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Identification of oxadiazoles as new drug leads for the control of schistosomiasis

Nature Medicine volume 14, pages 407–412 (2008)Cite this article

Abstract

Treatment for schistosomiasis, which is responsible for more than 280,000 deaths annually, depends almost exclusively on praziquantel. Millions of people are treated annually with praziquantel, and drug-resistant parasites thus are likely to evolve. Phosphinic amides and oxadiazole 2-oxides, identified from a quantitative high-throughput screen, were shown to inhibit a parasite enzyme, thioredoxin glutathione reductase (TGR), with activities in the low micromolar to low nanomolar range. Incubation of parasites with these compounds led to rapid inhibition of TGR activity and parasite death. The activity of the oxadiazole 2-oxides was associated with a donation of nitric oxide. Treatment of schistosome-infected mice with 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide led to marked reductions in worm burdens from treatments against multiple parasite stages and egg-associated pathologies. The compound was active against the three major schistosome species infecting humans. These protective effects exceed benchmark activity criteria set by the World Health Organization for lead compound development for schistosomiasis.

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Figure 1: Activity of oxadiazole 2-oxides and phosphinic amides against thioredoxin glutathione reductase and cultured Schistosoma mansoni worms.
Figure 2: The action of compounds 3 and 9 on thioredoxin glutathione reductase activities in extracts prepared from cultured Schistosoma mansoni worms.
Figure 3: In vivo drug treatment with compound 9.

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References

  1. Hotez, P.J. et al. Control of neglected tropical diseases. N. Engl. J. Med. 357, 1018–1027 (2007).

    Article  CAS  Google Scholar 

  2. van der Werf, M.J. et al. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop. 86, 125–139 (2003).

    Article  Google Scholar 

  3. King, C.H., Dickman, K. & Tisch, D.J. Reassessment of the cost of chronic helminthic infection: a meta-analysis of disability-related outcomes in endemic schistosomiasis. Lancet 365, 1561–1569 (2005).

    Article  Google Scholar 

  4. Steinmann, P., Keiser, J., Bos, R., Tanner, M. & Utzinger, J. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect. Dis. 6, 411–425 (2006).

    Article  Google Scholar 

  5. Fenwick, A. & Webster, J.P. Schistosomiasis: challenges for control, treatment and drug resistance. Curr. Opin. Infect. Dis. 19, 577–582 (2006).

    Article  Google Scholar 

  6. Herwaldt, B.L., Tao, L.F., van Pelt, W., Tsang, V.C. & Bruce, J.I. Persistence of Schistosoma haematobium infection despite multiple courses of therapy with praziquantel. Clin. Infect. Dis. 20, 309–315 (1995).

    Article  CAS  Google Scholar 

  7. Murray-Smith, S.Q., Scott, B.J., Barton, D.P. & Weinstein, P. A case of refractory schistosomiasis. Med. J. Aust. 165, 458 (1996).

    CAS  PubMed  Google Scholar 

  8. Ismail, M. et al. Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated from Egyptian villagers. Am. J. Trop. Med. Hyg. 60, 932–935 (1999).

    Article  CAS  Google Scholar 

  9. Fallon, P.G. & Doenhoff, M.J. Drug-resistant schistosomiasis: resistance to praziquantel and oxamniquine induced in Schistosoma mansoni in mice is drug specific. Am. J. Trop. Med. Hyg. 51, 83–88 (1994).

    Article  CAS  Google Scholar 

  10. Utzinger, J., Xiao, S.H., Tanner, M. & Keiser, J. Artemisinins for schistosomiasis and beyond. Curr. Opin. Investig. Drugs 8, 105–116 (2007).

    CAS  PubMed  Google Scholar 

  11. Cioli, D., Pica-Mattoccia, L. & Archer, S. Drug resistance in schistosomes. Parasitol. Today 9, 162–166 (1993).

    Article  CAS  Google Scholar 

  12. Abdulla, M.H., Lim, K.C., Sajid, M., McKerrow, J.H. & Caffrey, C.R. Schistosomiasis mansoni: novel chemotherapy using a cysteine protease inhibitor. PLoS Med. 4, e14 (2007).

    Article  Google Scholar 

  13. Moreira, L.S., Piló-Veloso, D., de Mello, R.T., Coelho, P.M. & Nelson, D.L. A study of the activity of 2-(alkylamino)-1-phenyl-1-ethanethiosulfuric acids against infection by Schistosoma mansoni in a murine model. Trans. R. Soc. Trop. Med. Hyg. 101, 385–390 (2007).

    Article  CAS  Google Scholar 

  14. Townsend, D.M., Tew, K.D. & Tapiero, H. The importance of glutathione in human disease. Biomed. Pharmacother. 57, 145–155 (2003).

    Article  CAS  Google Scholar 

  15. Lillig, C.H. & Holmgren, A. Thioredoxin and related molecules-from biology to health and disease. Antioxid. Redox Signal. 9, 25–47 (2007).

    Article  CAS  Google Scholar 

  16. Alger, H.M. & Williams, D.L. The disulfide redox system of Schistosoma mansoni and the importance of a multifunctional enzyme, thioredoxin glutathione reductase. Mol. Biochem. Parasitol. 121, 129–139 (2002).

    Article  CAS  Google Scholar 

  17. Kuntz, A.N. et al. Thioredoxin glutathione reductase from Schistosoma mansoni: an essential parasite enzyme and a key drug target. PLoS Med. 4, e206 (2007).

    Article  Google Scholar 

  18. Inglese, J. et al. Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc. Natl. Acad. Sci. USA 103, 11473–11478 (2006).

