Hemigramicidin-TEMPO conjugates: novel mitochondria-targeted anti-oxidants.
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.
Fink
Mitchell P
MP
Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States. finkmp@ccm.upmc.edu
Macias
Carlos A
CA
Xiao
Jingbo
J
Tyurina
Yulia Y
YY
Jiang
Jianfei
J
Belikova
Natalia
N
Delude
Russell L
RL
Greenberger
Joel S
JS
Kagan
Valerian E
VE
Wipf
Peter
P
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D005609:Free Radicals / Q000494:pharmacology / Q000627:therapeutic use; D006096:Gramicidin; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors*
D000975:Antioxidants; D003497:Cyclic N-Oxides; D005609:Free Radicals; D017382:Reactive Oxygen Species; C523959:XJB-5-131; D006096:Gramicidin; C003959:TEMPO