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首页> 外文期刊>Biochemical Pharmacology >Inhibition of Plasmodium falciparum pH regulation by small molecule indole derivatives results in rapid parasite death.
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Inhibition of Plasmodium falciparum pH regulation by small molecule indole derivatives results in rapid parasite death.

机译：小分子吲哚衍生物抑制恶性疟原虫的pH调节可导致寄生虫快速死亡。

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摘要

The V-type H+ATPase is critical during the intraerythrocytic stage of the human malaria parasite Plasmodium falciparum. It is responsible for maintaining a near-neutral cytosolic pH (pH 7.3), an acidic digestive vacuole (pH 4.5-5.5) and the generation of an inside-negative plasma membrane potential (approximately -95 mV). Inhibition of this pump is therefore likely to result in profound physiological disturbances within the parasite and parasite death, as illustrated previously by the antiplasmodial activity of the potent and specific inhibitors of the V-type H+-ATPase, bafilomycin A(1) and concanamycin A. In this study we examined the antiplasmodial activity of a series of compounds previously designed, on the basis of the active structural constituents of bafilomycin A(1), to inhibit the osteoclast V-type H+-ATPase. The compounds were tested against up to 4 strains of P. falciparum with varying chloroquine sensitivities. Of the 30 novel compounds tested, 9 had sub-micromolar antiplasmodial IC(50) values, with the most active compound having an IC(50) of 160+/-20 nM. The activity of a number of these compounds was investigated in more detail. We show that these inhibitors acidify the parasite cytosol within seconds and that some inhibitors irreversibly kill the parasite within 0.5-4 h. The antiplasmodial activity of the V-type H+-ATPase inhibitors was strongly correlated with their ability to acidify the parasite cytosol (correlation coefficient 0.98). In combination studies, we show that the inhibitors act indifferently when combined with current antimalarials. Our data support the disruption of parasite pH regulation through inhibition of its V-type H+-ATPase as an antimalarial approach.
机译：V型H + ATPase在人类疟疾寄生虫恶性疟原虫的红细胞内阶段至关重要。它负责维持接近中性的胞质pH值（pH 7.3），酸性消化液（pH 4.5-5.5）并产生内负质膜电位（约-95 mV）。因此，抑制该泵很可能导致寄生虫和寄生虫死亡内发生严重的生理紊乱，如先前由V型H + -ATPase，巴氟霉素A（1）和伴刀豆球蛋白A的有效抑制剂和特定抑制剂的抗血浆活性所表明的那样。在这项研究中，我们检查了先前设计的一系列化合物的抗疟原虫活性，这些化合物是根据bafilomycin A（1）的活性结构成分来抑制破骨细胞V型H + -ATPase的。测试了这些化合物针对多达4种具有不同氯喹敏感性的恶性疟原虫菌株。在测试的30种新化合物中，有9种具有亚微摩尔抗血浆IC（50）值，而活性最高的化合物的IC（50）为160 +/- 20 nM。更详细地研究了许多这些化合物的活性。我们显示这些抑制剂在几秒钟内酸化了寄生虫的细胞质，并且某些抑制剂在0.5-4小时内不可逆地杀死了寄生虫。 V型H + -ATPase抑制剂的抗血浆活性与其酸化寄生虫胞质溶胶的能力密切相关（相关系数0.98）。在组合研究中，我们表明与目前的抗疟药联合使用时，抑制剂的作用无关紧要。我们的数据支持通过抑制其V型H + -ATPase作为抗疟方法来破坏寄生虫的pH调节。

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