Reactive oxygen species (ROS) generated in mitochondria are thought to play a critical role in various pathologies associated with cell injury, aging, and death. Selective delivery of redox modifiers into these organelles may represent a particularly effective therapeutic strategy, but remains a practical challenge. Recent approaches are based on the tethering of a ROS scavenger to a vehicle with increased selectivity toward mitochondria.Our hemigramicidin-TEMPO conjugates rely on the homology of mitochondrial membranes to bacterial cell walls, and the hypothesis of the use of segments of the antibiotic gramicidin S as selective targeting agents. Among these, the (E)-alkene dipeptide isostere XJB-5-131 proved to be a novel and effective mitochondrial ROS and electron scavenging agent. The direct tethering of 4-amino-TEMPO to a shortened peptide isostere sequence of XJB-5-131 provided jp4_039, a lead compound among a unique class of small molecule-nitroxide conjugates that can serve as potent radioprotectors and radiation injury mitigators.

Novel non peptide-nitroxide conjugates for targeting mitochondria

239th National Meeting (2010)

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