Novel Small Molecule Therapeutics for Hemorrhagic Shock

Hemorrhagic shock and tissue hypoxia result in tissue conditions that are at risk of damage upon restored blood circulation. Subsequent oxygen reperfusion increases oxidative species concentrations even further, accelerating the decline of a patient’s systemic health. A patient undergoing severe blood loss suffers hypoxia during which lactic acid and other reactive oxidative species enter the circulatory system. These oxidative species are generated by “electron leakage” from the mitochondria and quickly spread throughout the circulatory system, oxidizing tissues and triggering cell death. Primary causes of hemorrhagic shock include penetrating and blunt trauma, gastrointestinal bleeding, and obstetrical bleeding. Controlling the activity of the reactive oxidative species is as crucial to patient survival as is controlling the bleeding.

Description

Investigators have developed a novel molecular delivery mechanism that allows hemorrhagic shock therapeutics to be targeted directly to the cell’s mitochondria. The lead compound, XJB-5-131, is a targeted nitroxide agent that allows delivery of the antioxidant TEMPO to the mitochondria using a peptide-like fragment of the antibiotic Gramicidin S. This localized concentration of TEMPO was found to provide greater therapeutic effects than those associated with standard TEMPO administration, providing test subjects with significantly longer survival times during prolonged hemorrhaging. This technology platform additionally allows for conjugation of the mitochondria targeting fragment of Gramicidin S to potentially any drug for delivery to the mitochondria for such indications.

Applications

· Treatment of any acute disease or condition that is associated with cellular damage or dysfunction caused by excessive mitochondrial production of reactive oxygen species, such as hemorrhagic shock, septic shock, or stroke

Advantages

· Intravenous treatment increases subject survival time during hemorrhagic shock, providing a greater window for treatment
· Preserves the protective mucosal lining of the intestines
· Antioxidant “payload” can be quickly directed to the mitochondria
· Lower conjugate drug concentrations can be administered
· Intravenous application delivers protection to the entire circulatory system’s endothelial lining

Invention Readiness

Proof of concept established Mouse and rat data available

IP Status

https://patents.google.com/patent/US20070161573A1; https://patents.google.com/patent/US7718603B1; https://patents.google.com/patent/US9006186B2; https://patents.google.com/patent/US20150297578A1

Related Publication(s)

Hoye, A. T., Davoren, J. E., Wipf, P., Fink, M. P., & Kagan, V. E. (2008). Targeting Mitochondria. Accounts of Chemical Research, 41(1), 87–97. https://doi.org/10.1021/ar700135m