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Liver fluke β-tubulin isotype 2 binds albendazole and is thus a probable target of this drug

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Abstract

Albendazole is a benzimidazole drug which can be used to treat liver fluke (Fasciola hepatica) infections. Its mode of action is believed to be the inhibition of microtubule formation through binding to β-tubulin. However, F. hepatica expresses at least six different isotypes of β-tubulin, and this has confused, rather than clarified, understanding of the molecular mechanisms of benzimidazole drugs in this organism. Recombinant F. hepatica β-tubulin proteins were expressed in, and purified from, Escherichia coli. These proteins were then used in pull-down assays in which albendazole was covalently linked to Sepharose. β-Tubulin isotype 2 was pulled down in this assay, and this interaction could be reduced by adding competing albendazole. Molecular modelling of β-tubulin isotypes suggests that changes in the side change conformations of residue 200 in the putative albendazole binding site may be important in determining whether, or not, a particular isotype will bind to the drug. These results, together with previous work demonstrating that albendazole causes disruption of microtubules in the liver fluke, strongly suggest that β-tubulin isotype 2 is one of the targets of this drug.

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Abbreviations

ABZ:

Albendazole

ABZ.SO:

Albendazole sulphoxide

IPTG:

Isopropyl-β-d-thiogalactopyranoside

rmsd:

Root mean square deviation

TCBZ:

Triclabendazole

VdW:

Van der Waal’s

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Acknowledgements

EC and LAR were in receipt of PhD studentships from the Department of Agriculture and Rural Development (Northern Ireland).

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Author notes

  1. Emma Chambers

    Present address: South Eastern Regional College, Castle Street, Lisburn, County Down, BT27 4SU, UK

  2. Louise A. Ryan

    Present address: Abbott Ireland Diagnostics Division, Finisklin Business Park, Sligo, Co. Sligo, Ireland

Authors and Affiliations

  1. School of Biological Sciences, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK

    Emma Chambers, Louise A. Ryan, Elizabeth M. Hoey, Alan Trudgett, Neil V. McFerran, Ian Fairweather & David J. Timson

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  1. Emma Chambers
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Correspondence to David J. Timson.

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Chambers, E., Ryan, L.A., Hoey, E.M. et al. Liver fluke β-tubulin isotype 2 binds albendazole and is thus a probable target of this drug. Parasitol Res 107, 1257–1264 (2010). https://doi.org/10.1007/s00436-010-1997-5

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  • DOI: https://doi.org/10.1007/s00436-010-1997-5

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