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

J L  Whittingham; I  Leal; C  Nguyen; G  Kasinathan; E  Bell; A F  Jones; C  Berry; A  Benito; J P  Turkenburg; E J  Dodson; L M R  Perez; Tony Wilkinson; N G  Johansson; R  Brun; I H  Gilbert; D G  Pacanowska; K S  Wilson

doi:10.1016/j.str.2004.11.015

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

J L Whittingham, I Leal, C Nguyen, G Kasinathan, E Bell, A F Jones, C Berry, A Benito, J P Turkenburg, E J Dodson, L M R Perez, Tony Wilkinson, N G Johansson, R Brun, I H Gilbert, D G Pacanowska, K S Wilson

Chemistry

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	329-338
Number of pages	10
Journal	Structure
Volume	13
Issue number	2
DOIs	https://doi.org/10.1016/j.str.2004.11.015
Publication status	Published - 8 Feb 2005

Keywords

CRYSTAL-STRUCTURE
PLASMODIUM-FALCIPARUM
MOLECULAR REPLACEMENT
MALARIA PARASITE
PYROPHOSPHATASE
PROGRAM
RECOGNITION
REFINEMENT
EXPRESSION
MOLSCRIPT

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10.1016/j.str.2004.11.015

http://dx.doi.org/10.1016/j.str.2004.11.015

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., Perez, L. M. R., Wilkinson, T., Johansson, N. G., Brun, R., Gilbert, I. H., Pacanowska, D. G., & 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

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title = "dUTPase as a platform for antimalarial drug design: Structural basis for the selectivity of a class of nucleoside inhibitors",

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.",

keywords = "CRYSTAL-STRUCTURE, PLASMODIUM-FALCIPARUM, MOLECULAR REPLACEMENT, MALARIA PARASITE, PYROPHOSPHATASE, PROGRAM, RECOGNITION, REFINEMENT, EXPRESSION, MOLSCRIPT",

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Whittingham, JL, Leal, I, Nguyen, C, Kasinathan, G, Bell, E, Jones, AF, Berry, C, Benito, A, Turkenburg, JP, Dodson, EJ, Perez, LMR, Wilkinson, T, Johansson, NG, Brun, R, Gilbert, IH, Pacanowska, DG & Wilson, KS 2005, 'dUTPase as a platform for antimalarial drug design: Structural basis for the selectivity of a class of nucleoside inhibitors', Structure, vol. 13, no. 2, pp. 329-338. https://doi.org/10.1016/j.str.2004.11.015

TY - JOUR

T1 - dUTPase as a platform for antimalarial drug design

T2 - Structural basis for the selectivity of a class of nucleoside inhibitors

AU - Whittingham, J L

AU - Leal, I

AU - Nguyen, C

AU - Kasinathan, G

AU - Bell, E

AU - Jones, A F

AU - Berry, C

AU - Benito, A

AU - Turkenburg, J P

AU - Dodson, E J

AU - Perez, L M R

AU - Wilkinson, Tony

AU - Johansson, N G

AU - Brun, R

AU - Gilbert, I H

AU - Pacanowska, D G

AU - Wilson, K S

PY - 2005/2/8

Y1 - 2005/2/8

N2 - 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.

AB - 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.

KW - CRYSTAL-STRUCTURE

KW - PLASMODIUM-FALCIPARUM

KW - MOLECULAR REPLACEMENT

KW - MALARIA PARASITE

KW - PYROPHOSPHATASE

KW - PROGRAM

KW - RECOGNITION

KW - REFINEMENT

KW - EXPRESSION

KW - MOLSCRIPT

U2 - 10.1016/j.str.2004.11.015

DO - 10.1016/j.str.2004.11.015

M3 - Article

SN - 0969-2126

VL - 13

SP - 329

EP - 338

JO - Structure

JF - Structure

IS - 2

ER -