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dUTPase as a platform for anti-malarial drug design: structural basis for the selectivity of a class of nucleoside inhibitors.

Whittingham, J.L., Leal, I., Nguyen, C., Kasinathan, G., Bell, E., Jones, A.F., Berry, E., 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. and Wilson, K.S. (2005) dUTPase as a platform for anti-malarial drug design: structural basis for the selectivity of a class of nucleoside inhibitors. Structure, 13 (2). pp. 329-338. ISSN 0969-2126

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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 Å crystal structure of PfdUTPase in complex with one of these inhibitors reveals an atypical trimeric enzyme in which the triphenylmethane derivative can be seen to select for PfdUTPase by way of interactions between the trityl group and the side chains of residues Phe46 and Ile117. 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.

Item Type: Article
Academic Units: The University of York > Chemistry (York)
Depositing User: York RAE Import
Date Deposited: 11 Feb 2009 13:42
Last Modified: 11 Feb 2009 13:42
Published Version: http://dx.doi.org/10.1016/j.str.2004.11.015
Status: Published
Publisher: Elsevier
Identification Number: 10.1016/j.str.2004.11.015
URI: http://eprints.whiterose.ac.uk/id/eprint/7554

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