Chemiluminescence enhancement by trypanocidal drugs and by inhibitors of antioxidant enzymes in Trypanosoma cruzi

1988 ◽  
Vol 30 (3) ◽  
pp. 243-251 ◽  
Author(s):  
Cecilia Giulivi ◽  
Julio F. Turrens ◽  
Alberto Boveris
Keyword(s):  
Antioxidant Enzymes ◽  
Trypanosoma Cruzi ◽  
Trypanocidal Drugs

scholarly journals Peroxiredoxins play a major role in protecting Trypanosoma cruzi against macrophage- and endogenously-derived peroxynitrite

2008 ◽  
Vol 410 (2) ◽  
pp. 359-368 ◽  
Author(s):  
Lucía Piacenza ◽  
Gonzalo Peluffo ◽  
María Noel Alvarez ◽  
John M. Kelly ◽  
Shane R. Wilkinson ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Trypanosoma Cruzi ◽  
Fluorescence Probe ◽  
Reactive Oxygen ◽  
Cysteine Residue ◽  
Protective Effects ◽  
Nitrogen Species ◽  
Intact Cells ◽  
Tryparedoxin Peroxidase

There is increasing evidence that Trypanosoma cruzi antioxidant enzymes play a key immune evasion role by protecting the parasite against macrophage-derived reactive oxygen and nitrogen species. Using T. cruzi transformed to overexpress the peroxiredoxins TcCPX (T. cruzi cytosolic tryparedoxin peroxidase) and TcMPX (T. cruzi mitochondrial tryparedoxin peroxidase), we found that both cell lines readily detoxify cytotoxic and diffusible reactive oxygen and nitrogen species generated in vitro or released by activated macrophages. Parasites transformed to overexpress TcAPX (T. cruzi ascorbate-dependent haemoperoxidase) were also more resistant to H2O2 challenge, but unlike TcMPX and TcCPX overexpressing lines, the TcAPX overexpressing parasites were not resistant to peroxynitrite. Whereas isolated tryparedoxin peroxidases react rapidly (k=7.2×105 M−1·s−1) and reduce peroxynitrite to nitrite, our results demonstrate that both TcMPX and TcCPX peroxiredoxins also efficiently decompose exogenous- and endogenously-generated peroxynitrite in intact cells. The degree of protection provided by TcCPX against peroxynitrite challenge results in higher parasite proliferation rates, and is demonstrated by inhibition of intracellular redox-sensitive fluorescence probe oxidation, protein 3-nitrotyrosine and protein–DMPO (5,5-dimethylpyrroline-N-oxide) adduct formation. Additionally, peroxynitrite-mediated over-oxidation of the peroxidatic cysteine residue of peroxiredoxins was greatly decreased in TcCPX overexpressing cells. The protective effects generated by TcCPX and TcMPX after oxidant challenge were lost by mutation of the peroxidatic cysteine residue in both enzymes. We also observed that there is less peroxynitrite-dependent 3-nitrotyrosine formation in infective metacyclic trypomastigotes than in non-infective epimastigotes. Together with recent reports of up-regulation of antioxidant enzymes during metacyclogenesis, our results identify components of the antioxidant enzyme network of T. cruzi as virulence factors of emerging importance.

scholarly journals Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection

2002 ◽  
Author(s):  
Juan Carlos Villar ◽  
Luis Angel Villar ◽  
Jose Antonio Marin-Neto ◽  
Shah Ebrahim ◽  
Salim Yusuf
Keyword(s):  
Trypanosoma Cruzi ◽  
Trypanocidal Drugs ◽  
Cruzi Infection

scholarly journals Structure-Based Virtual Screening and In Vitro Evaluation of New Trypanosoma cruzi Cruzain Inhibitors

2019 ◽  
Vol 20 (7) ◽  
pp. 1742 ◽  
Author(s):  
Verónica Herrera-Mayorga ◽  
Edgar Lara-Ramírez ◽  
Karla Chacón-Vargas ◽  
Charmina Aguirre-Alvarado ◽  
Lorena Rodríguez-Páez ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Trypanosoma Cruzi ◽  
Selection Process ◽  
Chronic Phase ◽  
Inhibitory Effect ◽  
Pharmacological Treatments ◽  
Trypanocidal Activity ◽  
Trypanocidal Drugs ◽  
Cruzain Inhibitors

Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects; therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 ± 9.9 μM) and trypomastigote (IC50 = 166.21 ± 14.5 μM and 185.1 ± 8.5 μM on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs.

scholarly journals Trypanosoma cruzi: chemotherapy with benznidazole in mice inoculated with strains from Paraná State and from different endemic areas of Brazil

1997 ◽  
Vol 39 (5) ◽  
pp. 283-290 ◽  
Author(s):  
Max Jean de Ornelas TOLEDO ◽  
Ana Lúcia Falavigna GUILHERME ◽  
José Carlos da SILVA ◽  
Marco Venício de GASPERI ◽  
Andréa Pereira MENDES ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Drug Susceptibility ◽  
The Other ◽  
Inflammatory Lesions ◽  
Triatoma Sordida ◽  
Northwestern Region ◽  
Endemic Areas ◽  
Different Levels ◽  
Trypanocidal Drugs

Strains of Trypanosoma cruzi from different geographical areas have shown different levels of susceptibility to trypanocidal drugs. The susceptibility in vivo to benznidazole was investigated in eighteen strains of T. cruzi. Twelve were isolated from chronic chagasic patients from different Chagas’ disease endemic areas. The other six strains were isolated from the northwestern region of Paraná state; two of them from patients three from triatomines (Triatoma sordida) and one from wild reservoir (Didelphis sp.). To test drug the infected mice were divided into two groups of twenty. One group was treated with benznidazole for twenty consecutive days and the other group was used as untreated control. The treatment began after detection of the infection by direct blood examination or haemoculture. The control of cure was done through haemoculture and indirect immunofluorescence test. The drug eliminated the inflammatory lesions of the skeletal muscle of mice considered cured and from the heart of most of them. Moreover, the inflammatory lesions were reduced in treated but not cured animals. The T. cruzi strains studied showed a gradient of drug susceptibility that varied from 0% to 100%. Ten strains were considered sensitive to the treatment (61 to 100% of cure), one strain was partially sensitive (50% of cure) and seven strains were considered resistant to the treatment (0 to 40% of cure). This variation was observed both in strains of T. cruzi isolated from domestic and sylvatic cycles

scholarly journals A Fluorinated Phenylbenzothiazole Arrests the Trypanosoma cruzi Cell Cycle and Diminishes the Infection of Mammalian Host Cells

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Roberto I. Cuevas-Hernández ◽  
Richard M. B. M. Girard ◽  
Sarai Martínez-Cerón ◽  
Marcelo Santos da Silva ◽  
Maria Carolina Elias ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Structural Characteristics ◽  
Chronic Phase ◽  
Human Infection ◽  
Host Cells ◽  
Mammalian Host ◽  
Content Type ◽  
Trypanocidal Drugs

ABSTRACT Chagas disease (CD) is a human infection caused by Trypanosoma cruzi. CD was traditionally endemic to the Americas; however, due to migration it has spread to countries where it is not endemic. The current chemotherapy to treat CD induces several side effects, and its effectiveness in the chronic phase of the disease is controversial. In this contribution, substituted phenylbenzothiazole derivatives were synthesized and biologically evaluated as trypanocidal agents against Trypanosoma cruzi. The trypanocidal activities of the most promising compounds were determined through systematic in vitro screening, and their modes of action were determined as well. The physicochemical-structural characteristics responsible for the trypanocidal effects were identified, and their possible therapeutic application in Chagas disease is discussed. Our results show that the fluorinated compound 2-methoxy-4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl] phenol (BT10) has the ability to inhibit the proliferation of epimastigotes [IC50(Epi) = 23.1 ± 1.75 μM] and intracellular forms of trypomastigotes [IC50(Tryp) = 8.5 ± 2.9 μM] and diminishes the infection index by more than 80%. In addition, BT10 has the ability to selectively fragment 68% of the kinetoplastid DNA compared with 5% of nucleus DNA. The mode of action for BT10 on T. cruzi suggests that the development of fluorinated phenylbenzothiazole with electron-withdrawing substituent is a promising strategy for the design of trypanocidal drugs.

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