Double-drug development against antioxidant enzymes from Plasmodium falciparum
Double-drug development against antioxidant enzymes from Plasmodium falciparum
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DOI：
10.1179/135100003225002916
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发表时间：
2003-01-01
期刊：
影响因子：
3.8
通讯作者：
Davioud-Charvet, E
中科院分区：
文献类型：
--
作者：
Biot, C;Dessolin, J;Davioud-Charvet, E
迫切和持续地需要治疗疟疾的新药。疟原虫暴露在较高的活性氧通量下，需要高活性的细胞内抗氧化系统。一个最重要的抗氧化系统是由二硫键还原酶(DR)循环的(二)硫醇，即恶性疟原虫和人的谷胱甘肽还原酶(GR)和恶性疟原虫的硫氧还蛋白还原酶(TrxR)。我们跨学科研究的目的是证实DR抑制剂是抗疟疾药物。这类化合物本身是活性的，但除此之外，它们还可以逆转寄生虫对其他药物的硫醇耐药性。目前，人们正在研究常用抗疟疾药物氯喹(CQ)对DR抑制剂逆转耐药性的作用。我们最近的策略是基于从寄生虫和宿主红细胞合成谷胱甘肽还原酶抑制剂。为了达到协同或相加的效果，设计了针对恶性疟原虫两种不同的基本功能的双头前药，即谷胱甘肽再生和血红素解毒。前药是通过生物可逆地将GR抑制剂与4-氨基喹啉部分连接起来制备的，4-氨基喹啉部分已知集中在寄生虫的酸性食物液泡中。药物-酶相互作用与伯氏疟原虫感染小鼠体内和体外对CQ耐药株的抗寄生虫作用相关，也与对人类细胞无细胞毒性有关。由于最近发现恶性疟原虫的TrxR与GR抑制后观察到的残留的谷胱甘肽二硫化物还原能力有关，因此未来通过扰乱寄生虫氧化还原平衡来发挥作用的抗疟疾候选药物的发展是基于基于TrxR抑制剂的新型双药物的设计作为潜在的抗疟疾药物候选。
New drugs against malaria are urgently and continuously needed. Plasmodium parasites are exposed to higher fluxes of reactive oxygen species and need high activities of intracellular antioxidant systems. A most important antioxidative system consists of (di)thiols which are recycled by disulfide reductases (DR), namely both glutathione reductases (GR) of the malarial parasite Plasmodium falciparum and man, and the thioredoxin reductase (TrxR) of P. falciparum. The aim of our interdisciplinary research is to substantiate DR inhibitors as antimalarial agents. Such compounds are active per se but, in addition, they can reverse thiol-based resistance against other drugs in parasites. Reversal of drug resistance by DR inhibitors is currently investigated for the commonly used antimalarial drug chloroquine (CQ). Our recent strategy is based on the synthesis of inhibitors of the glutathione reductases from parasite and host erythrocyte. With the expectation of a synergistic or additive effect, double-headed prodrugs were designed to be directed against two different and essential functions of the malarial parasite P. falciparum, namely glutathione regeneration and heme detoxification. The prodrugs were prepared by linking bioreversibly a GR inhibitor to a 4-aminoquinoline moiety which is known to concentrate in the acidic food vacuole of parasites. Drug-enzyme interaction was correlated with antiparasitic action in vitro on strains resistant towards CQ and in vivo in Plasmodium berghei-infected mice as well as absence of cytotoxicity towards human cells. Because TrxR of P. falciparum was recently shown to be responsible for the residual glutathione disulfide-reducing capacity observed after GR inhibition in P. falciparum, future development of antimalarial drug-candidates that act by perturbing the redox equilibrium of parasites is based on the design of new double-drugs based on TrxR inhibitors as potential antimalarial drug candidates.