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Eckstein-Ludwig, U., Webb, R. J., van Goethem, I. D. A., East, J. M., Lee, A. G., Kimura, M., O'Neill, P. M., Bray, Patrick, Ward, Stephen 
ORCID: https://orcid.org/0000-0003-2331-3192 and Krishna, S.
(2003)
'Artemisinins target the SERCA of Plasmodium falciparum'. Nature, Vol 424, Issue 6951, pp. 957-961.
Abstract
Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available(1), rapidly killing all asexual stages of Plasmodium falciparum(2). Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria(1), a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience(3-5) their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins(6). Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Plasmodium falciparum; Antimalarials; Drug resistance; Artemisia annua; Sweet Wormwood; Malaria - treatment; sarco/ endoplasmic reticulum Ca2�-ATPase (SERCA) |
| Subjects: | QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials QW Microbiology and Immunology > QW 45 Microbial drug resistance. General or not elsewhere classified. |
| Faculty: Department: | Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group |
| Digital Object Identifer (DOI): | https://doi.org/10.1038/nature01813 |
| Depositing User: | Ms Julia Martin |
| Date Deposited: | 13 Nov 2012 10:09 |
| Last Modified: | 17 Jul 2020 10:57 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/2531 |
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