Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex III and validates this parasite’s ETC as an attractive target for chemotherapy. Among the ETC dehydrogenases from P. falciparum, dihydroorotate dehydrogenase, an essential enzyme used in de novo pyrimidine biosynthesis, and complex III are the two enzymes that have been characterized and validated as drug targets in the blood-stage parasite, while complex II has been shown to be essential for parasite survival in the mosquito stage; therefore, these enzymes and complex II are considered candidate drug targets for blocking parasite transmission. In this study, we identified siccanin as the first (to our knowledge) nanomolar inhibitor of the P. falciparum complex II. Moreover, we demonstrated that siccanin also inhibits complex III in the low-micromolar range. Siccanin did not inhibit the corresponding complexes from mammalian mitochondria even at high concentrations. Siccanin inhibited the growth of P. falciparum with IC₅₀ of 8.4 μM. However, the growth inhibition of the P. falciparum blood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC₅₀ = 10.26 μM) and Dd2-ELQ300 strains (EC₅₀ = 18.70 μM), suggesting a third mechanism of action that is unrelated to mitochondrial ETC inhibition. Hence, siccanin has at least a dual mechanism of action, being the first potent and selective inhibitor of P. falciparum complexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs.

中文翻译：

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Siccanin 是恶性疟原虫线粒体复合物 II 和复合物 III 的双靶点抑制剂

恶性疟原虫含有几个线粒体电子传递链 (ETC) 脱氢酶，将电子从各自的底物穿梭到泛醌池，电子从泛醌池连续转移到复合物 III、复合物 IV，最后转移到分子氧。抗疟药 atovaquone 可抑制复合物 III，并证实这种寄生虫的 ETC 是一种有吸引力的化疗靶点。在来自恶性疟原虫的 ETC 脱氢酶中、二氢乳清酸脱氢酶（一种用于从头嘧啶生物合成中的必需酶）和复合物 III 是已被表征和验证为血液期寄生虫药物靶标的两种酶，而复合物 II 已被证明对寄生虫在蚊子阶段；因此，这些酶和复合物 II 被认为是阻断寄生虫传播的候选药物靶点。在这项研究中，我们确定 siccanin 是第一个（据我们所知）恶性疟原虫复合物 II 的纳摩尔抑制剂。此外，我们证明了 siccanin 还在低微摩尔范围内抑制复合物 III。即使在高浓度下，Siccanin 也不会抑制哺乳动物线粒体中的相应复合物。Siccanin 抑制恶性疟原虫的生长IC ₅₀为 8.4 μM。然而，恶性疟原虫血期的生长抑制与 ETC 抑制无关，这可以通过 yDHODH-3D7 (EC ₅₀ = 10.26 μM) 和 Dd2-ELQ300 菌株 (EC ₅₀ = 18.70 μM ) 对 siccanin 缺乏抗性来证明)，表明第三种作用机制与线粒体 ETC 抑制无关。因此，siccanin 至少具有双重作用机制，是第一个有效和选择性的恶性疟原虫复合物 II 和 III 抑制剂，优于哺乳动物酶，因此是开发新型抗疟药物的潜在候选者。