ABSTRACT
BACKGROUND The current chemotherapy for Chagas disease is based on monopharmacology with low efficacy and drug tolerance. Polypharmacology is one of the strategies to overcome these limitations. OBJECTIVES Study the anti-Trypanosoma cruzi activity of associations of benznidazole (Bnz) with three new synthetic T. cruzi-triosephosphate isomerase inhibitors, 2, 3, and 4, in order to potentiate their actions. METHODS The in vitro effect of the drug combinations were determined constructing the corresponding isobolograms. In vivo activities were assessed using an acute murine model of Chagas disease evaluating parasitaemias, mortalities and IgG anti-T. cruzi antibodies. FINDINGS The effect of Bnz combined with each of these compounds, on the growth of epimastigotes, indicated an additive action or a synergic action, when combining it with 2 or 3, respectively, and an antagonic action when combining it with 4. In vivo studies, for the two chosen combinations, 2 or 3 plus one fifth equivalent of Bnz, showed that Bnz can also potentiate the in vivo therapeutic effects. For both combinations a decrease in the number of trypomastigote and lower levels of anti-T. cruzi IgG-antibodies were detected, as well clear protection against death. MAIN CONCLUSIONS These results suggest the studied combinations could be used in the treatment of Chagas disease.
Subject(s)
Triose-Phosphate Isomerase/chemistry , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/immunology , Nitroimidazoles/pharmacology , Antibodies, Protozoan , Drug Synergism , Drug Therapy, CombinationABSTRACT
A pair of primers was synthesized according to the DNA sequence of Schistosoma japonicum Philippine strain, and the mRNA of adult worms of S. japonicum Chinese strain was prepared. The gene of triose-phosphate isomerase of S. japonicum Chinese strain (SjC TPI) was successfully cloned from the mRNA through reverse transcription polymerase chain reaction (RT-PCR) technic with the primers. The DNA sequence of the gene showed that the open reading frame of encoding SjC TPI DNA includes 759bp, which has 84% homology to Sm TPI, 99.7% homology to SjP TPI. The analysis of deduced amino acid sequence of SjC TPI indicates that SjC TPI is 84.9% (214/252) identical with Sm TPI and 99.2% (250/252) with SjP TPI. The peptide-structure analysis presents 7 extra-surface, hydrophilic regions in the molecule of SjC TPI, the molecular weight of SjC TPI is 27,619. The isoelectric point is 7.38.