Trypanothione: A Novel Bis(glutathionyl)spermidine Cofactor for Glutathione Reductase in Trypanosomatids

Fairlamb, Alan H.; Blackburn, Peter; Ulrich, Peter; Chait, Brian T.; Cerami, Anthony

doi:10.1126/science.3883489

Cited by 660 publications

(401 citation statements)

References 22 publications

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“…Benzoyl chloride was purchased from Merck Schuchardt (Germany) and [1,[4][5][6][7][8][9][10][11][12][13][14] C]putrescine dihydrochloride (110 mCi/mmol) was obtained from NEN Life Science Products, Inc. (Boston, MA, USA). DFMO was a gift from the Merrell Dow Research Institute (Cincinnati, OH, USA).…”

Section: Chemicalsmentioning

confidence: 99%

“…Cells were collected by centrifugation (3000Ug, 10 min) and resuspended in fresh SDM-79 medium at a concentration of 2U10 8 parasites/ml with or without the addition of CHA. [1,[4][5][6][7][8][9][10][11][12][13][14] C]Putrescine (0.3 WCi/ml) was added and after incubation for 24^60 h at 28³C, parasites were sedimented, washed with PBS and resuspended in 100 Wl of 0.2 M perchloric acid. Cell extracts were neutralized with KOH and precipitates discarded after centrifugation.…”

Section: In Vivo Labeling With Radioactive Putrescinementioning

confidence: 99%

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Spermidine is essential for normal proliferation of trypanosomatid protozoa

2001

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Trypanosomatid parasites containing a metabolically unstable ornithine decarboxylase (ODC) are naturally resistant to high levels of K K-difluoromethylornithine (DFMO) because this ODC inhibitor, though causing a drastic reduction of intracellular putrescine, elicits only a moderate decrease of the spermidine endogenous pool. In this study we have used a combination of DFMO with cyclohexylamine (CHA ; biscyclohexylammonium sulfate), an inhibitor of spermidine synthase, to reach a more complete depletion of spermidine. Under these conditions we have observed the arrest of proliferation not only in trypanosomatids with stable ODC but also in parasites with an enzyme of high turnover rate. In all cases the reinitiation of proliferation occurred only after the addition of exogenous spermidine, and neither putrescine nor spermine were able to induce the same effect. ß

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Section: Chemicalsmentioning

confidence: 99%

Section: In Vivo Labeling With Radioactive Putrescinementioning

confidence: 99%

Spermidine is essential for normal proliferation of trypanosomatid protozoa

2001

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“…We evaluated more than 3,000 extracts from plant and fungi using an inhibition assay with trypanothione reductase (TR) (unpublished results). This enzyme is a validated molecular target in Trypanosoma and Leishmania species (Fairlamb et al 1985, Dumas et al 1997, Tovar et al 1998, Krieger et al 2000. As a result of the screening, we found that the ethyl acetate extract of the culture of Lentinus strigosus, a basidiomycete fungus belonging to the Polyporaceae family (Pegler 1983), was able to inhibit 100% of the enzyme activity at 20 µg/ml.…”

mentioning

confidence: 97%

A potent trypanocidal component from the fungus Lentinus strigosus inhibits trypanothione reductase and modulates PBMC proliferation

Cota

Rosa

Fagundes

et al. 2008

Mem. Inst. Oswaldo Cruz

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The fungus Lentinus strigosus (Pegler 1983) (Polyporaceae, basidiomycete) was selected in a screen for inhibitory activity on Trypanosoma cruzi trypanothione reductase (TR). The crude extract of L. strigosus was able to completely inhibit TR at 20 µg/ml. Two triquinane sesquiterpenoids (dihydrohypnophilin and hypnophilin), in addition to two panepoxydol derivatives (neopanepoxydol and panepoxydone), were isolated using a bioassay-guided fractionation protocol. Hypnophilin and panepoxydone displayed IC 50 values of 0.8 and 38.9 µM in the TR assay, respectively, while the other two compounds were inactive. The activity of hypnophilin was confirmed in a secondary assay with the intracellular amastigote forms of T. cruzi, in which it presented an IC 50 value of 2.5 µM. Quantitative flow cytometry experiments demonstrated that hypnophilin at 4 µM also reduced the proliferation of human peripheral blood monocluear cells (PBMC) stimulated with phytohemaglutinin, without any apparent interference on the viability of lymphocytes and monocytes. As the host immune response plays a pivotal role in the adverse events triggered by antigen release during treatment with trypanocidal drugs, the ability of hypnophilin to kill the intracellular forms of T. cruzi while modulating human PBMC proliferation suggests that this terpenoid may be a promising prototype for the development of new chemotherapeutical agents for Chagas disease. Key words: fungal natural products -Chagas disease -drug discovery -immunomodulators -BasidiomycotaChagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects millions of people in Latin America, having an enormous economic and social impact in the endemic areas. These patients rely on treatment with nitrofuran (nifurtimox; Bayer) or nitroimidazol (benznidazole; Roche), medicines that display little or no activity in chronic infections, in spite of their beneficial effect during the acute phase of the disease (Cançado 2002, Coura & Castro 2002. However, significant differences in the therapeutic effectiveness are observed between these two drugs, especially when considering distinct geographical areas, which is probably due to the occurrence of naturally resistant and susceptible T. cruzi strains (Filardi & Brener 1987, Toledo et al. 2003. Furthermore, both drugs cause several side effects that contribute to their reduced use in clinical medicine (Cançado 1985). Thus, new compounds are needed to develop more effective medicines to treat Chagas disease, espe- cially in its chronic phase, is needed (Schmidt & KrauthSiegel 2002, Nwaka & Ridley 2003. However, due to low profit prospects, the development of new trypanocidal drugs is not attractive to the pharmaceutical industry (Nwaka & Ridley 2003). Thus, this endeavor is being conducted mainly in academic laboratories (Fairlamb 1999).Among the many different strategies for drug discovery, screening the local biodiversity for bioactive natural products using appropriate bioassays is an interesting alternative for researchers in affec...

