Challenges in Chagas Disease Drug Development

Francisco, Amanda Fortes; Jayawardhana, Shiromani; Olmo, F.J.; Lewis, Michael D.; Wilkinson, Shane R.; Taylor, Martin C.; Kelly, John M.

doi:10.3390/molecules25122799

Cited by 43 publications

(44 citation statements)

References 103 publications

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“…Available chemotherapy is based on Benznidazole and Nifurtimox, two drugs developed more than 50 years ago, which proved to be toxic, require a long treatment as compared to the rate of disease progression, and often develop drug resistance. Although many natural and synthetic compounds have been assayed for activity against T. cruzi , very few have successfully progressed through clinical trials [ 2 , 5 , 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Heteroleptic Oxidovanadium(V) Complexes with Activity against Infective and Non-Infective Stages of Trypanosoma cruzi

et al. 2021

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Five heteroleptic compounds, [VVO(IN-2H)(L-H)], where L are 8-hydroxyquinoline derivatives and IN is a Schiff base ligand, were synthesized and characterized in both the solid and solution state. The compounds were evaluated on epimastigotes and trypomastigotes of Trypanosoma cruzi as well as on VERO cells, as a mammalian cell model. Compounds showed activity against trypomastigotes with IC50 values of 0.29–3.02 μM. IN ligand and the new [VVO2(IN-H)] complex showed negligible activity. The most active compound [VVO(IN-2H)(L2-H)], with L2 = 5-chloro-7-iodo-8-hydroxyquinoline, showed good selectivity towards the parasite and was selected to carry out further biological studies. Stability studies suggested a partial decomposition in solution. [VVO(IN-2H)(L2-H)] affects the infection potential of cell-derived trypomastigotes. Low total vanadium uptake by parasites and preferential accumulation in the soluble proteins fraction were determined. A trypanocide effect was observed when incubating epimastigotes with 10 × IC50 values of [VVO(IN-2H)(L2-H)] and the generation of ROS after treatments was suggested. Fluorescence competition measurements with DNA:ethidium bromide adduct showed a moderate DNA interaction of the complexes. In vivo toxicity study on C. elegans model showed no toxicity up to a 100 μM concentration of [VVO(IN-2H)(L2-H)]. This compound could be considered a prospective anti-T. cruzi agent that deserves further research.

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Section: Introductionmentioning

confidence: 99%

Heteroleptic Oxidovanadium(V) Complexes with Activity against Infective and Non-Infective Stages of Trypanosoma cruzi

et al. 2021

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“…Amastigotes proliferate and differentiate to trypomastigotes, which are then released extracellularly secondary to macrophage disruption. Then, trypomastigotes infect other cells and colonize numerous tissues, such as the heart and gastrointestinal tract [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…This and other questions remain unanswered and unraveling the molecular mechanisms underlying infection and host immune response is essential to improve therapies for patients. At this time there is no vaccine available for this disease and the approved chemotherapy is very limited and has important secondary effects [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Nox2-derived superoxide radical is crucial to control acute Trypanosoma cruzi infection

et al. 2021

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Trypanosoma cruzi is a flagellated protozoan that undergoes a complex life cycle between hematophagous insects and mammals. In humans, this parasite causes Chagas disease, which in thirty percent of those infected, would result in serious chronic pathologies and even death. Macrophages participate in the first stages of infection, mounting a cytotoxic response which promotes massive oxidative damage to the parasite. On the other hand, T. cruzi is equipped with a robust antioxidant system to repeal the oxidative attack from macrophages. This work was conceived to explicitly assess the role of mammalian cell-derived superoxide radical in a murine model of acute infection by T. cruzi . Macrophages derived from Nox2-deficient (gp91 phox -/-) mice produced marginal amounts of superoxide radical and were more susceptible to parasite infection than those derived from wild type ( wt ) animals. Also, the lack of superoxide radical led to an impairment of parasite differentiation inside gp91 phox -/- macrophages. Biochemical or genetic reconstitution of intraphagosomal superoxide radical formation in gp91 phox -/- macrophages reverted the lack of control of infection. Along the same line, gp91 phox -/- infected mice died shortly after infection. In spite of the higher lethality, parasitemia did not differ between gp91 phox -/- and wt animals, recapitulating an observation that has led to conflicting interpretations about the importance of the mammalian oxidative response against T. cruzi . Importantly, gp91 phox -/- mice presented higher and disseminated tissue parasitism, as evaluated by both qPCR- and bioimaging-based methodologies. Thus, this work supports that Nox2-derived superoxide radical plays a crucial role to control T. cruzi infection in the early phase of a murine model of Chagas disease.

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“…The World Health Organization [1] recommends treating Chagas disease using benznidazole and nifurtimox. Both medicines are effective if given early in the acute phase, but their effectiveness is reduced in the more advanced stages; in addition, there is an increase in the frequency of adverse effects with increasing patient age [4,5]. The most common side effects are rashes, fever, generalized edema, lymphadenopathy, myalgia, arthralgia, gastrointestinal disorders, neutropenia, thrombocytopenic purpura, and peripheral polyneuropathy [6].…”

Section: Introductionmentioning

confidence: 99%

A Trypsin Inhibitor from Moringa oleifera Flowers Modulates the Immune Response In Vitro of Trypanosoma cruzi-Infected Human Cells

et al. 2020

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Trypanosoma cruzi causes the lethal Chagas disease, which is endemic in Latin America. Flowers of Moringa oleifera (Moringaceae) express a trypsin inhibitor (MoFTI) whose toxicity to T. cruzi trypomastigotes was previously reported. Here, we studied the effects of MoFTI on the viability of human peripheral blood mononuclear cells (PBMCs) as well as on the production of cytokines and nitric oxide (NO) by T. cruzi-infected PBMCs. Incubation with MoFTI (trypsin inhibitory activity: 62 U/mg) led to lysis of trypomastigotes (LC50 of 43.5 µg/mL) but did not affect the viability of PBMCs when tested at concentrations up to 500 µg/mL. A selectivity index > 11.48 was determined. When T. cruzi-infected PBMCs were treated with MoFTI (43.5 or 87.0 µg/mL), the release of the pro-inflammatory cytokine TNF-α and INF-γ, as well as of NO, was stimulated. The release of the anti-inflammatory cytokine IL-10 also increased. In conclusion, the toxicity to T. cruzi and the production of IL-10 by infected PBMCs treated with MoFTI suggest that this molecule may be able to control parasitemia while regulating the inflammation, preventing the progress of Chagas disease. The data reported here stimulate future investigations concerning the in vivo effects of MoFTI on immune response in Chagas disease.

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Challenges in Chagas Disease Drug Development

Cited by 43 publications

References 103 publications

Heteroleptic Oxidovanadium(V) Complexes with Activity against Infective and Non-Infective Stages of Trypanosoma cruzi

Heteroleptic Oxidovanadium(V) Complexes with Activity against Infective and Non-Infective Stages of Trypanosoma cruzi

Nox2-derived superoxide radical is crucial to control acute Trypanosoma cruzi infection

A Trypsin Inhibitor from Moringa oleifera Flowers Modulates the Immune Response In Vitro of Trypanosoma cruzi-Infected Human Cells

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