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

Abstract

Background/Aim 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. Materials and Methods 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. Results The results demonstrate the superiority of JP4-039 as a systemic radiation mitigator. Conclusion: Structure–activity relationships and bioassays demonstrate that JP4-039 is an optimized small-molecule radiation mitigator.

Radiation Protection and Mitigation by Natural Antioxidants and Flavonoids: Implications to Radiotherapy and Radiation Disasters

“…Targeting mitochondrial ROS is one of the new strategies that has also shown promising results. Development of 4-Amino-Tempo is the best example of a mitochondrial targeted derivative [16][17][18]. Selenium, Selenium-L-methionine, ascorbic acid etc., are natural agents that have proved effective.…”

“Only a Life Lived for Others Is Worth Living”: Redox Signaling by Oxygenated Phospholipids in Cell Fate Decisions

“…The importance of CLox accumulation as a pathogenic mechanism has been confirmed by the protective effects of several mitochondria-targeted inhibitors of CL oxidation (7,37,66,69,119,148). Among them, a series of newly developed electron scavengers (XJB-5-125, XJB-5-131, JP4-039) capable of preventing the formation of H 2 O 2 as a source of oxidizing equivalents for the cyt c/CL catalyzed reactions were very effective ( Fig.…”

“…Among them, a series of newly developed electron scavengers (XJB-5-125, XJB-5-131, JP4-039) capable of preventing the formation of H 2 O 2 as a source of oxidizing equivalents for the cyt c/CL catalyzed reactions were very effective ( Fig. 6) (37,66,119). Another group of effective regulators includes imidazole-substituted fatty acids whereby strong liganding of the imidazole group with the heme-Fe prevented its further participation in the catalysis of the peroxidase CL oxidation ( Fig.…”

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part III. Countermeasures under early stages of development along with ‘standard of care’ medicinal and procedures not requiring regulatory approval for use

“…Recent work has demonstrated JP4-039 (gramicidine S (GS)nitroxide) to be a potent radiomitigator and it is safe when used in a variety of radiation exposures (Goff et al 2011;Berhane et al 2014;Epperly et al 2014Epperly et al , 2017. JP4-039 is a mitochondrial-targeted GS-nitroxide; its radiomitigation and protection properties are due to mitochondrial localization and the negation of oxidative stress-meditative events in the mitochondrial membrane.…”