Artemisinins target the SERCA of Plasmodium falciparum
Artemisinins target the SERCA of Plasmodium falciparum
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DOI：
10.1038/nature01813
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发表时间：
2003-08-21
期刊：
影响因子：
64.8
通讯作者：
Krishna, S
中科院分区：
文献类型：
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作者：
Eckstein-Ludwig, U;Webb, RJ;Krishna, S
青蒿素是从青蒿（青蒿）中提取的，是目前最有效的抗疟药（1），可迅速杀死恶性疟原虫的所有无性阶段（2）。青蒿素是一种倍半萜内酯，广泛用于治疗耐多药疟疾（1），这种疾病每年夺去100万人的生命。尽管有广泛的临床和实验室经验（3-5），但尚未确定其分子靶点。活化青蒿素与各种生物大分子形成加合物，包括血红素、免疫控制肿瘤蛋白（TCTP）和其他高分子量蛋白（6）。在这里，我们表明，青蒿素，而不是奎宁或氯喹，抑制恶性疟原虫的SERCA直向同源物（PfATP 6）在非洲爪蟾卵母细胞具有类似的效力毒胡萝卜素（另一种倍半萜内酯和高度特异性的SERCA抑制剂）。正如所预测的，毒胡萝卜素也拮抗青蒿素的杀寄生虫活性。脱氧青蒿素缺乏内过氧化物桥，并且作为PfATP 6的抑制剂和抗疟药都是无效的。铁螯合去铁胺废除青蒿素的抗寄生虫活性，并相应地减弱PfATP 6的抑制。用BODIPY-毒胡萝卜素标记的寄生虫成像细胞溶质区室，并被青蒿素竞争。荧光青蒿素标记寄生虫相似，不可逆的Fe 2+依赖的方式。这些数据提供了令人信服的证据表明，青蒿素通过抑制铁激活后的食物液泡外的PfATP 6发挥作用。
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.