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Redox-Active Metal Complexes in Trypanosomatids

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Redox-Active Therapeutics

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Abstract

The first metal-based drugs to show therapeutic efficacy against parasitic diseases, more specifically diseases caused by trypanosomatids, were arsenic and antimony complexes. Among these, pentavalent antimonials are still extensively used in the treatment of cutaneous and visceral leishmaniasis. This chapter will describe in details the current knowledge on the mechanism of action of antimonial drugs for leishmaniasis. Interestingly, pentavalent antimonials affect the parasite viability through both Sb(III)-induced imbalance of thiol metabolism in parasite and Sb(V)-induced stimulation of macrophage microbicidal activity, causing parasite death by oxidative stress. We will also discuss the mechanism of action of gold complexes under study as drug candidates for leishmaniasis.

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Abbreviations

ABC:

ATP-binding cassette

Cys:

Cysteine

Cys-Gly:

Cysteinyl-glycine

GSH:

Glutathione

iNOS:

Inducible nitric oxide synthase

NO:

Nitric oxide

MRPA:

Multidrug resistance-associated protein A

ROS:

Reactive oxygen species

TR:

Trypanothione reductase

T(SH)2 :

Reduced trypanothione

WHO:

World Health Organization

References

  1. Nussbaum K, Honek J, Cadmus CM, Efferth T. Trypanosomatid parasites causing neglected diseases. Curr Med Chem. 2010;17:1594–617.

    Article  CAS  PubMed  Google Scholar 

  2. WHO [Internet]. C2015. Neglected tropical diseases. http://www.who.int/neglected_diseases/diseases/en/.

  3. Riethmiller S. From atoxyl to salvarsan: searching for the magic bullet. Chemotherapy. 2005;51:234–42.

    Article  CAS  PubMed  Google Scholar 

  4. Chersterman C. Dr. Ernest A. H. Friedheim. A tribute on his eightieth birthday. Trans R Soc Trop Med Hyg. 1979;73:597–8.

    Article  Google Scholar 

  5. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leucemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354–60.

    CAS  PubMed  Google Scholar 

  6. Duffin J, René P. Anti-moine; anti-biotique: The public fortunes of the secret properties of antimony potassium tartrate (tartar emetic). J Hist Med Allied Sci. 1991;46:440–56.

    Article  CAS  PubMed  Google Scholar 

  7. Vianna G. Tratamento da leishmaniose tegumentar por injeções intravenosas de tártaro emético. 7 Congresso Brasileiro de Medicina Tropical de São Paulo, São Paulo, Brasil. 1912;4:426-8.

    Google Scholar 

  8. Peters W. The treatment of kala-azar. New approaches to an old problem. Indian J Med Res. 1981;73:1–18.

    PubMed  Google Scholar 

  9. Frézard F, Demicheli C, Ribeiro RR. Pentavalent antimonials: new perspectives for old drugs. Molecules. 2009;14:2317–36.

    Article  PubMed  Google Scholar 

  10. Fricker SP, Mosi RM, Cameron BR, Baird I, Zhu Y, Anastassov V, et al. Metal compounds for the treatment of parasitic diseases. J Inorg Biochem. 2008;102:1839–45.

    Article  CAS  PubMed  Google Scholar 

  11. Navarro M, Gabiani C, Chiara M, Messore L, Gambino D. Metal-based drugs for malaria, trypanosomiasis and leishmaniasis: recent achievements and perspectives. Drug Discov Today. 2010;15:1070–8.

    Article  CAS  PubMed  Google Scholar 

  12. Setzer WN. Trypanosomatid disease drug discovery and target identification. Future Med Chem. 2013;5:1703–4.

    Article  CAS  Google Scholar 

  13. Croft SL, Seifert K, Yardley V. Current scenario of drug development for leishmaniasis. Indian J Med Res. 2006;123:399–410.

    CAS  PubMed  Google Scholar 

  14. Mukbel RM, Patten Jr C, Gibson K, Ghosh M, Petersen C, Jones DE. Macrophage killing of Leishmania amazonensis amastigotes requires both nitric oxide and superoxide. Am J Trop Med Hyg. 2007;76:669–75.

