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Drug Targets: Screening for Small Molecules that Inhibit Fasciola hepatica Enzymes

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Fasciola hepatica

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2137))

Abstract

The in vitro screening of small molecules for enzymatic inhibition provides an efficient means of finding new compounds for developing drug candidates. This strategy has the advantage of being rapid and inexpensive to perform. Enzymes are suitable targets for screening when simple methods to obtain them and measure their activities are available and there is evidence of their essential role in the parasite’s life cycle. Here, we describe the screening of small molecules as inhibitors of two Fasciola hepatica enzyme targets (cathepsin L and triose phosphate isomerase), an initial step to find new potential compounds for drug development strategies.

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References

  1. Brennan GP, Fairweather I, Trudgett A, Hoey EM, McCoy M, McConville M et al (2007) Understanding triclabendazole resistance. Exp Mol Pathol 82:104–109

    Article  CAS  Google Scholar 

  2. Boray J, Crowfoot P, Strong M, Allison J, Schellenbaum M, von Orelli M et al (1983) Treatment of immature and mature Fasciola hepatica infections in sheep with triclabendazole. Vet Rec 113:315–317

    Article  CAS  Google Scholar 

  3. Kelley JM, Elliott TP, Beddoe T, Anderson G, Skuce P, Spithill TW (2016) Current threat of Triclabendazole resistance in Fasciola hepatica. Trends Parasitol 32(6):458–469

    Article  CAS  Google Scholar 

  4. Copeland R (2013) Evaluation of enzyme inhibitors in drug discovery. In: A guide for medicinal chemists and pharmacologists, 2nd edn. John Wiley & Sons, Inc., Hoboken, New Jersey

    Google Scholar 

  5. Baker NC, Ekins S, Williams AJ, Tropsha A (2018) A bibliometric review of drug repurposing. Drug Discov Today 23(3):661–672

    Article  CAS  Google Scholar 

  6. Cancela M, Acosta D, Rinaldi G, Silva E, Durán R, Roche L et al (2008) A distinctive repertoire of cathepsins is expressed by juvenile invasive Fasciola hepatica. Biochimie 10:1461–1475

    Article  Google Scholar 

  7. Robinson MW, Tort JF, Lowther J, Donnelly SM, Wong E, Xu W et al (2008) Proteomics and phylogenetic analysis of the cathepsin L protease family of the helminth pathogen Fasciola hepatica: expansion of a repertoire of virulence associated factors. Mol Cell Proteomics 6:1111–1123

    Article  Google Scholar 

  8. McGonigle L, Mousley A, Marks NJ, Brennan GP, Dalton JP, Spithill TW et al (2008) The silencing of cysteine proteases in Fasciola hepatica newly excysted juveniles using RNA interference reduces gut penetration. Int J Parasitol 38(2):149–750

    Article  CAS  Google Scholar 

  9. Corvo I, Cancela M, Cappetta M, Pi-Denis N, Tort JF, Roche L (2009) The major cathepsin L secreted by the invasive juvenile Fasciola hepatica prefers proline in the S2 subsite and can cleave collagen. Mol Biochem Parasitol 167(1):41–47

    Article  CAS  Google Scholar 

  10. Lowther J, Robinson MW, Donnelly SM, Xu W, Stack CM, Matthews JM, Dalton JP (2009) The importance of pH in regulating the function of the Fasciola hepatica cathepsin L1 cysteine protease. PLoS Negl Trop Dis 3(1):e369

    Article  Google Scholar 

  11. Donnelly S, O’Neill SM, Stack CM, Robinson MW, Turnbull L, Whitchurch C, Dalton JP (2010) Helminth cysteine proteases inhibit TRIF -dependent activation of macrophages via degradation of TLR3. J Biol Chem 285(5):3383–3392

    Article  CAS  Google Scholar 

  12. Robinson MW, Dalton JP, O’Brien BA, Donnelly S (2013) Fasciola hepatica: the therapeutic potential of a worm secretome. Int J Parasitol 43(3-4):283–291

    Article  CAS  Google Scholar 

  13. Zinsser VL, Hoey EM, Trudgett A, Timson DJ (2013) Biochemical characterisation of triose phosphate isomerase from the liver fluke Fasciola hepatica. Biochimie 95:2182–2189

    Article  CAS  Google Scholar 

  14. Olivares-Illana V, Perez-Montfort R, Lopez-Calahorra F, Costas M, Rodriguez-Romero A, Tuena de Gomez-Puyou M (2006) Structural differences in triosephosphate isomerase from different species and discovery of a multitrypanosomatid inhibitor. Biochemistry 45:2556–2560

    Article  CAS  Google Scholar 

  15. Enriquez-Flores S, Rodriguez-Romero A, Hernandez-Alcantara G, De la Mora-De la Mora I, Gutierrez-Castrellon P et al (2008) Species-specific inhibition of Giardia lamblia triosephosphate isomerase by localized perturbation of the homodimer. Mol Biochem Parasitol 157:179–186

    Article  CAS  Google Scholar 

  16. Alvarez G, Aguirre-López B, Varela J, Cabrera M, Merlino A, López GV et al (2010) Massive screening yields novel and selective triosephosphate isomerase dimer-interface-irreversible inhibitors with anti-trypanosomal activity. Eur J Med Chem 45:5767–5772

    Article  CAS  Google Scholar 

  17. Ferraro F, Merlino A, Dell Oca N, Gil J, Tort JF, Gonzalez M et al (2016) Identification of Chalcones as Fasciola hepatica Cathepsin L inhibitors using a comprehensive experimental and computational approach. PLoS Negl Trop Dis 10(7):e0004834

    Article  Google Scholar 

  18. Cabrera M, Simoens M, Falchi G, Lavaggi ML, Piro OE, Castellano EE et al (2007) Synthetic chalcones, flavanones, and flavones as antitumoral agents: biological evaluation and structure-activity relationships. Bioorg Med Chem 15(10):3356–3367

    Article  CAS  Google Scholar 

  19. Rzychon M, Chmiel D, Stec-Niemczyk J (2004) Modes of inhibition of cysteine proteases. Acta Biochim Pol 51(4):861–873

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Universidad de la República and PEDECIBA, Uruguay and the Science and Innovation Fund, Uruguay—United Kingdom (British Embassy Montevideo, Grant SPF.2014.F001).

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Ferraro, F., Cabrera, M.A., Álvarez, G.I., Corvo, I. (2020). Drug Targets: Screening for Small Molecules that Inhibit Fasciola hepatica Enzymes. In: Cancela, M., Maggioli, G. (eds) Fasciola hepatica. Methods in Molecular Biology, vol 2137. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0475-5_17

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  • DOI: https://doi.org/10.1007/978-1-0716-0475-5_17

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0474-8

  • Online ISBN: 978-1-0716-0475-5

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