Komatsuya Keisuke, Sakura Takaya, Shiomi Kazuro, Ōmura Satoshi, Hikosaka Kenji, Nozaki Tomoyoshi, Kita Kiyoshi, Inaoka Daniel Ken
Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Laboratory of Biomembrane, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Pharmaceuticals (Basel). 2022 Jul 21;15(7):903. doi: 10.3390/ph15070903.
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 , 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 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 with IC of 8.4 μM. However, the growth inhibition of the blood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC = 10.26 μM) and Dd2-ELQ300 strains (EC = 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 complexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs.
包含几种线粒体电子传递链（ETC）脱氢酶，这些脱氢酶将电子从各自的底物穿梭至泛醌池，电子再从泛醌池依次转移至复合物III、复合物IV，最终传递至分子氧。抗疟药物阿托伐醌可抑制复合物III，并证实该寄生虫的ETC是化疗的一个有吸引力的靶点。在疟原虫的ETC脱氢酶中，二氢乳清酸脱氢酶是从头嘧啶生物合成中使用的一种必需酶，复合物III是已被鉴定并确认为血液期寄生虫药物靶点的两种酶，而复合物II已被证明对疟原虫在蚊子阶段的存活至关重要；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。在本研究中，我们鉴定出siccanin是（据我们所知）首个对复合物II具有纳摩尔抑制活性的抑制剂。此外，我们还证明siccanin在低微摩尔浓度范围内也能抑制复合物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以8.4 μM的IC50抑制疟原虫的生长。然而，疟原虫血液期的生长抑制与ETC抑制无关，yDHODH - 3D7（EC50 = 10.26 μM）和Dd2 - ELQ300菌株（EC50 = 18.70 μM）对siccanin缺乏抗性就证明了这一点，这表明存在一种与线粒体ETC抑制无关的第三种作用机制。因此，siccanin至少具有双重作用机制，是首个对疟原虫复合物II和III比对哺乳动物酶更具强效和选择性的抑制剂，所以是开发新型抗疟药物的潜在候选物。
