Department of Biochemistry and Australian Research Council Centre of Excellence for Coherent X-ray Science, La Trobe University, 3086 Melbourne, Australia.
Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11405-10. doi: 10.1073/pnas.1104063108. Epub 2011 Jun 27.
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.
在疟疾流行的大多数国家，联合疗法包括青蒿素衍生物被推荐作为一线抗疟药物。然而，青蒿素的作用机制尚未完全阐明，而且有报道称寄生虫对这种药物的敏感性降低，这威胁到了此类药物的应用。我们用几小时的时间来治疗疟原虫，以模拟临床接触半衰期短的青蒿素的情况。我们发现药物治疗会延迟寄生虫的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，青蒿素的强大活性依赖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、通过基因缺失敲除半胱氨酸蛋白酶 falcipain-2 或直接剥夺宿主细胞裂解物，都会显著降低青蒿素的敏感性。血红蛋白的消化也是青蒿素诱导寄生虫细胞质内氧化应激加剧所必需的。早期寄生虫的血红蛋白消化受阻为其在短期青蒿素暴露下生存提供了一种机制。这些见解将有助于设计新的药物和新的治疗策略以规避耐药性。
