Fink Mitchell P, Macias Carlos A, Xiao Jingbo, Tyurina Yulia Y, Jiang Jianfei, Belikova Natalia, Delude Russell L, Greenberger Joel S, Kagan Valerian E, Wipf Peter
Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
Biochem Pharmacol. 2007 Sep 15;74(6):801-9. doi: 10.1016/j.bcp.2007.05.019. Epub 2007 May 29.
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-NH(2)-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.
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多种急慢性疾病发病机制的重要基础。线粒体是大多数细胞内ROS的主要来源。因此，人们对开发专门靶向并集中于线粒体的药理性ROS清除剂越来越感兴趣。许多具有这些一般特性的化合物已在各种体外和体内氧化还原应激模型中进行了合成和评估。在这些更有前景的线粒体靶向抗氧化剂中，有一些采用了源自抗生素短杆菌肽S的各种肽（或类肽部分）作为靶向构建体，并采用稳定自由基4-氨基-2,2,6,6-四甲基哌啶-N-氧基（4-NH(2)-TEMPO）作为ROS清除“有效载荷”。其中一种半短杆菌肽-TEMPO缀合物XJB-5-131已被证明可改善大鼠致死性出血后的肠黏膜损伤并延长其存活时间。
