Trypanosoma cruzi RNA-binding protein DRBD3: perinuclear foci formation during benznidazole exposure
Daniela Ferreira ChameDANIELA DE LAET-SOUZAHelaine Graziele Santos VieiraE. B. TaharaAndréa Mara MacedoCarlos Renato MachadoGlória Regina Franco
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Abstract:
Benznidazole (BZ) is the trypanocidal compound of choice for Chagas disease, a neglected tropical disease in the Americas. However, this drug often fails to cure the infection. The regulation of gene expression in Trypanosoma cruzi, the causative agent of Chagas disease, is based on post-transcriptional mechanisms. When environmental changes cause translational arrest, RNA-binding proteins, and their target mRNAs assemble into cytoplasmic bodies, known as RNA granules, which act as RNA sorting centers. We have characterized the T. cruzi RNA-binding protein DRBD3, which has two RRMs domains, and a C-terminal low-complexity sequence rich in proline and glutamines. Using a tagged form of TcDRBD3 (rTcDRBD3), we showed that this protein resides in the cytoplasm, but localizes into perinuclear cytoplasmic foci after BZ exposure. RNA staining after BZ also showed that this molecule accumulates into perinuclear cytoplasmic foci. Moreover, BZ and puromycin treatment enhanced the colocalization of rTcDRBD3 and RNA, suggesting that TcDRBD3 granules repertoire harbors RNAs released from polysomes. Under starvation, rTcDRBD3 granules localized throughout the cytoplasm and also increased in number in the presence of puromycin. Our results suggest that TcDRBD3 accumulates into perinuclear granules that harbor RNA and also that its localization varies according to the type of stress.Keywords:
Benznidazole
Benznidazole
Pentamidine
Amastigote
Chagas Disease
Nifurtimox
Kinetoplastida
Trypanocidal agent
Polyamine
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Trypanosoma cruzi naturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure of T. cruzi infection in the majority of cases. In this study, we have extended our previous investigations of more effective, higher dose, intermittent administration protocols using the FDA-approved drug benznidazole (BNZ), in experimentally infected mice and in naturally infected dogs and nonhuman primates (NHP). Collectively, these studies demonstrate that twice-weekly administration of BNZ for more than 4 months at doses that are ~2.5-fold that of previously used daily dosing protocols, provided the best chance to obtain parasitological cure. Dosing less frequently or for shorter time periods was less dependable in all species. Prior treatment using an ineffective dosing regimen in NHPs did not prevent the attainment of parasitological cure with an intensified BNZ dosing protocol. Furthermore, parasites isolated after a failed BNZ treatment showed nearly identical susceptibility to BNZ as those obtained prior to treatment, confirming the low risk of induction of drug resistance with BNZ and the ability to adjust the treatment protocol when an initial regimen fails. These results provide guidance for the use of BNZ as an effective treatment for T. cruzi infection and encourage its wider use, minimally in high value dogs and at-risk NHP, but also potentially in humans, until better options are available.
Benznidazole
Chagas Disease
Nifurtimox
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Benznidazole
Nifurtimox
Trypanocidal agent
Chagas Disease
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Trypanosoma cruzi (T. cruzi) is a parasitic protozoan transmitted to mammalian hosts by blood-sucking triatomine bugs. Infections by T. cruzi, known as Chagas' disease, pose a major public health problem in endemic countries in Central and South America. New chemotherapeutic agents are desired because of the lack of effective vaccines, undesirable side effects of anti-chagasic drugs in use such as nifurtimox and benznidazole, and the emergence of parasite resistance to these drugs. In the past two decades, novel advances and an improved understanding of the biology and biochemistry of T. cruzi have led to the identification of various targets for chemotherapy to treat Chagas' disease. In addition, many efforts have been undertaken to develop antichagasic agents, such as designed and synthesized compounds, natural products, and their derivatives, against a number of targets. Here, I mainly review recent studies on the antichagasic activities of natural products.
Benznidazole
Nifurtimox
Chagas Disease
Antiparasitic agent
Triatominae
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Benznidazole
Chagas Disease
Kinetoplastida
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We investigated the in vitro action of an hydrosoluble 2-nitroimidazole, Etanidazole (EZL), against Trypanosoma cruzi, the etiologic agent of Chagas disease. EZL displayed lethal activity against isolated trypomastigotes as well as amastigotes of T. cruzi (RA strain) growing in Vero cells or J774 macrophages, without affecting host cell viability. Although not completely equivalent to Benznidazole (BZL), the reference drug for Chagas chemotherapy, EZL takes advantage in exertingits anti-T. cruzi activity for longer periods without serious toxic side effects, as those recorded in BZL-treated patients. Our present results encourage further experiments to study in depth the trypanocidal properties of this drug already licensed for use in human cancers.
Benznidazole
Amastigote
Chagas Disease
Nifurtimox
Vero cell
Trypanocidal agent
Protozoan parasite
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Benznidazole
Chagas Disease
Trypanocidal agent
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It was reported previously that 2-n-propylquinoline was active against the epimastigote form of Trypanosoma cruzi. The effects of oral treatments with benznidazole and 2-n-propylquinoline were evaluated in Balb/c mice infected with T. cruzi chronically. The reference drug and 2-n-propylquinoline were administered 60 days post-infection for 30 days at 25 mg/mL. At 35 days post-treatment, the serological tests (ELISA) of the 2-n- propylquinoline-treated mice were significantly different from the controls (p = 0.01) and the benznidazole-treated mice (p = 0.03), while this was not the case at 85 days post-treatment. These results are encouraging for continuing the investigation of other analogues of 2-n-propylquinoline in experimental chronic Chagas' disease.
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Chagas Disease
Nifurtimox
Kinetoplastida
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Comparative studies of drug susceptibility of five strains of Trypanosoma cruzi in vivo and in vitro
A comparative study showed that 5 laboratory strains of Trypanosoma cruzi could be divided into a non-responsive group (Sonya clone and Colombiana) and a responsive group (Tulahuén, Y and Peru), based on long-term treatment of mouse infections with nifurtimox and benznidazole. In vitro sensitivity of epimastigotes and blood-stream trypomastigotes in macrophage cultures did not distinguish the strains, nor did the rate of development of nifurtimox resistance by epimastigote cultures. 7 novel anti-T. cruzi compounds also behaved similarly with respect to the 2 groups. A small decrease in sensitivity was observed in vitro by non-responsive strains of T. cruzi after re-isolation from treated mice. It is postulated that there could be an immunological component involved in successful treatment of T. cruzi infection.
Benznidazole
Nifurtimox
Chagas Disease
Kinetoplastida
clone (Java method)
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Benznidazole
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