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Inhibition of Plasmodium falciparum lysophospholipase by anti-malarial drugs and sulphydryl reagents

Published online by Cambridge University Press:  06 April 2009

R. Zidovetzki ,
I. W. Sherman ,
J. Prudhomme  and
J. Crawford
R. Zidovetzki
Affiliation:
Departments of Biology and Neuroscience, University of California, Riverside, CA 92521, USA
I. W. Sherman
Affiliation:
Departments of Biology and Neuroscience, University of California, Riverside, CA 92521, USA
J. Prudhomme
Affiliation:
Departments of Biology and Neuroscience, University of California, Riverside, CA 92521, USA
J. Crawford
Affiliation:
Departments of Biology and Neuroscience, University of California, Riverside, CA 92521, USA
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Summary

The activity of lysophospholipase of human erythrocytes increased by about 3 orders of magnitude upon infection with Plasmodium falciparum. The apparent Km for hydrolysis of lysophosphatidylcholine by this enzyme was 50 ± 7μM and the apparent Vmax 6·8±0·6 nmol/h × 106 cells. The activity was Ca2+ independent and had a broad pH maximum at pH 8. The enzyme was insensitive to such anti-malarials as mefloquine and arteether and was only weakly inhibited by chloroquine, with a 50% inhibition concentration (IC50) of 70 mM. The anti-malarials quinine and quinacrine were more efficient inhibitors, with IC50s of 2·6 mM and 0·7 mM, respectively. The sulphydryl agents p–hydroxymercuribenzoate (pHMB) and thimerosal were considerably more potent, inhibiting the plasmodial lysophospholipase with IC50s of 18 μM and 10 μM, respectively. When present at 10 μM prior to invasion, both pHMB and thimerosal arrested the growth and reinvasion capacity of P. falciparum in culture. In a synchronized P. falciparum culture the continuous presence of 5 μM thimerosal dramatically decreased total parasitaemia and, within 4 days, totally abolished the capacity of the surviving parasites to reinvade. Thus the plasmodial lysophospholipase may represent a potential new target for anti-malarial chemotherapy.

Keywords

malariathimerosalsulphydryl reagentsPlasmodium falciparum
Type
Research Article
Information
Parasitology , Volume 108 , Issue 3 , April 1994 , pp. 249 - 255
Copyright
Copyright © Cambridge University Press 1994

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