Inositol metabolism in Trypanosoma cruzi: potential target for chemotherapy against Chagas' disease

Oliveira, Mécia M.; Einicker‐Lamas, Marcelo

doi:10.1590/s0001-37652000000300015

Cited by 11 publications

(3 citation statements)

References 37 publications

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“…40 In trypanosomatids, some of those components have been reported for Leishmania, 41,42 T. rangeli, 43 and T. cruzi. 44,45 The intra-and interspecies variations in glycoconjugate assembly may originate from innumerous combinatory sequences dependent on the action and specificity of glycosidases and glycosyltransferases. Consequently, this variation allows carbohydrates to be important sources of biological diversity.…”

Section: Discussionmentioning

confidence: 99%

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Soares¹,

Torrecilhas²,

Assis³

et al. 2012

The American Journal of Tropical Medicine and Hygiene

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Section: Discussionmentioning

confidence: 99%

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Soares¹,

Torrecilhas²,

Assis³

et al. 2012

The American Journal of Tropical Medicine and Hygiene

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“…Enzymes involved in sphingolipid biosynthesis and degradation pathways, such as inositol-phosphoryl ceramide synthase 1 (Ipc1) (35) and inositol phosphosphingolipid-phospholipase C1 (Isc1) (53), have been found to promote pathogenicity in C. neoformans. The importance of sphingolipids for pathogenicity has also been recognized in some parasitic pathogens, including Leishmania and Trypanosoma species, and related enzymes have been proposed as potential drug targets (36,37,45,60,67). The diacyglycerol (DAG)-protein kinase C1 (Pkc1) signaling pathway is critical for virulence factor production and pathogenicity in C. neoformans (18,19,24,25).…”

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confidence: 99%

Two Major Inositol Transporters and Their Role in Cryptococcal Virulence

Wang

Liu²,

Delmas³

et al. 2011

Eukaryot Cell

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Cryptococcus neoformans is an AIDS-associated human fungal pathogen and the most common cause of fungal meningitis, with a mortality rate over 40% in AIDS patients. Significant advances have been achieved in understanding its disease mechanisms. Yet the underlying mechanism of a high frequency of cryptococcal meningitis remains unclear. The existence of high inositol concentrations in brain and our earlier discovery of a large inositol transporter (ITR) gene family in C. neoformans led us to investigate the potential role of inositol in Cryptococcus-host interactions. In this study, we focus on functional analyses of two major ITR genes to understand their role in virulence of C. neoformans. Our results show that ITR1A and ITR3C are the only two ITR genes among 10 candidates that can complement the growth defect of a Saccharomyces cerevisiae strain lacking inositol transporters. Both S. cerevisiae strains heterologously expressing ITR1A or ITR3C showed high inositol uptake activity, an indication that they are major inositol transporters. Significantly, itr1a itr3c double mutants showed significant virulence attenuation in murine infection models. Mutating both ITR1A and ITR3C in an ino1 mutant background activates the expression of several remaining ITR candidates and does not show more severe virulence attenuation, suggesting that both inositol uptake and biosynthetic pathways are important for inositol acquisition. Overall, our study provides evidence that host inositol and fungal inositol transporters are important for Cryptococcus pathogenicity.

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“…Tiam1 facilitates activation of the Rac1 GTPase [4], which, through an undefined mechanism, is correlated with T. cruzi amastigote cell invasion [5]. The entry of T.cruzi trypomastigotes into the cell is known to strongly stimulate the formation of lipid products; in particular, phosphatidylinositol-3-phosphate (PI3P) [6]. The loss of PI3P binding to the pleckstrin homology (PH) domain of Tiam1 results in decreased Rac1 expression [4], suggesting that inhibitors of this binding site could slow proliferation of T. cruzi amastigotes and thus be of therapeutic value.…”

Section: Introductionmentioning

confidence: 99%

Combating Chagas Disease Through Inhibition of Tiam1, a Rho GTPase Guanine Nucleotide Exchange Factor

Krishna

Xie

Bourne³

et al. 2016

Preprint

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Chagas disease is a major cardiovascular affliction primarily endemic to Latin American countries, affecting some ten to twelve million people worldwide. The currently available drugs, Benznidazole and Nifurtimox, are ineffecteive in the disease's chronic stages and induce severe side effects. In an attempt to improve this situation we use an in silico drug repurposing strategy to correlate drug-protein interactions with positive clinical outcomes. The strategy involves a protein functional site similarity search, along with computational docking studies and, given the findings, a phosphatidylinositol (PIP) strip test to determine the activity of Posaconazole, a recently developed antifungal triazole, in conjunction with Tiam1, a Rho GTPase Guanine Nucleotide Exchange Factor. The results from both computational and in vitro studies indicate possible inhibition of phosphoinositides via Posaconazole, preventing Rho GTPase-induced proliferation of T. cruzi, the etiological agent of Chagas Disease. SynopsisWhile Benznidazole and Nifurtimox are effective in the acute phase of Chagas' disease, their inefficacy in the disease's chronic phase and severe side effects motivate the search for more novel treatment pathways. Antifungal triazoles have shown promise in murine models of Chagas. Using a computational platform, the authors find that these drugs may be used to combat Chagas Disease through a previously unknown mechanism. If correct, this model could be used to motivate the production of new vaccines for Chagas. Furthermore, the model demonstrates the efficacy of computational testing in the preliminary search for effective drug candidates.

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Inositol metabolism in Trypanosoma cruzi: potential target for chemotherapy against Chagas' disease

Cited by 11 publications

References 37 publications

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Two Major Inositol Transporters and Their Role in Cryptococcal Virulence

Combating Chagas Disease Through Inhibition of Tiam1, a Rho GTPase Guanine Nucleotide Exchange Factor

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