Hemigramicidin-TEMPO conjugates: novel mitochondria-targeted antioxidants

Abstract

Reactive oxygen species (ROS) are reactive, partially reduced derivatives of molecular oxygen. ROS are important in the pathogenesis of a wide range of acute pathologic processes, including ischemia/reperfusion injury, sepsis, and shock. Accordingly, effective ROS scavengers might be useful therapeutic agents for these conditions. Since mitochondria are the primary sites for ROS production within cells, it seems reasonable that targeting ROS scavengers to these organelles could be a particularly effective strategy. Indeed, a number of compounds or classes of compounds have been described that are based on this concept. One approach consists of coupling a payload--the portion of the molecule with ROS-scavenging activities--to a targeting moiety--the portion of the molecule that promotes selective accumulation within mitochondria. For example, the payload portion of XJB-5-131 consists of a stable nitroxide radical, which has been extensively investigated as a cytoprotective agent in a number of experimental models of oxidative stress. The targeting portion of XJB-5-131 consists of a portion of the membrane-active cyclopeptide antibiotic, gramicidin S. The gramicidin segment was used to target the nitroxide payload to mitochondria because antibiotics of this type have a high affinity for bacterial membranes and because of the close relationship between bacteria and mitochondria. In a rat model of hemorrhagic shock, delayed treatment with XJB-5-131 has been shown to prolong survival time in the absence of resuscitation with blood or a large volume of crystalloid fluid. Compounds like XJB-5-131 warrant further evaluation for the treatment of hemorrhagic shock as well as other acute conditions associated with increased mitochondrial production of ROS.