A monoclonal antibody that inhibits Trypanosoma cruzi growth in vitro and its reaction with intracellular triosephosphate isomerase

Cortés-Figueroa, Arturo Ángel; Pérez‐Torres, Armando; Salaiza, Norma; Cabrera, Nallely; Escalona‐Montaño, Alma Reyna; Rondán, A.; Aguirre-Garcı́a, Marı́a Magdalena; Gómez‐Puyou, Armando; Pérez‐Montfort, Ruy; Becker, Ingeborg

doi:10.1007/s00436-007-0803-5

Cited by 19 publications

(13 citation statements)

References 23 publications

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“…It is relevant to point out that others have demonstrated that triosephosphate isomerase has a cytotoxic effect on other parasites (47)(48)(49). Having a well-characterized molecular target (i.e., GlTIM) will help to develop more efficient and specific antigiardial drugs that can be used as a coadjuvant treatment or in cases of extremely virulent and resistant strains.…”

Section: Discussionmentioning

confidence: 99%

Giardial Triosephosphate Isomerase as Possible Target of the Cytotoxic Effect of Omeprazole in Giardia lamblia

Reyes‐Vivas

Mora

Castillo-Villanueva

et al. 2014

Antimicrob Agents Chemother

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Giardiasis is highly prevalent in the developing world, and treatment failures with the standard drugs are common. This work deals with the proposal of omeprazole as a novel antigiardial drug, focusing on a giardial glycolytic enzyme used to follow the cytotoxic effect at the molecular level. We used recombinant technology and enzyme inactivation to demonstrate the capacity of omeprazole to inactivate giardial triosephosphate isomerase, with no adverse effects on its human counterpart. To establish the specific target in the enzyme, we used single mutants of every cysteine residue in triosephosphate isomerase. The effect on cellular triosephosphate isomerase was evaluated by following the remnant enzyme activity on trophozoites treated with omeprazole. The interaction of omeprazole with giardial proteins was analyzed by fluorescence spectroscopy. The susceptibility to omeprazole of drug-susceptible and drug-resistant strains of Giardia lamblia was evaluated to demonstrate its potential as a novel antigiardial drug. Our results demonstrate that omeprazole inhibits giardial triosephosphate isomerase in a species-specific manner through interaction with cysteine at position 222. Omeprazole enters the cytoplasmic compartment of the trophozoites and inhibits cellular triosephosphate isomerase activity in a dose-dependent manner. Such inhibition takes place concomitantly with the cytotoxic effect caused by omeprazole on trophozoites. G. lamblia triosephosphate isomerase (GlTIM) is a cytoplasmic protein which can help analyses of how omeprazole works against the proteins of this parasite and in the effort to understand its mechanism of cytotoxicity. Our results demonstrate the mechanism of giardial triosephosphate isomerase inhibition by omeprazole and show that this drug is effective in vitro against drug-resistant and drug-susceptible strains of G. lamblia.

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Section: Discussionmentioning

confidence: 99%

Giardial Triosephosphate Isomerase as Possible Target of the Cytotoxic Effect of Omeprazole in Giardia lamblia

Reyes‐Vivas

Mora

Castillo-Villanueva

et al. 2014

Antimicrob Agents Chemother

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“…TcTIM is considered a potential target for anti-trypanosomal drugs [7][8][9]. This enzyme is involved in the glycolysis pathway of the parasite.…”

Section: Introductionmentioning

confidence: 99%

3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

et al. 2015

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Abstract:The current pharmacological Chagas disease treatments, using Nifurtimox or Benznidazole, show limited therapeutic results and are associated with potential side effects, OPEN ACCESSMolecules 2015, 20 14596 like mutagenicity. Using random screening we have identified new chemotypes that were able to inhibit relevant targets of the Trypanosoma cruzi. We found 3H-[1,2]dithioles with the ability to inhibit Trypanosoma cruzi triosephosphate isomerase (TcTIM). Herein, we studied the structural modifications of this chemotype to analyze the influence of volume, lipophilicity and electronic properties in the anti-T. cruzi activity. Their selectivity to parasites vs. mammalian cells was also examined. To get insights into a possible mechanism of action, the inhibition of the enzymatic activity of TcTIM and cruzipain, using the isolated enzymes, and the inhibition of membrane sterol biosynthesis and excreted metabolites, using the whole parasite, were achieved. We found that this structural framework is interesting for the generation of innovative drugs for the treatment of Chagas disease.

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“…cruzi dependence on glycolysis makes enzymes in this pathway excellent drug targets. Particularly, triosephosphate isomerase from Trypanosoma cruzi (TcTIM), widely investigated for the search of small molecular weight compounds that could selectively inhibit it, killing the parasite [2][3][4] . TIM catalyzes the isomerization of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate in the fifth step of the glycolytic pathway.…”

Section: Introductionmentioning

confidence: 99%

1,2,4-thiadiazol-5(4H)-ones: a new class of selective inhibitors of Trypanosoma cruzi triosephosphate isomerase. Study of the mechanism of inhibition

Álvarez

Aguirre-López

Cabrera

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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A monoclonal antibody that inhibits Trypanosoma cruzi growth in vitro and its reaction with intracellular triosephosphate isomerase

Cited by 19 publications

References 23 publications

Giardial Triosephosphate Isomerase as Possible Target of the Cytotoxic Effect of Omeprazole in Giardia lamblia

Giardial Triosephosphate Isomerase as Possible Target of the Cytotoxic Effect of Omeprazole in Giardia lamblia

3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

1,2,4-thiadiazol-5(4H)-ones: a new class of selective inhibitors of Trypanosoma cruzi triosephosphate isomerase. Study of the mechanism of inhibition

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