Irreversible effect of cysteine protease inhibitors on the release of malaria parasites from infected erythrocytes
Irreversible effect of cysteine protease inhibitors on the release of malaria parasites from infected erythrocytes
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DOI：
10.1111/j.1462-5822.2008.01242.x
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发表时间：
2009-01-01
影响因子：
3.4
通讯作者：
Zimmerberg, Joshua
中科院分区：
文献类型：
--
作者：
Glushakova, Svetlana;Mazar, Julia;Zimmerberg, Joshua
通过用活细胞共聚焦显微镜和高压冷冻和冷冻替代细胞的电子显微镜研究半胱氨酸蛋白酶抑制疟疾寄生虫培养物灭活，我们报道了可能受半胱氨酸蛋白酶调节的疟疾寄生虫从红细胞中释放的准确步骤：打开红细胞膜，释放寄生虫以备下一轮感染。在周期的最后几分钟内抑制半胱氨酸蛋白酶并不影响寄生虫液泡的破裂，但不可逆转地阻止宿主细胞膜随后的破裂，锁定寄生寄生虫，这些寄生虫在圈养后几个小时内死亡。宿主细胞内成熟寄生虫的这种不可逆转的失活使疟原虫半胱氨酸蛋白酶成为抗疟疾药物的靶标，因为寄生虫特异性半胱氨酸蛋白酶抑制剂可能显著增加多靶点药物的鸡尾酒。
By studying the inactivation of malaria parasite culture by cysteine protease inhibition using confocal microscopy of living cells and electron microscopy of high-pressure frozen and freeze-substituted cells, we report the precise step in the release of malaria parasites from erythrocytes that is likely regulated by cysteine proteases: the opening of the erythrocyte membrane, liberating parasites for the next round of infection. Inhibition of cysteine proteases within the last few minutes of cycle does not affect rupture of the parasitophorus vacuole but irreversibly blocks the subsequent rupture of the host cell membrane, locking in resident parasites, which die within a few hours of captivity. This irreversible inactivation of mature parasites inside host cells makes plasmodial cysteine proteases attractive targets for antimalarials, as parasite-specific cysteine protease inhibitors may significantly augment multi-target drug cocktails.