    Article  CAS  Google Scholar 

  19. Simeonov, A. et al. Quantitative high-throughput screen identifies inhibitors of the Schistosoma mansoni redox cascade. PLoS Negl. Trop. Dis 2, e127 (2008).

    Article  Google Scholar 

  20. Ramirez, B. et al. Schistosomes: challenges in compound screening. Expert Opin. Drug Discov. 2 (Suppl. 1), S53–S61 (2007).

    Article  CAS  Google Scholar 

  21. Feelisch, M., Schönafinger, K. & Noack, E. Thiol-mediated generation of nitric oxide accounts for the vasodilator action of furoxans. Biochem. Pharmacol. 44, 1149–1157 (1992).

    Article  CAS  Google Scholar 

  22. Akaike, T. et al. Antagonistic action of imidazolineoxyl N-oxides against endothelium-derived relaxing factor/NO through a radical reaction. Biochemistry 32, 827–832 (1993).

    Article  CAS  Google Scholar 

  23. Trouiller, P. et al. Drug development for neglected diseases: a deficient market and a public-health policy failure. Lancet 359, 2188–2194 (2002).

    Article  Google Scholar 

  24. Austin, C.P., Brady, L.S., Insel, T.R. & Collins, F.S. NIH Molecular Libraries Initiative. Science 306, 1138–1139 (2004).

    Article  CAS  Google Scholar 

  25. Cerecetto, H. & Porcal, W. Pharmacological properties of furoxans and benzofuroxans: recent developments. Mini Rev. Med. Chem. 5, 57–71 (2005).

    Article  CAS  Google Scholar 

  26. James, S.L. & Glaven, J. Macrophage cytotoxicity against schistosomula of Schistosoma mansoni involves arginine-dependent production of reactive nitrogen intermediates. J. Immunol. 143, 4208–4212 (1989).

    CAS  PubMed  Google Scholar 

  27. Medana, C. et al. Furoxans as nitric oxide donors. 4-Phenyl-3-furoxancarbonitrile: thiol-mediated nitric oxide release and biological evaluation. J. Med. Chem. 37, 4412–4416 (1994).

    Article  CAS  Google Scholar 

  28. Nordberg, J. & Arner, E.S. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic. Biol. Med. 31, 1287–1312 (2001).

    Article  CAS  Google Scholar 

  29. Nwaka, S. & Hudson, A. Innovative lead discovery strategies for tropical diseases. Nat. Rev. Drug Discov. 5, 941–955 (2006).

    Article  CAS  Google Scholar 

  30. Sabah, A.A., Fletcher, C., Webbe, G. & Doenhoff, M.J. Schistosoma mansoni: chemotherapy of infections of different ages. Exp. Parasitol. 61, 294–303 (1986).

    Article  CAS  Google Scholar 

  31. Shuhua, X., Chollet, J., Weiss, N.A., Bergquist, R.N. & Tanner, M. Preventive effect of artemether in experimental animals infected with Schistosoma mansoni. Parasitol. Int. 49, 19–24 (2000).

    Article  CAS  Google Scholar 

  32. Lewis, F. Schistosomiasis. in Current Protocols in Immunology (eds. Coligan, J.E., Kruisbeek, A.M., Margulies, D.H., Shevach, E.M. & Strober, W.) 19.1.1–19.1.28 (John Wiley & Sons, New York, 1998).

    Google Scholar 

  33. Bergmeyer, H.U. & Bernt, E. Lactate dehydrogenase. in Methods of Enzymatic Analysis Vol. 2 (ed. Bergmeyer, H.U.) 574–548 (Academic Press, New York, 1974).

    Chapter  Google Scholar 

  34. Aguirre, G. et al. Furoxan derivatives as cytotoxic agents: preliminary in vivo antitumoral activity studies. Pharmazie 61, 54–59 (2006).

    CAS  PubMed  Google Scholar 

  35. Skehan, P. et al. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 82, 107–112 (1990).

    Article  Google Scholar 

  36. Nims, R.W. et al. Colorimetric methods for the determination of nitric oxide concentration in neutral aqueous solutions. Methods 7, 48–54 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by US National Institutes of Health (NIH)/National Institute of Mental Health grant R03MH076449 (D.L.W.) and by NIH/National Institute of Allergy and Infectious Diseases (NIAID) grant R01AI065622 (D.L.W.), and in part by the NIH Roadmap for Medical Research Molecular Libraries Program. Schistosome life stages used in this research were supplied in part by the NIAID Schistosomiasis Resource Center at the Biomedical Research Institute (Rockville, Maryland, USA) through NIAID Contract N01-AI-30026.

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Authors and Affiliations

  1. Department of Biological Sciences, Illinois State University, Normal, 61790, Illinois, USA

    Ahmed A Sayed & David L Williams

  2. NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892-3370, Maryland, USA

    Anton Simeonov, Craig J Thomas, James Inglese & Christopher P Austin

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  1. Ahmed A Sayed
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Contributions

A.A.S., A.S. and D.L.W. designed the research. A.A.S. performed enzyme, cultured worm and in vivo experiments. A.A.S. and D.L.W. analyzed the data. C.J.T. and A.S. contributed oxadiazole 2-oxide reagents. A.A.S., D.L.W., A.S., J.I., C.J.T. and C.P.A. discussed the results and wrote the paper.

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Correspondence to Christopher P Austin or David L Williams.

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Sayed, A., Simeonov, A., Thomas, C. et al. Identification of oxadiazoles as new drug leads for the control of schistosomiasis. Nat Med 14, 407–412 (2008). https://doi.org/10.1038/nm1737

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