Species-specific inhibition of Giardia lamblia triosephosphate isomerase by localized perturbation of the homodimer

Enríquez-Flores, Sergio; Rodrı́guez-Romero, Adela; Hernández-Alcántara, Gloria; Mora, Ignacio De la Mora-De la; Gutiérrez‐Castrellón, Pedro; Carvajal, Karla; López-Velázquez, Gabriel; Reyes‐Vivas, Horacio

doi:10.1016/j.molbiopara.2007.10.013

Cited by 34 publications

(82 citation statements)

References 31 publications

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“…We already demonstrated the role of thiol-reactive compounds on the inactivation of GlTIM (22,24). Taking into account the mechanism of action of omeprazole on proton pump enzymes, which is based on its capacity to react with Cys, we performed enzyme inactivation assays using omeprazole against recombinant GlTIM and recombinant human TIM (HsTIM).…”

Section: Resultsmentioning

confidence: 99%

“…Added to this, the VSPs of Giardia confer antigenic variation (1), and their overexpression is related to high virulence (44). Such conditions have driven our group to search for new antigiardial drugs, with a special interest in triosephosphate isomerase as a molecular target (22,24,31). Based on our previous data, we proposed omeprazole and its isomers (G. López-Ve- lázquez and H. Reyes-Vivas, 6 October 2008, Mexican Patent Office) as drugs with a potential to inhibit GlTIM and kill Giardia trophozoites.…”

Section: Discussionmentioning

confidence: 99%

“…Strategies ranging from the development of vaccines to the search for new molecular targets are currently being addressed (1,20). The enzymes of the glycolytic pathway in G. lamblia have been proposed as potential targets for drug design (21,22) because the organism lacks oxidative phosphorylation (23). Our group has demonstrated the mechanism of inactivation of the giardial glycolytic enzyme triosephosphate isomerase (GlTIM) by chemical modification with thiol-reactive compounds (22,24).…”

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confidence: 99%

“…The enzymes of the glycolytic pathway in G. lamblia have been proposed as potential targets for drug design (21,22) because the organism lacks oxidative phosphorylation (23). Our group has demonstrated the mechanism of inactivation of the giardial glycolytic enzyme triosephosphate isomerase (GlTIM) by chemical modification with thiol-reactive compounds (22,24). In line with this, omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole) drew our attention because it is a drug that is safely used in humans and shows a molecular mechanism of action based on the chemical modification of cysteines (Cys).…”

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confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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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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“…Otherwise, the fluke enzymes show high predicted structural similarity to the human ones [117,118]. In a number of unicellular parasites, covalent modification of TPI at surface-exposed cysteine residues has proved to be a successful strategy for the identification of species-specific TPI inhibitors [121][122][123][124][125][126][127][128]. One of these residues is conserved in S. mansoni TPI (as Cys-221), suggesting that there is potential for a similar approach.…”

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Metabolic enzymes of helminth parasites: potential as drug targets

Timson¹

2015

CPPS

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Metabolic pathways which extract energy from carbon compounds are essential for an organism's survival. Therefore, inhibition of enzymes in these pathways represents a potential therapeutic strategy to combat parasitic infections. However, the high degree of similarity between host and parasite enzymes makes this strategy potentially difficult. Nevertheless, several existing drugs to treat infections by parasitic helminths (worms) target metabolic enzymes. These include the trivalent antimonials which target phosphofructokinase and Clorsulon which targets phosphoglycerate mutase and phosphoglycerate kinase. Glycolytic enzymes from a variety of helminths have been characterised biochemically, and some inhibitors identified. To date none of these inhibitors have been developed into therapies. Many of these enzymes are externalised from the parasite and so are also of interest in the development of potential vaccines. Less work has been done on tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. Again, while some inhibitors have been identified none have been developed into drug-like molecules. Barriers to the development of novel drugs targeting metabolic enzymes include the lack of experimentally determined structures of helminth enzymes, lack of direct proof that the enzymes are vital in the parasites and lack of cell culture systems for many helminth species. Nevertheless, the success of Clorsulon (which discriminates between highly similar host and parasite enzymes) should inspire us to consider making serious efforts to discover novel anthelminthics which target metabolic enzymes.

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

Benítez‐Cardoza

Brieba

Arroyo³

et al. 2022

Archiv der Pharmazie

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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 IC 50 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.

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Species-specific inhibition of Giardia lamblia triosephosphate isomerase by localized perturbation of the homodimer

Cited by 34 publications

References 31 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

Metabolic enzymes of helminth parasites: potential as drug targets

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

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