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.
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.
McMillan
P J
PJ
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.
Patzewitz
E M
EM
Young
S E
SE
Westrop
G D
GD
Coombs
G H
GH
Engman
L
L
Müller
S
S
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D003505:Cyclodextrins / Q000737:chemistry; D006801:Humans; D008970:Molecular Weight; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry / Q000378:metabolism*; D014246:Trichomonas vaginalis / Q000187:drug effects* / Q000201:enzymology*
D000981:Antiprotozoal Agents; D003505:Cyclodextrins; D013880:Thioredoxin-Disulfide Reductase