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“…:, o conhecimento desses alvos, graças ao desenvolvimento da genõmica, proteõmica e bioinformática (FAIRLAMB, 1999), permite antever futuro mais promissor na pesquisa de novos antichagásicos. Entre eles, sobressaem as proteases (McKERROW et ai., 1995) e a tripanotiona redutase (FAIRLAMB, CERAMI, 1985; FAIRLAMB et ai., 1985; JOCKERS-SCHERUBL, SCHIRMER, KRAUTH-SIEGEL,1989). Além da tripanotiona redutase e das enzimas auxiliares que sintetizam tripanotiona, a triparedoxina e a triparedoxina peroxidase, recentemente identificadas em T. cruzi por LOPEZ et ai.…”

Section: Alvos Bioquímicos Na Pesquisa De Novos Antichagásicosunclassified

“…É bem conhecida e relatada a deficiência do sistema de destoxificação do T.cruzi frente ao estresse oxidativo (VIODÉ et aI., 1997). Esse parasita não tem catalase e glutationa peroxidase e a glutationa redutase é substituída por enzima específica do parasito denominada tripanotiona redutase (FAIRLAMB, CERAMI, 1985; FAIRLAMB et aI., 1985; JOCKERS-SCHERUBL, SCHIRMER, KRAUTH-SIEGEL,1989; HENDERSON et aI., 1991). A tripanotiona redutase constitui-se em um dos principais alvos do planejamento de novos antichagásicos (FAIRLAMB, 1999).…”

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Antichagásicos potenciais: síntese de bases de Mannich do hidroximetilnitrofural

Trossini¹

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2000). OBJETIVOSFace ao exposto e ante à escassez de alternativas quimioterápicas contra a doença de Chagas, representadas, atualmente, por apenas dois fármacos, nifurtimox e benznidazol, nenhum deles ativo na fase crônica da doença e apresentando alta incidência de efeitos adversos, é imperativa a busca por novos antichagásicos.Utilizando-se a latenciação, CHUNG (1996) PESSOA, MARTINS, 1988;SILVA, 1985). Entretanto, as melhores condições de vida da população norte-americana e as condições das espécies locais de triatomíneos fazem com que a infecção humana pelo vetor seja extremamente rara nos EUA. Porém, face à intensa migração do México e América Central para os EUA, há, atualmente, cerca de 100.000 pessoas infectadas neste último (NICKERSON et aI., 1981; GRANT et aI., 1989 Fonte: Reports by National Chagas ' Disease Control Programmes, 1993 Gustavo Henrique Goulart rross;n; _Re_vl_'sã_o_Bi_bl-'ioge.....ro.::....ífi_co Ciclo evolutivo do T. cruzi (DIAS, 1992)Figura 8 -Ciclo biológico do T. cruzi.Fonte: (WHO, 2003).o ciclo biológico do T. cruzi inicia-se pela ingestão, pelo vetor triatomíneo, de sangue infectado contendo as formas tripomastigotas do parasita. Os parasitas ingeridos sofrem diferenciação para a forma epimastigota no lume intestinal do inseto, local onde ocorre a proliferação parasitária. Os parasitas, ao atingir a parte posterior do intestino do inseto vetor, modificam-se para formas tripomastigotas metacíclicas, que são as formas infectantes do parasita. Estas são eliminadas pelas fezes e urina do triatomíneo. A infecção pelo T. cruzi tem início quando os parasitas eliminados pelo inseto entram em contato com uma lesão na pele ou mucosa do vertebrado. A maneira mais comum de transmissão é a vetorial, através da picada do "barbeiro", que, durante a ingestão de sangue, deposita suas fezes próximas ao local da picada. A picada provoca irritações locais, facilitando o acesso do parasita ao interior do organismo. Caso a picada seja próxima aos olhos ou à boca, o parasita pode penetrar pelas mucosas. Dentro do organismo do vertebrado as formas tripomastigotas metacíclicas do parasita passam por Gustavo HenrÜJue Goulart TrossiniRevisão Bibliográfica 13 transfonnação para as fonnas amastigotas, reproduzindo-se por fissão binária. O hospedeiro apresenta hipersensibilidade no local de entrada do parasita com intensa destruição celular. Esta faz com que fonnas amastigotas se transformem em tripomastigotas, que são liberadas nos vasos periféricos e estarão aptas para infectar novas células em outros pontos do organismo, como músculos lisos e tecido nervoso. Assim, a transfonnação de amastigotas para tripomastigotas pode ocorrer em outros pontos do organismo, continuando o ciclo da infecção. Com a picada do hospedeiro por um novo agente vetor não contaminado e a ingestão de fonnas sanguíneas do parasita, junto com sangue do hospedeiro, essas se transfonnam em fonnas fusifonnes denominadas epimastigotas. Estas se desenvolvem no aparelho digestivo do parasita e são transmitidas a outros indivíduos verteb...

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Trypanothione: A Novel Bis(glutathionyl)spermidine Cofactor for Glutathione Reductase in Trypanosomatids

Cited by 660 publications

References 22 publications

Spermidine is essential for normal proliferation of trypanosomatid protozoa

Spermidine is essential for normal proliferation of trypanosomatid protozoa

A potent trypanocidal component from the fungus Lentinus strigosus inhibits trypanothione reductase and modulates PBMC proliferation

Antichagásicos potenciais: síntese de bases de Mannich do hidroximetilnitrofural

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