    CAS  PubMed  Google Scholar 

  15. Van Assche T, Deschacht M, da Luz RA, Maes L, Cos P. Leishmania-macrophage interactions: insights into the redox biology. Free Radic Biol Med. 2011;51:337–51.

    Article  Google Scholar 

  16. Krauth-Siegel RL, Comini MA. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim Biophys Acta. 2008;1780:1236–48.

    Article  CAS  PubMed  Google Scholar 

  17. Bocedi A, Dawood KF, Fabrini R, Federici G, Gradoni L, Pedersen JZ, et al. Trypanothione efficiently intercepts nitric oxide as a harmless iron complex in trypanosomatid parasites. FASEB J. 2010;24:1035–42.

    Article  CAS  PubMed  Google Scholar 

  18. Ferreira CS, Martins PS, Demicheli C, Brochu C, Ouellette M, Frézard F. Thiol-induced reduction of antimony(V) into antimony(III): a comparative study with trypanothione, cysteinylglycine, cysteine and glutathione. Biometals. 2003;16:441–3.

    Article  CAS  Google Scholar 

  19. Goodwin LC, Page JE. A study of the excretion of organic antimonials using a polarographic procedure. Biochem J. 1943;22:236–40.

    Google Scholar 

  20. Hansen C, Hansen EW, Hansen HR, Gammelgaard B, Sturup S. Reduction of Sb(V) in a human macrophage cell line measured by HPLC-ICP-MS. Biol Trace Elem Res. 2011;144:234–43.

    Article  CAS  PubMed  Google Scholar 

  21. Shaked-Mishan P, Ulrich N, Ephros M, Zilberstein D. Novel intracellular Sb(V) reducing activity correlates with antimony susceptibility in Leishmania donovani. J Biol Chem. 2001;276:3971–6.

    Article  CAS  PubMed  Google Scholar 

  22. Wyllie S, Fairlamb AH. Differential toxicity of antimonial compounds and their effects on glutathione homeostasis in a human leukaemia monocyte cell line. Biochem Pharmacol. 2006;71:257–67.

    Article  CAS  PubMed  Google Scholar 

  23. Sereno D, Cavaleyra M, Zemzoumi K, Maquaire S, Ouaissi A, Lemesre JL. Axenically grown amastigotes of Leishmania infantum used as an in vitro model to investigate the pentavalent antimony mode of action. Antimicrob Agents Chemother. 1998;42:3097–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Frézard F, Demicheli C, Ferreira CS, Costa MAP. Glutathione-induced conversion of pentavalent antimony to trivalent antimony in meglumine antimoniate. Antimicrob Agents Chemother. 2001;45:913–6.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Carrio J, de Colmenares M, Riera C, Gallego M, Arboix M, Portus M. Leishmania infantum: stage-specific activity of pentavalent antimony related with the assay conditions. Exp Parasitol. 2000;95:209–14.

    Article  CAS  PubMed  Google Scholar 

  26. Yan SC, Li F, Ding KY, Sun H. Reduction of pentavalent antimony by trypanothione and formation of a binary and ternary complex of antimony(III) and trypanothione. J Biol Inorg Chem. 2003;8:689–97.

    Article  CAS  PubMed  Google Scholar 

  27. Fairlamb AH, Cerami A. Metabolism and functions of trypanothione in the Kinetoplastida. Annu Rev Microbiol. 1992;46:695–729.

    Article  CAS  PubMed  Google Scholar 

  28. Denton H, McGregor JC, Coombs GH. Reduction of anti-leishmanial pentavalent antimonial drugs by a parasite-specific thiol-dependent reductase, TDR1. Biochem J. 2004;381:405–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhou Y, Messier N, Ouellette M, Rosen BP, Mukhopadhyay R. Leishmania major LmACR2 is a pentavalent antimony reductase that confers sensitivity to the drug Pentostam. J Biol Chem. 2004;279:37445–51.

    Article  CAS  Google Scholar 

  30. Salaün P, Frézard F. Unexpectedly high levels of antimony (III) in the pentavalent antimonial drug Glucantime: insights from a new voltammetric approach. Anal Bioanal Chem. 2013;405:5201–14.

