Effects of the G-quadruplex-binding drugs quarfloxin and CX-5461 on the malaria parasite Plasmodium falciparum.
Effects of the G-quadruplex-binding drugs quarfloxin and CX-5461 on the malaria parasite Plasmodium falciparum.
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DOI：
10.1016/j.ijpddr.2023.11.007
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发表时间：
2023-12
影响因子：
4
通讯作者：
Merrick, Catherine J.
中科院分区：
文献类型：
--
作者：
Craven, Holly M.;Nettesheim, Guilherme;Cicuta, Pietro;Blagborough, Andrew M.;Merrick, Catherine J.
恶性疟原虫是人类疟疾最致命的病原体。这种寄生虫历史上对大多数药物产生了耐药性，包括目前的一线治疗，因此需要新的治疗靶点。我们之前对寄生虫DNA和RNA中的鸟嘌呤四重复合物（G4s）的研究已经强调了它们对寄生虫生物学的影响，并揭示了G4稳定化合物是重新定位的有希望的候选者。特别值得一提的是，曾被用作抗癌剂的四氟灵，能杀死所有发育阶段的血期寄生虫，杀伤速度快，效力达纳摩尔级。本文探讨了石英烯及其衍生物CX-5461的分子机理。在体外，这两种化合物都与恶性疟原虫编码的G4序列结合。在cello中，quarfloxin比CX-5461更有效，可以在小鼠模型中阻止血期疟疾的建立。据报道，CX-5461在人类细胞中显示出明显的DNA损伤活性，而四氟辛对DNA损伤的影响较弱。这两种化合物都引起寄生虫的转录失调，但受影响的基因很大程度上不同，再次表明不同的作用模式。因此，CX-5461可能主要作为一种DNA损伤剂作用于疟原虫和哺乳动物细胞中，而四氟灵的完全抗疟作用模式可能是寄生虫特异性的，目前尚不清楚。G4稳定化合物四氟辛在体外和体内均对人疟原虫和小鼠疟原虫具有有效的抗疟作用。相关化合物CX-5461目前正在进行抗癌试验，其作用主要是在疟原虫中造成DNA损伤，就像在人类细胞中一样。四氟辛的抗疟机制与CX-5461不同，其毒性更大，但对DNA的损伤更小：它可能是疟原虫特异性的和多因素的。
Plasmodium falciparum is the deadliest causative agent of human malaria. This parasite has historically developed resistance to most drugs, including the current frontline treatments, so new therapeutic targets are needed. Our previous work on guanine quadruplexes (G4s) in the parasite's DNA and RNA has highlighted their influence on parasite biology, and revealed G4 stabilising compounds as promising candidates for repositioning. In particular, quarfloxin, a former anticancer agent, kills blood-stage parasites at all developmental stages, with fast rates of kill and nanomolar potency. Here we explored the molecular mechanism of quarfloxin and its related derivative CX-5461. In vitro, both compounds bound to P. falciparum-encoded G4 sequences. In cellulo, quarfloxin was more potent than CX-5461, and could prevent establishment of blood-stage malaria in vivo in a murine model. CX-5461 showed clear DNA damaging activity, as reported in human cells, while quarfloxin caused weaker signatures of DNA damage. Both compounds caused transcriptional dysregulation in the parasite, but the affected genes were largely different, again suggesting different modes of action. Therefore, CX-5461 may act primarily as a DNA damaging agent in both Plasmodium parasites and mammalian cells, whereas the complete antimalarial mode of action of quarfloxin may be parasite-specific and remains somewhat elusive. The G4 stabilising compound quarfloxin is an effective antimalarial, both in vitro on human malaria parasites and in vivo on murine malaria parasites. The related compound CX-5461, currently in trials against cancer, acts primarily to cause DNA damage in Plasmodium parasites, as it does in human cells. The antimalarial mechanism of quarfloxin is not identical to that of CX-5461, being more toxic but less DNA damaging: it is probably Plasmodium-specific and multi-factorial.
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影响因子：
14.9
作者：
Renaud de la Faverie A;Guédin A;Bedrat A;Yatsunyk LA;Mergny JL
通讯作者：
Mergny JL
影响因子：
5.8
作者：
Barnett, Derek W.;Garrison, Erik K.;Marth, Gabor T.
通讯作者：
Marth, Gabor T.
影响因子：
3.8
作者：
Craven HM;Bonsignore R;Lenis V;Santi N;Berrar D;Swain M;Whiteland H;Casini A;Hoffmann KF
通讯作者：
Hoffmann KF
影响因子：
4.4
作者：
Gage, Hunter L.;Merrick, Catherine J.
通讯作者：
Merrick, Catherine J.
DOI：
10.1073/pnas.1921649117
发表时间：
2020-02-25
影响因子：
11.1
作者：
Bruno, Peter M.;Lu, Mengrou;Pritchard, Justin R.
通讯作者：
Pritchard, Justin R.