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 IC 50 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.

Human Triosephosphate Isomerase Is a Potential Target in Cancer Due to Commonly Occurring Post-Translational Modifications

“…This latter is important since cysteines, with their oxidation-sensitive sulfur atom, are responsive to different redox conditions. Thereby, Cys residues have been involved in strategies to target the TIM of several organisms, including in human cells [ 57 , 58 , 59 , 79 ].…”

“…As a result, researchers have investigated this protein as a potential target for treating these diseases [30,56]. Contrary to what happens in developing drugs directed to parasite TIMs [57][58][59], the main reason for failing to find a drug against HsTIM is that the structure of this enzyme is conserved between metastatic and normal cells.…”