    Article  PubMed  Google Scholar 

  31. Sun H, Yan SC, Cheng WS. Interaction of antimony tartrate with the tripeptide glutathione. Eur J Biochem. 2000;267:5450–7.

    Article  CAS  PubMed  Google Scholar 

  32. Légaré D, Richard D, Mukhopadhyay R, Stierhof YD, Rosen BP, Haimeur A, et al. The Leishmania ATP-binding cassette protein PGPA is an intracellular metal-thiol transporter ATPase. J Biol Chem. 2001;276:26301–7.

    Article  PubMed  Google Scholar 

  33. Mukhopadhyay R, Dey S, Xu N, Gage D, Lightbody J, Ouellette M, et al. Trypanothione overproduction and resistance to antimonials and arsenicals in Leishmania. Proc Natl Acad Sci U S A. 1996;93:10383–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baiocco P, Colotti G, Franceschini S, Ilari A. Molecular basis of antimony treatment in leishmaniasis. J Med Chem. 2009;52:2603–12.

    Article  CAS  PubMed  Google Scholar 

  35. Wyllie S, Cunningham ML, Fairlamb AH. Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani. J Biol Chem. 2004;279:39925–93.

    Article  CAS  PubMed  Google Scholar 

  36. Moreira W, Leprohon P, Ouellette M. Tolerance to drug-induced cell death favours the acquisition of multidrug resistance in Leishmania. Cell Death Dis. 2011;2, e201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Demicheli C, Frézard F, Mangrum JB, Farrell NP. Interaction of trivalent antimony with a CCHC zinc finger domain: potential relevance to the mechanism of action of antimonial drugs. Chem Commun. 2008;39:4828–30.

    Article  Google Scholar 

  38. Frézard F, Silva H, Pimenta AM, Farrell N, Demicheli C. Greater binding affinity of trivalent antimony to a CCCH zinc finger domain compared to a CCHC domain of kinetoplastid proteins. Metallomics. 2012;4:433–40.

    Article  PubMed  Google Scholar 

  39. Webb JR, McMaster WR. Molecular cloning and expression of a Leishmania major gene encoding a single-stranded DNA-binding protein containing nine “CCHC” zinc finger motifs. J Biol Chem. 1998;268:13994–4002.

    Google Scholar 

  40. Lai WS, Kennington EA, Blackshear PJ. Interactions of CCCH zinc finger proteins with mRNA: non-binding tristetraprolinmutants exert an inhibitory effect on degradation of AU-rich element-containing mRNAs. J Biol Chem. 2002;277:9606–13.

    Article  CAS  Google Scholar 

  41. Clayton C, Shapira M. Post-transcriptional regulation of gene expression in trypanosomes and leishmanias. Mol Biochem Parasitol. 2007;156:93–101.

    Article  CAS  PubMed  Google Scholar 

  42. Demicheli C, Frézard F, Lecouvey M, Garnier-Suillerot A. Antimony(V) complex formation with adenine nucleosides in aqueous solution. Biochim Biophys Acta. 2002;1570:192–8.

    Article  CAS  PubMed  Google Scholar 

  43. Lucumi A, Robledo S, Gama V, Saravia NG. Sensitivity of Leishmania viannia panamensis to pentavalent antimony is correlated with the formation of cleavable DNA-protein complexes. Antimicrob Agents Chemother. 1998;42:1990–5.

    CAS  PubMed Central  Google Scholar 

  44. Pathak MK, Yi T. Sodium stibogluconate is a potent inhibitor of protein tyrosine phosphatases and augments cytokine responses in hemopoietic cell lines. J Immunol. 2001;167:3391–7.

    Article  CAS  PubMed  Google Scholar 

  45. Chai Y, Yan S, Wong ILK, Chow LMC, Sun H. Complexation of antimony [Sb(V)] with guanosine 5′-monophosphate and guanosine 5′-diphospho-D-mannose: formation of both mono and bis-adducts. J Inorg Biochem. 2005;99:2257–63.

    Article  CAS  PubMed  Google Scholar 

  46. Demicheli C, Santos LS, Ferreira CS, Bouchemal N, Hantz E, Eberlin MN, et al. Synthesis and characterization of Sb(V)–adenosine and Sb(V)–guanosine complexes in aqueous solution. Inorg Chim Acta. 2006;359:159–67.

