Interaction of benznidazole reactive metabolites with nuclear and kinetoplastic DNA, proteins and lipids fromTrypanosoma cruzi

Toranzo, E. G. D. De; Castro, J.A.; Cazzulo, Berta M. Franke de; Cazzulo, Juan J.

doi:10.1007/bf01941187

Cited by 71 publications

(43 citation statements)

References 19 publications

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“…Nifurtimox is a nitrofuran with a mechanism of action that (in a simplified manner) involves production of nitro-anion radiation, which in the presence of oxygen impedes the capacity of T. cruzi to detoxify the free radicals that act on it 37 . On the other hand, benznidazole acts by binding its metabolites to the nuclear deoxyribonucleic acid (DNA) of the parasite, and to its lipids and proteins 38,39 . Several clinical studies have been conducted and hundreds of patients have been treated with nifurtimox or benznidazole, with variations in the results between the studies and the regions where they were carried out.…”

Section: Drugs In Use and New Strategies For Treating Chagas Diseasementioning

confidence: 99%

Chagas disease: What is known and what should be improved: a systemic review

Coura

Borges-Pereira

2012

Rev. Soc. Bras. Med. Trop.

117

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This study consists of a broad review on what is known and what should be improved regarding knowledge of Chagas disease, not only through analysis on the main studies published on the topics discussed, but to a large extent based on experience of this subject, acquired over the past 50 years (1961-2011). Among the subjects covered, we highlight the pathogenesis and evolution of infection by Trypanosoma cruzi, drugs in use and new strategies for treating Chagas disease; the serological tests for the diagnosis and the controls of cure the infection; the regional variations in prevalence, morbidity and response to treatment of the disease; the importance of metacyclogenesis of T. cruzi in different species of triatomines and its capacity to transmit Chagas infection; the risks of adaptation of wild triatomines to human dwellings; the morbidity and need for a surveillance and control program for Chagas disease in the Amazon region and the need to prioritize initiatives for controlling Chagas disease in Latin America and Mexico and in non-endemic countries, which is today a major international dilemma. Finally, we raise the need for to create a new initiative for controlling Chagas disease in the Gran Chaco, which involves parts of Argentina, Bolivia and Paraguay.

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Section: Drugs In Use and New Strategies For Treating Chagas Diseasementioning

confidence: 99%

Chagas disease: What is known and what should be improved: a systemic review

Coura

Borges-Pereira

2012

Rev. Soc. Bras. Med. Trop.

117

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“…27 O íon superóxido formado é captado pela enzima superóxido dismutase (EC 1.15.1.1) gerando peróxido de hidrogênio (H 2 O 2 ) que, através da reação de Haber-Weiss na presença de íons Fe III , forma o radical hidroxila ( · OH). 28,29 A esta espécie tem sido atribuído o efeito tripanocida por mecanismos complexos que envolvem ligação a lipídeos, proteínas e ao DNA do T. cruzi. 27 Por outro lado, o fármaco 4 não atua através do ciclo redox e não depende diretamente de espécies reativas de oxigênio (ROS -reactive oxigen species).…”

Section: Aspectos Biológicosunclassified

“…27 O radical nitro formado em 4 estaria envolvido com seu efeito tripanocida através da formação de ligações covalentes com macromoléculas do T. cruzi (e.g., DNA e citocromo P450). 28 É descrito ainda que 4 aumenta a fagocitose e lisa o T. cruzi através de um mecanismo dependente de interferongama (IFN-g -interferon-gamma), 29 e inibe o crescimento do T. cruzi através da enzima NADH-fumarato redutase (EC 1.3.1.6).…”

Section: Aspectos Biológicosunclassified

“…Dentre estes, destacam-se as cumarinas (19,20), flavonoides (21) e ácidos anacárdicos (22) de origem natural; os derivados de produtos naturais como os análogos sintéticos do ácido anacardíaco (23); os compostos sintéticos derivados de planejamento racional como os nucleosídeos (24); os reativos intermediários de nitrogênio (óxido nítrico, nitroxil e peroxinirito) (25); e mais recentemente alguns complexos doadores de NO (26). [51][52][53][54][55][56] Metabolismo dependente de grupos tióis O principal mecanismo de defesa do T. cruzi contra o estresse oxidativo envolve os tióis tripanotiona (27), homotripanotiona (28), glutationa (29) e ovotiol (30) (Figura 6). 57 Tal hipótese é suportada pelo fato de que nenhuma catalase ou glutationa peroxidase é encontrada no parasita e a atividade da superóxido dismutase é muito reduzida.…”

Section: Via Glicolíticaunclassified

“…Principais tióis de tripanosomatídeos: tripanotiona (27), homotripanotiona (28), glutationa (29) e ovotiol (30) é incapaz de sintetizar ácido siálico e o único mecanismo de transferência deste ácido é através da trans-sialidase, esta enzima tem se tornado um alvo macromolecular promissor. 34 …”

Section: Figura 4 Inibidores Azólicos Cetoconazol (15) Fluconazol (unclassified

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Quimioterapia da doença de Chagas: estado da arte e perspectivas no desenvolvimento de novos fármacos

Dias¹,

Dessoy²,

Silva³

et al. 2009

Quím. Nova

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Dithiolproteine als Hüter des intrazellulären Redoxmilieus bei Parasiten: alte und neue Wirkstoff‐Targets bei Trypanosomiasis und Malaria

2005

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Parasitäre Erkrankungen wie Schlafkrankheit, Chagas‐Krankheit oder Malaria gehören zu den Hauptursachen weltweiter Armut. Dringend benötigt werden antiparasitäre Medikamente, die nicht nur wirksam, sondern für die Betroffenen auch erschwinglich und verfügbar sind. Ein Ansatz bei der Suche nach neuen Wirkstoffen (und der Wiederentdeckung alter) basiert auf dem Einsatz von Enzyminhibitoren, die die antioxidativen Systeme in den Pathogenen blockieren. Für Parasiten sind die antioxidativen Netzwerke essentiell, da sie vom menschlichen Wirt durch starke Oxidantien wie Peroxynitrit, Hypochlorit und Wasserstoffperoxid bekämpft werden. Das pathogeneigene Schutzsystem besteht aus etwa zwanzig Thiol‐ und Dithiolproteinen, die das intrazelluläre Redoxmilieu bei einem Potential von etwa −250 mV puffern. Im Zentrum dieses Redoxgefüges steht bei Trypanosomen und Leishmanien das parasitenspezifische Dithiol Trypanothion (N1,N8‐Bis(glutathionyl)spermidin). Malariaparasiten hingegen besitzen ein konservativeres System, das auf Glutathion und Thioredoxin basiert. Inhibitoren von antioxidativen Enzymen wie der Trypanothionreduktase sind per se parasitizid, darüber hinaus können sie aber auch die Entwicklung von Resistenz gegen andere antiparasitäre Wirkstoffe verzögern.

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Interaction of benznidazole reactive metabolites with nuclear and kinetoplastic DNA, proteins and lipids fromTrypanosoma cruzi

Cited by 71 publications

References 19 publications

Chagas disease: What is known and what should be improved: a systemic review

Chagas disease: What is known and what should be improved: a systemic review

Quimioterapia da doença de Chagas: estado da arte e perspectivas no desenvolvimento de novos fármacos

Dithiolproteine als Hüter des intrazellulären Redoxmilieus bei Parasiten: alte und neue Wirkstoff‐Targets bei Trypanosomiasis und Malaria

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