dUTPase as a platform for antimalarial drug design: structural basis for the selectivity of a class of nucleoside inhibitors

Jean L. Whittingham, Isabel Leal, Corinne Nguyen, Ganasan Kasinathan, Emma Bell, Andrew F. Jones, Colin Berry, Agustin Benito, Johan P. Turkenburg, Eleanor J. Dodson, Luis M. Ruiz Perez, Anthony J. Wilkinson, Nils Gunnar Johansson, Reto Brun, Ian H. Gilbert, Dolores Gonzalez Pacanowska, Keith S. Wilson

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    Abstract

    Pyrimidine metabolism is a major route for therapeutic intervention against malaria. Here we report inhibition and structural studies on the deoxyuridine nucleotidohydrolase from the malaria parasite Plasmodium falciparum (PfdUTPase). We have identified a series of triphenylmethane derivatives of deoxyuridine with antimalarial activity in vitro which inhibit specifically the Plasmodium dUTPase versus the human enzyme. A 2.4 Angstrom crystal structure of PfdUTPase in complex with one of these inhibitors reveals an atypical trimeric enzyme in which the triphenyl methane derivative can be seen to select for PfdUTPase by way of interactions between the trityl group and the side chains of residues Phe(46) and Ile(117). Immunofluorescence microscopy studies of parasitized red blood cells reveal that enzyme concentrations are highest during the trophozoite/schizont stages, suggesting that PfdUTPase has a major role in DNA replication. Taken together the data show that PfdUTPase may be considered as an antimalarial drug target.

    Original languageEnglish
    Pages (from-to)329-338
    Number of pages10
    JournalStructure
    Volume13
    Issue number2
    DOIs
    Publication statusPublished - Feb 2005

    Cite this

    Whittingham, J. L., Leal, I., Nguyen, C., Kasinathan, G., Bell, E., Jones, A. F., Berry, C., Benito, A., Turkenburg, J. P., Dodson, E. J., Ruiz Perez, L. M., Wilkinson, A. J., Johansson, N. G., Brun, R., Gilbert, I. H., Gonzalez Pacanowska, D., & Wilson, K. S. (2005). dUTPase as a platform for antimalarial drug design: structural basis for the selectivity of a class of nucleoside inhibitors. Structure, 13(2), 329-338. https://doi.org/10.1016/j.str.2004.11.015