University of Pittsburgh researchers have developed novel nitroxide-based lipid peroxidation mitigators designed to prevent ferroptotic cell death, a regulated form of non-apoptotic cell death. By synthesizing analogues of the benchmark ROS scavengers XJB-5-131 and JP4-039, this technology offers therapeutic opportunities in diseases and injuries involving ferroptosis pathways. Lead compounds could have a transformative impact on treating ischemia/reperfusion-induced tissue injury, acute kidney injury, and other pathologies.
Description
The invention focuses on mitigating ferroptosis and inflammation by designing new compositions of matter—specifically nitroxide-based compounds that prevent polyunsaturated lipid peroxidation. Ferroptosis, linked to redox biology, metabolism, and disease, is a cell death pathway relevant to numerous medical conditions. By targeting lipid peroxidation in mitochondria, these compounds offer the potential for broad application in medical research and therapeutic development.
Applications
• Investigative tool for probing the relevance of ferroptosis in disease mechanisms
•Therapeutic research in ischemia/reperfusion injuries and acute kidney injuries
• Potential applications in neurodegenerative disease therapeutic intervention
Advantages
The invention introduces novel compositions of matter that specifically target the ferroptosis pathway, particularly by preventing polyunsaturated lipid peroxidation in mitochondria. These compounds have shown efficacy in in vivo experiments, making them a promising therapeutic lead for diseases involving oxidative stress and lipid peroxidation. Their ability to mitigate ferroptosis provides a new therapeutic avenue for conditions such as ischemia/reperfusion injury and acute kidney injury.
Invention Readiness
The development is at a stage where continued in vivo testing and optimization are underway, with data suggesting that these compounds could be key in therapeutic strategies for conditions associated with ferroptosis. Recent studies have shown that JP4-039 significantly reduces apoptosis and inflammatory cell migration in irradiated mouse retinas, marking its first confirmed effect in retinal tissue. In fetal radiation injury models, JP4-039 administered on embryonic day 14.5 markedly reduced cell death in irradiated fetal brains. Additionally, JP4-039 has demonstrated potential in improving oxidative phosphorylation in endothelial cells in vitro and inducing coronary angiogenesis in post-acute myocardial infarction hearts in vivo. JP4-039 also protects kidneys from cisplatin-induced AKI by suppressing tubular oxidative stress and inhibiting proinflammatory and proapoptotic pathways.
IP Status
https://patents.google.com/patent/WO2021021699A1
