Effectiveness of Analogs of the GS-Nitroxide, JP4-039, as Total Body Irradiation Mitigators.

Abstract

Mitochondrial-targeted gramicidin S (GS)-nitroxide, JP4-039, has been demonstrated to be a potent radiation mitigator, and safe over a wide dose range. In addition, JP4-039 has organ-specific effectiveness when locally applied. We tested the effect of another GS-nitroxide, XJB-5-131, which has more effective mitochondrial localization, and compared these results to those for radiation mitigation against the hematopoietic syndrome, and two analogs of JP4-039, which have the same mitochondrial localization signal, but different chemical payloads: JRS527.084 contains a second nitroxide per molecule, and TK649.030 contains an ester group attached to the nitroxide. The results demonstrate the superiority of JP4-039 as a systemic radiation mitigator. Structure-activity relationships and bioassays demonstrate that JP4-039 is an optimized small-molecule radiation mitigator.