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Differential inhibition of high and low Mr thioredoxin reductases of parasites by organotelluriums supports the concept that low Mr thioredoxin reductases are good drug targets

Published online by Cambridge University Press:  04 November 2008

P. J. McMILLAN ,
E. M. PATZEWITZ ,
S. E. YOUNG ,
G. D. WESTROP ,
G. H. COOMBS ,
L. ENGMAN  and
S. MÜLLER
P. J. McMILLAN
Affiliation:
Division of Infection and Immunity and Wellcome Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, UK
E. M. PATZEWITZ
Affiliation:
Division of Infection and Immunity and Wellcome Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, UK
S. E. YOUNG
Affiliation:
Division of Infection and Immunity and Wellcome Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, UK
G. D. WESTROP
Affiliation:
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, The John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, UK
G. H. COOMBS
Affiliation:
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, The John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, UK
L. ENGMAN
Affiliation:
Department of Biochemistry and Organic Chemistry, University of Uppsala, Box 576, SE-751 23 Uppsala, Sweden
S. MÜLLER*
Affiliation:
Division of Infection and Immunity and Wellcome Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, UK
*
*Corresponding author: Division of Infection and Immunity and Wellcome Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, UK. Tel: (+)44 141 330 2383. Fax: (+) 44 141 330 4600. E-mail: s.muller@bio.gla.ac.uk
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Summary

Thioredoxin reductase (TrxR), a NADPH-dependent disulfide oxidoreductase, is vital in numerous cellular processes including defence against reactive oxygen species, cell proliferation and signal transduction. TrxRs occur in 2 forms, a high Mr enzyme characterized by those of mammals, the malaria parasite Plasmodium falciparum and some worms, and a low Mr form is present in bacteria, fungi, plants and some protozoan parasites. Our hypothesis is that the differences between the forms can be exploited in the development of selective inhibitors. In this study, cyclodextrin- and sulfonic acid-derived organotelluriums known to inhibit mammalian TrxR were investigated for their relative efficacy against P. falciparum TrxR (PfTrxR), a high Mr enzyme, and Trichomonas vaginalis TrxR (TvTrxR), a low Mr form of TrxR. The results suggest that selective inhibition of low Mr TrxRs is a feasible goal.

Keywords

inhibitionthioredoxin systemmalariaorganotellurium compoundsTrichomonasPlasmodium
Type
Research Article
Information
Parasitology , Volume 136 , Issue 1 , January 2009 , pp. 27 - 33
Copyright
Copyright © 2008 Cambridge University Press

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