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

• Published in: In vivo (Athens) Vol. 31; no. 1; pp. 39 - 44
• Main Authors: Epperly, Michael W, Sacher, Joshua R, Krainz, Tanja, Zhang, Xiaolin, Wipf, Peter, Liang, Mary, Fisher, Renee, Li, Song, Wang, Hong, Greenberger, Joel S
• Format: Journal Article
• Language: English
• Published: Greece International Institute of Anticancer Research 05.01.2017
• Subjects: Animals; Dose-Response Relationship, Radiation; Female; Mice; Mice, Inbred C57BL; Molecular Structure; Nitrogen Oxides - pharmacology; Radiation Injuries, Experimental - etiology; Radiation Injuries, Experimental - prevention & control; Radiation-Protective Agents - administration & dosage; Radiation-Protective Agents - pharmacology; Structure-Activity Relationship; Whole-Body Irradiation - adverse effects; radiation mitigation; GS-nitroxide; Oxidative stress
• ISSN: 1791-7549; 0258-851X; 1791-7549
• DOI: 10.21873/invivo.11022

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.