    Article  CAS  Google Scholar 

  47. Hansen HR, Pergantis SA. Mass spectrometric identification and characterization of antimony complexes with ribose-containing biomolecules and an RNA oligomer. Anal Bioanal Chem. 2006;385:821–33.

    Article  CAS  PubMed  Google Scholar 

  48. Ghosh M, Roy K, Roy S. Immunomodulatory effects of antileishmanial drugs. J Antimicrob Chemother. 2013;68:2834–8.

    Article  CAS  PubMed  Google Scholar 

  49. Mookerjee Basu J, Mookerjee A, Sen P, Bhaumik S, Sen P, Banerjee S, et al. Sodium antimony gluconate induces generation of reactive oxygen species and nitric oxide via phosphoinositide 3-kinase and mitogen-activated protein kinase activation in Leishmania donovani-infected macrophages. Antimicrob Agents Chemother. 2006;50:1788–97.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Muniz-Junqueira MI, Paula-Coelho VN. Meglumine antimonate directly increases phagocytosis, superoxide anion and TNF-α production, but only via TNF-α it indirectly increases nitric oxide production by phagocytes of healthy individuals, in vitro. Int Immunopharmacol. 2008;8:1633–8.

    Article  CAS  PubMed  Google Scholar 

  51. Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev. 2006;19:111–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Decuypere S, Vanaerschot M, Brunker K, Imamura H, Muller S, Khanal B, et al. Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background. PLoS Negl Trop Dis. 2012;6, e1514.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ouellette M, Drummelsmith J, Papadopoulou B. Leishmaniasis: drugs in the clinic, resistance and new developments. Drug Resist Updat. 2004;7:257–66.

    Article  CAS  PubMed  Google Scholar 

  54. Frézard F, Monte-Neto R, Reis PG. Antimony transport mechanisms in resistant leishmania parasites. Biophys Rev. 2014;6:119–32.

    Article  Google Scholar 

  55. Grondin K, Haimeur A, Mukhopadhyay R, Rosen BP, Ouellette M. Co-amplification of the gamma-glutamylcysteine synthetase gene gsh1 and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO J. 1997;16:3057–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Haimeur A, Guimond C, Pilote S, Mukhopadhyay R, Rosen BP, Poulin R, et al. Elevated levels of polyamines and trypanothione resulting from overexpression of the ornithine decarboxylase gene in arsenite-resistant Leishmania. Mol Microbiol. 1999;34:726–35.

    Article  CAS  PubMed  Google Scholar 

  57. Mandal G, Wyllie S, Singh N, Sundar S, Fairlamb AH, Chatterjee M. Increased levels of thiols protect antimony unresponsive Leishmania donovani field isolates against reactive oxygen species generated by trivalent antimony. Parasitology. 2007;134:1679–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mukherjee A, Padmanabhan PK, Singh S, Roy G, Girard I, Chatterjee M, et al. Role of ABC transporter MRPA, gamma-glutamylcysteine synthetase and ornithine decarboxylase in natural antimony-resistant isolates of Leishmania donovani. J Antimicrob Chemother. 2007;59:204–11.

    Article  CAS  PubMed  Google Scholar 

  59. Wyllie S, Mandal G, Singh N, Sundar S, Fairlamb AH, Chatterjee M. Elevated levels of tryparedoxin peroxidase in antimony unresponsive Leishmania donovani field isolates. Mol Biochem Parasitol. 2010;173:162–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Marsden PD. Pentavalent antimonials: old drugs for new diseases. Rev Soc Bras Med Trop. 1985;18:187–98.

    Article  Google Scholar 

  61. Dzamitika SA, Falcão CA, de Oliveira FB, Marbeuf C, Garnier-Suillerot A, Demicheli C et al. Role of residual Sb(III) in meglumine antimoniate cytotoxicity and MRP1-mediated resistance. Chem Biol Interact. 2006;160:217–24.

