Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III.
Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III.
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DOI：
10.3390/ph15070903
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发表时间：
2022-07-21
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影响因子：
--
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中科院分区：
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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转移到泛醌库，从泛醌库中电子依次转移到配合物III、配合物IV，最后转移到分子氧中。抗疟药物阿托伐醌抑制复合体III，并证实这种寄生虫的ETC是一个有吸引力的化疗靶点。在恶性疟原虫ETC脱氢酶中，二氢乙酸脱氢酶（一种用于重新合成嘧啶生物的必需酶）和络合物III是已被鉴定并证实为血液期寄生虫药物靶点的两种酶，而络合物II已被证明是寄生虫在蚊子期生存所必需的酶；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）恶性疟原虫复合体II的纳米摩尔抑制剂。此外，我们还证明了siccanin在低微摩尔范围内抑制复合物III。Siccanin即使在高浓度下也不会抑制哺乳动物线粒体中相应的复合物。Siccanin抑制恶性疟原虫生长，IC50值为8.4 μM。然而，恶性疟原虫血期的生长抑制与ETC抑制并不相关，yDHODH-3D7 （EC50 = 10.26 μM）和Dd2-ELQ300菌株（EC50 = 18.70 μM）对siccanin缺乏抗性，这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，是恶性疟原虫复合体II和III在哺乳动物酶上的第一个有效和选择性抑制剂，因此是开发一类新型抗疟药物的潜在候选者。
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.
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影响因子：
1.5
作者：
Ganesan, Suresh M.;Morrisey, Joanne M.;Ke, Hangjun;Painter, Heather J.;Laroiya, Kamal;Phillips, Margaret A.;Rathod, Pradipsinh K.;Mather, Michael W.;Vaidya, Akhil B.
通讯作者：
Vaidya, Akhil B.
DOI：
10.1073/pnas.1414221111
发表时间：
2014-12-16
影响因子：
11.1
作者：
Belen Jimenez-Diaz, Maria;Ebert, Daniel;Guy, R. Kiplin
通讯作者：
Guy, R. Kiplin
影响因子：
4.8
作者：
Bulusu, Vinay;Jayaraman, Vijay;Balaram, Hemalatha
通讯作者：
Balaram, Hemalatha
DOI：
10.4269/ajtmh.1964.13.515
发表时间：
1964-01-01
影响因子：
3.3
作者：
BRYANT, C;SMITH, MJH;VOLLER, A
通讯作者：
VOLLER, A
影响因子：
64.8
作者：
Gamo, Francisco-Javier;Sanz, Laura M.;Garcia-Bustos, Jose F.
通讯作者：
Garcia-Bustos, Jose F.