Repurposing of rabeprazole as an anti-Trypanosoma cruzi drug that targets cellular triosephosphate isomerase.

Trypanosoma cruzi is the causative agent of American trypanosomiasis, which mainly affects populations in Latin America. Benznidazole is used to control the disease, with severe effects in patients receiving this chemotherapy. Previous studies have demonstrated the inhibition of triosephosphate isomerase from T. cruzi, but cellular enzyme inhibition has yet to be established. This study demonstrates that rabeprazole inhibits both cell viability and triosephosphate isomerase activity in T. cruzi epimastigotes. Our results show that rabeprazole has an IC50 of 0.4 µM, which is 14.5 times more effective than benznidazole. Additionally, we observed increased levels of methyl-glyoxal and advanced glycation end products after the inhibition of cellular triosephosphate isomerase by rabeprazole. Finally, we demonstrate that the inactivation mechanisms of rabeprazole on triosephosphate isomerase of T. cruzi can be achieved through the derivatization of three of its four cysteine residues. These results indicate that rabeprazole is a promising candidate against American trypanosomiasis.

Synergistic effect of compounds directed to triosephosphate isomerase, a combination to develop drug against trichomoniasis.

The development of new drugs is continuous in the world; currently, saving resources (both economic ones and time) and preventing secondary effects have become a necessity for drug developers. Trichomoniasis is the most common nonviral sexually transmitted infection affecting more than 270 million people around the world. In our research group, we focussed on developing a selective and more effective drug against Trichomonas vaginalis, and we previously reported on a compound, called A4, which had a trichomonacidal effect. Later, we determined another compound, called D4, which also had a trichomonacidal effect together with favorable toxicity results. Both A4 and D4 are directed at the enzyme triosephosphate isomerase. Thus, we made combinations between the two compounds, in which we determined a synergistic effect against T. vaginalis, determining the IC50 and the toxicity of the best relationship to obtain the trichomonacidal effect. With these results, we can propose a combination of compounds that represents a promising alternative for the development of a new therapeutic strategy against trichomoniasis.

Looking for combination of benznidazole and Trypanosoma cruzi-triosephosphate isomerase inhibitors for Chagas disease treatment.

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.

Effect of enzymes on the growth of human and animal rotaviruses.

The growth of group A human, bovine, equine and porcine rotaviruses were enhanced by pretreatment of virus with pancreatin, trypsin, protease, alkaline phosphatase or pepsin and incorporation of these enzymes in maintenance medium. In contrast, alpha-amylase or lipase inhibited the growth of equine and porcine rotaviruses. The other enzymes, adenosine deaminase, lactase, lysozyme, ribonuclease or triose-phosphate isomerase gave little or no change in the growth of all four rotaviruses.

The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal.

In Krebs-Ringer phosphate buffer, the rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate was first order with respect to the triose phosphate with rates constant values of 1.94 +/- 0.02 x 10(-5) s-1 (n = 18) and 1.54 +/- 0.02 x 10(-4) s-1 (n = 18) at 37 degrees C, respectively. The rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate in the presence of red blood cell lysate was not significantly different from the non-enzymatic value (P > 0.05). Methylglyoxal formation from glycerone phosphate was increased in the presence of triose phosphate isomerase but this may be due to the faster non-enzymatic formation from the glyceraldehyde 3-phosphate isomerisation product. For red blood cells in vitro, the predicted non-enzymatic rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate may account for the metabolic flux through the glyoxalase system. The reactivity of glycerone phosphate and glyceraldehyde 3-phosphate towards the non-enzymatic formation of methylglyoxal under physiological conditions suggests that methylglyoxal formation is unavoidable from the Embden-Meyerhof pathway.