Hemigramicidin-TEMPO conjugates: Novel mitochondria-targeted anti-oxidants
Hemigramicidin-TEMPO conjugates: Novel mitochondria-targeted anti-oxidants
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DOI：
10.1016/j.bcp.2007.05.019
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发表时间：
2007-09-15
影响因子：
5.8
通讯作者：
Wipf, Peter
中科院分区：
文献类型：
--
作者：
Fink, Mitchell P.;Macias, Carlos A.;Wipf, Peter
由活性氧（ROS）介导的对各种细胞成分（如蛋白质和脂质）的氧化损伤被认为是各种急性和慢性疾病发病机制的重要机制。线粒体是大多数细胞内ROS的主要来源。因此，人们对开发特异性靶向线粒体并在线粒体内浓缩的药理学ROS清除剂越来越感兴趣。具有这些一般特征的许多化合物已被合成，并在各种体外和体内氧化还原应激模型中进行了评价。在这些靶向抗氧化剂中，更有前途的是采用衍生自抗生素短杆菌肽S的各种肽（或肽样部分）作为靶向构建体并采用稳定的自由基4-氨基-2，2，6，6-四甲基哌啶-N-氧基（4-NH2-TEMPO）作为清除ROS的有效载荷的那些。“其中一种哈米米菌素-TEMPO缀合物XJB-5 - 131已被证明可以改善肠粘膜损伤并延长遭受致命出血的大鼠的生存时间。(C)2007年爱思唯尔公司All rights reserved.
Oxidative damage to various cellular constituents (such as, proteins and lipids) mediated by reactive oxygen species (ROS) is thought to be an important mechanism underlying the pathogenesis of a variety of acute and chronic diseases. Mitochondria are the main source of ROS within most cells. Accordingly, there is increasing interest in the development of pharmacological ROS scavengers, which are specifically targeted to and concentrated within mitochondria. Numerous compounds with these general characteristics have been synthesized and evaluated in a variety of in vitro and in vivo models of redox stress. Among the more promising of these mitochondria-targeted anti-oxidants are those that employ various peptides (or peptide-like moieties) derived from the antibiotic, gramicidin S, as the targeting construct and employ the stable free radical, 4-amino- 2,2,6,6-tetramethylpiperidine-N-oxyl (4-NH2-TEMPO), as the ROS scavenging "payload." One of these hemigramicidin-TEMPO conjugates, XJB-5-131, has been shown to ameliorate intestinal mucosal injury and prolong survival in rats subjected to lethal hemorrhage. (C) 2007 Elsevier Inc. All rights reserved.