NADPH oxidase inhibitors: a decade of discovery from Nox2ds to HTS.
NADPH oxidase inhibitors: a decade of discovery from Nox2ds to HTS.
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DOI：
10.1007/s00018-012-1009-2
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发表时间：
2012-07
影响因子：
8
通讯作者：
Pagano, Patrick J.
中科院分区：
文献类型：
--
作者：
Cifuentes-Pagano, Eugenia;Csanyi, Gabor;Pagano, Patrick J.
NADPH氧化酶（Nox）是活性氧（ROS）的主要来源。在过去的二十年中，nox衍生的ROS在涉及氧化应激的无数疾病的发展中发挥了关键作用。相反，氮氧化物也参与正常细胞功能所必需的信号机制。这些酶在生理和病理生理条件下的研究变得相当复杂，因为发现了7种异构体：Nox1到5以及Duox1和2，每种异构体都有自己特定的细胞质成分、调节控制机制、亚细胞定位和/或组织分布。由于缺乏同种异构体特异性抑制剂，对特定系统中单个同种异构体的作用的清晰理解受到阻碍。在动物模型中，敲除或敲除方法为多种氮氧化物异构体在细胞和组织信号传导中的复杂相互作用的复杂问题提供了明确的答案。然而，这些异质同工酶的复杂结构和相互作用预测了Nox亚基的多效性作用，因此抑制这些蛋白质几乎肯定会产生不良影响。因此，作为治疗和药理学工具，基于分子的抑制剂在设计上继续证明是非常有用和合理的。不幸的是，许多可用的抑制剂已被证明是非特异性的，属于清除剂或多种ROS来源抑制剂的类别。在这里，我们将回顾过去十年来在开发NADPH氧化酶特异性抑制剂方面所做的一些努力，从肽抑制剂nox2s -tat到最近从高通量筛选活动中出现的小分子抑制剂。
NADPH oxidases (Nox) are established as major sources of reactive oxygen species (ROS). Over the past two decades, Nox-derived ROS have emerged as pivotal in the development of myriad diseases involving oxidative stress. In contrast, Nox are also involved in signaling mechanisms necessary for normal cell function. The study of these enzymes in physiological and pathophysiological conditions is made considerably more complex by the discovery of 7 isoforms: Nox1 through 5 as well as Duox1 and 2, each with its own specific cytosolic components, regulatory control mechanisms, subcellular localization and/or tissue distribution. A clear understanding of the role individual isoforms play in a given system is hindered by the lack of isoform-specific inhibitors. In animal models, knockdown or knockout methodologies are providing definitive answers to perplexing questions of the complex interplay of multiple Nox isoforms in cell and tissue signaling. However, the complex structures and interactions of these heteromeric isozymes predict pleiotropic actions of the Nox subunits and thus suppression of these proteins is almost certain to have untoward effects. Thus, as both therapies and pharmacological tools, molecule-based inhibitors continue to prove extremely useful and rational in design. Unfortunately, many of the available inhibitors have proven non-specific, falling into the category of scavengers or inhibitors of more than one source of ROS. Here, we will review some of the efforts that have been undertaken to develop specific inhibitors of NADPH oxidase over the past decade, from the peptidic inhibitor Nox2ds-tat to more recent small molecule inhibitors that have emerged from high-throughput screening campaigns.
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影响因子：
4
作者：
Gianni, Davide;Taulet, Nicolas;Zhang, Hui;DerMardirossian, Celine;Kister, Jeremy;Martinez, Luis;Roush, William R.;Brown, Steven J.;Bokoch, Gary M.;Rosen, Hugh
通讯作者：
Rosen, Hugh
影响因子：
7.4
作者：
Csanyi, Gabor;Taylor, W. Robert;Pagano, Patrick J.
通讯作者：
Pagano, Patrick J.
影响因子：
7.3
作者：
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通讯作者：
Keri, Gyoergy
DOI：
10.1152/ajpheart.00413.2004
发表时间：
2005-02-01
影响因子：
4.8
作者：
Dourron, HM;Jacobson, GM;Pagano, PJ
通讯作者：
Pagano, PJ
DOI：
10.1073/pnas.91.2.664
发表时间：
1994-01-18
影响因子：
11.1
作者：
FAWELL, S;SEERY, J;BARSOUM, J
通讯作者：
BARSOUM, J