treatments for 48 hours. IC50 values of 14.7 and 34.85 μg/mL in 24 hours of treatment and 37,3 and 22,40 μg/mL in 48 hours of treatment were obtained for T. gondii and T. cruzi, respectively. Our results show that the antivirals studied here can be promising alternatives for the development of new therapies for Toxoplasmosis and Chagas Disease.