1,4-naphthoquinones and other NADPH-dependent glutathione reductase-catalyzed redox cyclers as antimalarial agents.
1,4-naphthoquinones and other NADPH-dependent glutathione reductase-catalyzed redox cyclers as antimalarial agents.
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DOI：
10.2174/1381612811319140003
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发表时间：
2013
影响因子：
3.1
通讯作者：
Davioud-Charvet E
中科院分区：
文献类型：
--
作者：
Belorgey D;Lanfranchi DA;Davioud-Charvet E
同型二聚体黄素酶谷胱甘肽还原酶催化NADPH依赖性谷胱甘肽二硫化物还原。该反应对于保持人体细胞和人体病原体恶性疟原虫中的氧化还原稳态是重要的。设计了不同类型的NADPH依赖性二硫还原酶抑制剂的各种化学系列，以评估每种抑制模式对寄生虫繁殖的影响。对疟疾寄生虫在文化中的最有效的和具体的影响，观察到氧化还原活性剂作为破坏性底物的谷胱甘肽还原酶的疟原虫感染的红细胞。在它们的氧化形式中，这些氧化还原活性化合物在受感染的红细胞的胞质溶胶中被NADPH依赖性黄素酶催化的反应还原。在它们的还原形式中，这些化合物可以将分子氧还原为活性氧，或者将氧化剂如高铁血红蛋白（寄生虫的主要营养素）还原为不可消化的血红蛋白。此外，对人谷胱甘肽还原酶的氟化自杀底物的研究表明，谷胱甘肽还原酶催化的3-苄基萘醌生物活化为相应的还原3-苯甲酰基代谢物对于所观察到的抗疟活性是必不可少的。总之，抗疟疾的铅萘醌类药物被认为是干扰靶细胞的主要氧化还原平衡。这些作用导致寄生虫的发育停滞，并有助于巨噬细胞清除寄生的红细胞。
The homodimeric flavoenzyme glutathione reductase catalyzes NADPH-dependent glutathione disulfide reduction. This reaction is important for keeping the redox homeostasis in human cells and in the human pathogen Plasmodium falciparum. Different types of NADPH-dependent disulfide reductase inhibitors were designed in various chemical series to evaluate the impact of each inhibition mode on the propagation of the parasites. Against malaria parasites in cultures the most potent and specific effects were observed for redox-active agents acting as subversive substrates for both glutathione reductases of the Plasmodium-infected red blood cells. In their oxidized form, these redox-active compounds are reduced by NADPH-dependent flavoenzyme-catalyzed reactions in the cytosol of infected erythrocytes. In their reduced forms, these compounds can reduce molecular oxygen to reactive oxygen species, or reduce oxidants like methemoglobin, the major nutrient of the parasite, to indigestible hemoglobin. Furthermore, studies on a fluorinated suicide-substrate of the human glutathione reductase indicate that the glutathione reductase-catalyzed bioactivation of 3-benzylnaphthoquinones to the corresponding reduced 3-benzoyl metabolites is essential for the observed antimalarial activity. In conclusion, the antimalarial lead naphthoquinones are suggested to perturb the major redox equilibria of the targeted cells. These effects result in development arrest of the parasite and contribute to the removal of the parasitized erythrocytes by macrophages.
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影响因子：
2.7
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