    Article  CAS  PubMed  Google Scholar 

  62. Lecureur V, Le Thiec A, Le Meur A, Amiot L, Drenou B, Bernard M, et al. Potassium antimonyl tartrate induces caspase- and reactive oxygen species-dependent apoptosis in lymphoid tumoral cells. Br J Haematol. 2002;119:608–15.

    Article  CAS  PubMed  Google Scholar 

  63. Lösler S, Schlief S, Kneifel C, Thiel E, Schrezenmeier H, Rojewski MT. Antimony trioxide- and arsenic-trioxide-induced apoptosis in myelogenic and lymphatic cell lines, recruitment of caspases, and loss of mitochondrial membrane potential are enhanced by modulators of the cellular glutathione redox system. Ann Hematol. 2009;88:1047–58.

    Article  PubMed  Google Scholar 

  64. Timerstein MA, Plews PI, Walker CV, Woolery MD, Wey HE, Toraason MA. Antimony induces oxidative-stress and toxicity in cultured cardiac myocytes. Toxicol Appl Pharmacol. 1995;130:41–7.

    Article  Google Scholar 

  65. Kato KC, Morais-Teixeira E, Reis PG, Silva-Barcellos NM, Salaün P, Campos PP, et al. Hepatotoxicity of pentavalent antimonial drug: possible role of residual Sb(III) and protective effect of ascorbic acid. Antimicrob Agents Chemother. 2014;58:481–8.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Berners-Price SJ, Filipovska A. Gold compounds as therapeutic agents for human diseases. Metallomics. 2011;3:863–73.

    Article  CAS  PubMed  Google Scholar 

  67. Debnath A, Parsonage D, Andrade RM, He C, Cobo ER, Hirata K, et al. A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target. Nat Med. 2012;18:956–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lewis MG, DaFonseca S, Chomont N, Palamara AT, Tardugno M, Mai A et al. Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. AIDS. 2011;25:1347–56.

    Article  CAS  PubMed  Google Scholar 

  69. De Luca A, Hartinger CG, Dyson PJ, Lo Bello M, Casini A. A new target for gold(I) compounds: glutathione-S-transferase inhibition by auranofin. J Inorg Biochem. 2013; 119:38–42.

    Article  PubMed  Google Scholar 

  70. Ilari A, Baiocco P, Messori L, Fiorillo A, Boffi A, Gramiccia M, et al. A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition. Amino Acids. 2012;42:803–11.

    Article  CAS  PubMed  Google Scholar 

  71. Sharlow ER, Leimgruber S, Murray S, Lira A, Sciotti RJ, Hickman M, et al. Auranofin is an apoptosis-simulating agent with in vitro and in vivo anti-leishmanial activity. ACS Chem Biol. 2014;9:663–72.

    Article  CAS  PubMed  Google Scholar 

  72. Colotti G, Ilari A, Fiorillo A, Baiocco P, Cinellu MA, Maiore L, et al. Metal-based compounds as prospective antileishmanial agents: inhibition of trypanothione reductase by selected gold complexes. ChemMedChem. 2013;8:1634–7.

    CAS  PubMed  Google Scholar 

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Acknowledgment

We acknowledge the Brazilian agencies CNPq, FAPEMIG and CAPES for financial support. We thank the support of NSF-CHE-1413189 and Sciences Without Borders CAPES PVES 154/2012.

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Authors and Affiliations

  1. Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil

    Cynthia Demicheli

  2. Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil

    Frédéric Frézard

  3. Department of Chemistry, Virginia Commonwealth University, 1001 W. Main Street, Richmond, VA, 23220, USA

    Nicholas P. Farrell

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  1. Cynthia Demicheli
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Correspondence to Cynthia Demicheli .

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Editors and Affiliations

  1. Duke University School of Medicine, Durham, North Carolina, USA

    Ines Batinić-Haberle

  2. Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil

    Júlio S. Rebouças

  3. Duke University School of Medicine, Durham, North Carolina, USA

    Ivan Spasojević

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Demicheli, C., Frézard, F., Farrell, N.P. (2016). Redox-Active Metal Complexes in Trypanosomatids. In: Batinić-Haberle, I., Rebouças, J., Spasojević, I. (eds) Redox-Active Therapeutics. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-30705-3_30

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