Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion
Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion
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DOI：
10.1073/pnas.1104063108
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发表时间：
2011-07-12
影响因子：
11.1
通讯作者：
Tilley, Leann
中科院分区：
文献类型：
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作者：
Klonis, Nectarios;Crespo-Ortiz, Maria P.;Tilley, Leann
在大多数疟疾流行的国家，建议将包含青蒿素衍生物的联合治疗方案作为一线抗疟药。然而，青蒿素的作用机制尚未完全了解，并且寄生虫敏感性降低的报道威胁了该类药物的有效性。我们对恶性疟原虫进行了几个小时的治疗，以模拟临床暴露于短半衰期青蒿素的情况。我们发现药物治疗可以延缓寄生虫生长并抑制血红蛋白的摄取，即使在亚致死浓度下也是如此。我们表明，有效的青蒿素活性取决于寄生虫对血红蛋白的消化。用半胱氨酸蛋白酶抑制剂抑制血红蛋白酶活性，通过基因删除敲除半胱氨酸蛋白酶 falcipain-2，或直接剥夺宿主细胞裂解物，可显着降低青蒿素敏感性。青蒿素诱导的寄生虫细胞质氧化应激加剧也需要血红蛋白消化。早期寄生虫对血红蛋白消化的抑制为短期青蒿素暴露提供了一种生存机制。这些见解将有助于设计新药和新治疗策略，以规避耐药性。
Combination regimens that include artemisinin derivatives are recommended as first line antimalarials in most countries where malaria is endemic. However, the mechanism of action of artemisinin is not fully understood and the usefulness of this drug class is threatened by reports of decreased parasite sensitivity. We treated Plasmodium falciparum for periods of a few hours to mimic clinical exposure to the short half-life artemisinins. We found that drug treatment retards parasite growth and inhibits uptake of hemoglobin, even at sublethal concentrations. We show that potent artemisinin activity is dependent on hemoglobin digestion by the parasite. Inhibition of hemoglobinase activity with cysteine protease inhibitors, knockout of the cysteine protease falcipain-2 by gene deletion, or direct deprivation of host cell lysate, significantly decreases artemisinin sensitivity. Hemoglobin digestion is also required for artemisinin-induced exacerbation of oxidative stress in the parasite cytoplasm. Arrest of hemoglobin digestion by early stage parasites provides a mechanism for surviving short-term artemisinin exposure. These insights will help in the design of new drugs and new treatment strategies to circumvent drug resistance.