Targeting aquaporin function: potent inhibition of aquaglyceroporin-3 by a gold-based compound.
Targeting aquaporin function: potent inhibition of aquaglyceroporin-3 by a gold-based compound.
复制标题
靶向水通道蛋白功能：基于黄金的化合物对水甘露糖蛋白3的有效抑制。
DOI：
10.1371/journal.pone.0037435
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Soveral G
中科院分区：
文献类型：
--
作者：
Martins AP;Marrone A;Ciancetta A;Galán Cobo A;Echevarría M;Moura TF;Re N;Casini A;Soveral G
水通道蛋白是传导水和小溶质（如甘油）的膜通道，参与许多生理功能。基于水通道蛋白的调节药物被预测在治疗多种疾病方面具有广泛的潜在用途。直到今天，很少有AQP抑制剂被描述为适合临床开发的候选者。在这里，我们报道了金（III）配合物在人红细胞（hRBC）和AQP3转染的PC12细胞上筛选的有效抑制AQP3通道。在测试的各种金属化合物中，Auphen对AQP3的活性最高（在hRBC中IC50 = 0.8±0.08µM）。有趣的是，该化合物对AQP1的透水性影响很小。金的抑制机制与金（III）与蛋白质的巯基（如半胱氨酸残基的硫酸盐）相互作用的能力有关。另外对可能的金化合物/AQP加合物的DFT和建模研究提供了在分子水平上对该体系的初步描述。人类AQP3同源模型的质周表面映射证明了Cys40的巯基可能是与金（III）配合物结合的候选者。此外，通过对接方法对Au配合物的非共价结合进行了研究，发现它们与AQP3的结合优于AQP1。Auphen的高选择性和低浓度依赖性抑制作用（在纳摩尔范围内）以及其高水溶性使该化合物成为未来体内研究的合适药物先导。这些结果可能为AQP药物开发提供新的金属基支架。
Aquaporins (AQPs) are membrane channels that conduct water and small solutes such as glycerol and are involved in many physiological functions. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of several diseases. Until today few AQP inhibitors have been described as suitable candidates for clinical development. Here we report on the potent inhibition of AQP3 channels by gold(III) complexes screened on human red blood cells (hRBC) and AQP3-transfected PC12 cells by a stopped-flow method. Among the various metal compounds tested, Auphen is the most active on AQP3 (IC50 = 0.8±0.08 µM in hRBC). Interestingly, the compound poorly affects the water permeability of AQP1. The mechanism of gold inhibition is related to the ability of Au(III) to interact with sulphydryls groups of proteins such as the thiolates of cysteine residues. Additional DFT and modeling studies on possible gold compound/AQP adducts provide a tentative description of the system at a molecular level. The mapping of the periplasmic surface of an homology model of human AQP3 evidenced the thiol group of Cys40 as a likely candidate for binding to gold(III) complexes. Moreover, the investigation of non-covalent binding of Au complexes by docking approaches revealed their preferential binding to AQP3 with respect to AQP1. The high selectivity and low concentration dependent inhibitory effect of Auphen (in the nanomolar range) together with its high water solubility makes the compound a suitable drug lead for future in vivo studies. These results may present novel metal-based scaffolds for AQP drug development.
登录
查看更多内容
DOI：
10.1016/j.bbrc.2011.04.057
发表时间：
2011-05-13
影响因子：
3.1
作者：
Campos, Elisa;Moura, Teresa F.;Soveral, Graca
通讯作者：
Soveral, Graca
DOI：
10.1073/pnas.0507225103
发表时间：
2006-01-10
影响因子：
11.1
作者：
Beitz, E;Wu, BH;Zeuthen, T
通讯作者：
Zeuthen, T
影响因子：
56.9
作者：
de Groot, BL;Grubmüller, H
通讯作者：
Grubmüller, H
影响因子：
4.4
作者：
HAY, PJ;WADT, WR
通讯作者：
WADT, WR
影响因子：
2.7
作者：
Huber, Vincent J.;Tsujita, Mika;Nakada, Tsutomu
通讯作者：
Nakada, Tsutomu