Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents
Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents
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DOI：
10.1016/j.bmcl.2006.01.027
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发表时间：
2006-04-15
影响因子：
2.7
通讯作者：
Becker, K
中科院分区：
文献类型：
--
作者：
Andricopulo, AD;Akoachere, MB;Becker, K
恶性疟原虫硫氧还蛋白还原酶(PfTrxR：NADPH+Trx(S)(2)+H+NADP(+)+Trx(SH)(2))是一种高M-r黄素依赖的TrxR，它通过位于C端甘氨酸反端的CysXXXXCys对还原硫氧还蛋白(Trx)。在这方面，PfTrxR与人类对应的PfTrxR有很大的不同，后者在相同的位置带有Cys-SEC氧化还原对。PfTrxR基本上参与了寄生虫的抗氧化防御和氧化还原调节，此前已被基因敲除研究证实为疟疾化疗的潜在药物靶点。此外，人类TrxR存在于大多数癌细胞中，其水平是正常细胞的10倍。在这里，我们报告了一系列有效的PfTrxR抑制剂的发现。3种最有希望的抑制剂，3种(IC50PfTrxR=2亩M和IC50hTrxR=50亩M)，7种(IC50PfTrxR=2亩M和IC50hTrxR=140亩M)，11种(IC50PfTrxR=0.5亩M和IC50hTrxR=4亩M)对寄生虫酶具有选择性。对这些化合物对PfTrxR催化反应影响的详细机理表征表明，对底物和辅因子都有明显的非竞争性抑制。对于最具特异性的PfTrxR抑制剂7，进行了基于硫醇共轭模型的烷基化反应机理研究。此外，三个化合物在体外对抗氯喹恶性疟原虫K1株均具有较低的微摩尔活性。(C)2006爱思唯尔有限公司。保留所有权利。
Plasmodium falciparum thioredoxin reductase (PfTrxR:NADPH+Trx(S)(2)+H+ NADP(+)+Trx(SH)(2)) is a high M-r flavin-dependent TrxR that reduces thioredoxin (Trx) via a CysXXXXCys pair located penultimately to the C-terminal Gly. In this respect, PfTrxR differs significantly from its human counterpart which bears a Cys-Sec redox pair at the same position. PfTrxR is essentially involved in antioxidant defense and redox regulation of the parasite and has been previously validated by knock-out studies as a potential drug target for malaria chemotherapy. Moreover, human TrxR is present in most cancer cells at levels tenfold higher than in normal cells. Here we report the discovery of a series of potent inhibitors of PfTrxR. The three most promising inhibitors, 3 (IC50PfTrxR=2 mu M and IC50hTrxR=50 mu M), 7 (IC50PfTrxR=2 mu M and IC50hTrxR=140 mu M), and 11 (IC50PfTrxR=0.5 mu M and IC50hTrxR=4 mu M) were selective for the parasite enzyme. Detailed mechanistic characterization of the effects of these compounds on the PfTrxR-catalyzed reaction showed clear uncompetitive inhibition with respect to both substrate and cofactor. For the most specific PfTrxR inhibitor 7, an alkylation mechanism study based oil a thiol conjugation model was performed. Furthermore, all three compounds were active in the lower micromolar range on the chloroquine-resistant P. falciparum strain K1 in vitro. (C) 2006 Elsevier Ltd. All rights reserved.