Mitochondria are key organelles that perform essential cellular functions and play pivotal roles in cell death and survival signaling. Hence, they represent an attractive target for drugs to treat metabolic, degenerative and hyperproliferative diseases. Shuttling organelle-specific agents or prodrugs into mitochondria holds considerable promise as an effective therapeutic strategy. XJB-5-131 (XJB) is a mitochondrial targeted reactive therapeutic that delivers a nitroxide, 4-amino-TEMPO (4-AT), to the inner mitochondrial membrane. It has shown in vivo efficacy against hemorrhagic shock, traumatic brain injury (TBI), and age-related neurodegenerative diseases, such as Huntington’s disease (HD), and it reduces tissue damage during brain microdialysis and decreases aging-related intervertebral disk degeneration. The compound neutralizes electrons escaping from the electron transport chain in the IMM and ROS before they can impact membranes, proteins, and DNA. XJB is currently at the preclinical development stage. In vitro and in vivo biological analyses have demonstrated that it is superior to 4-AT or TEMPO alone in preventing ischemia-reperfusion-induced mitochondrial superoxide production and caspase activation, thus reducing apoptosis and enhancing cell survival in primary cortical neurons. In vivo, XJB-5-131 shows promising drug-like behavior in preliminary pharmacokinetic studies. Close structural analogs of XJB-5-131 also demonstrated efficacy in models of radiation damage prevention and mitigation. Studies are underway to evaluate the ADME-Tox profile of XJB-5-131 and to determine if it can serve as a therapeutic for mitochondrial diseases.

Therapeutic opportunities of chemical targeting of mitochondria

249th National Meeting (2015)

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