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

Abstract

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.

Keywords:

• Chagas disease
• glycolysis
• proton pump inhibitors
• methylglyoxal
• molecular docking

Acknowledgements

We thank the technical assistance of Ing. Manuel Ortínez, Q.B.P. Miriam Vázquez Acevedo, and M.V.Z. Héctor Malagón Rivera from Instituto de Fisiología Celular, Universidad Nacional Autónoma de México.

Author contributions

Conceptualization: SE-F. and I.G.-T.; Formal Analysis: SE-F., G.L.-V, I. G.-T.; Funding Acquisition: S.E-F., G.L.-V., L.A.F.-L.; Investigation: I.G.-T., SE-F. I.D.-D., G.L.-V, N.C., L.A.F.-L.; methodology: SE-F. and I.G.-T.; resources: R.P.-M., I.B., R. H., J.H.-L.; software: SE-F.; writing-original draft preparation: S. E.-F., I.G.-T. writing-review and editing: R. P.-M., S. E.-F., I.G.-T., G.L.-V. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by the Recursos Fiscales para Investigación Program from the Instituto Nacional de Pediatría, S.S. Under Grants [2019/062, 2019/072, and 2020/016].