Researchers from University of Pittsburgh have identified a series of molecules capable of targeting a spectrum of inflammatory disorders.
Description
Inflammatory disorders occur when the immune system is highly activated and secretes high levels of pro-inflammatory cytokines (e.g., IL-6, IL-?, and TNF?) in response to the activation of immune effector cells by pathogens, irritants, or in response to host cell injury. The subsequent cytokine storm can result in profound tissue injury or death. Through identification of a novel target driving cytokine production, these novel molecules can act as a broad-spectrum therapeutic in a wide array of inflammatory disorders.
Applications
Autoimmune disease such as Crohn's disease, arthritis, or psoriasis;
Sepsis;
Pneumonia
Advantages
Sepsis, often a consequence of a cytokine storm, is the cause of death in over half a million people each year in the US alone. Current efforts to treat cytokine storms focus on targeting specific cytokines or inhibiting upstream surface receptors with limited or no success. In sepsis, and other inflammatory disorders, an array of cytokines are responsible for systematic inflammation, meaning targeting one cytokine alone will not prevent damage from another. Other treatments for sepsis include antimicrobial agents, although efficacy is reduced in severe infections due to antimicrobial resistance.
These novel compounds are designed to target a ubiquitin E3 ligase subunit found on TNF receptor associated factors (TRAF). TRAFs interact with a wide range of receptors, activating key transcription factors, leading to cytokine gene expression. Reducing cellular TRAF concentration would result in deactivation of downstream cytokine activation, and is a previously unexplored therapeutic target. Additionally, with selective inhibition of TRAFs, off-target effects could be limited.
Invention Readiness
Two novel ubiquitin E3 ligase subunits linked to cytokine response through regulation of TRAF protein signaling have been identified. Docking studies found benzathine derivatives selectively bind to the subunit responsible for activating TRAF protein signaling. In vitro studies demonstrated one such compound, BC-1215, could significantly suppress a wide array of cytokines including IL1-a, IL-1b, IL-23, and TNFa. In vivo studies in mouse septic shock models have shown therapeutic benefit from BC-1215 in doses well below predicted toxicity. Reduction in lung injury following pneumonia and H1N1 exposure, amelioration of colitis, and treatment of dermatological inflammation was also observed in vivo.
IP Status
https://patents.google.com/patent/US20160235747A1Related Publication(s)
Das, A., Wang, X., Wei, J., Hoji, A., Coon, T. A., Popescu, I., Brown, M., Frizzell, S., Iasella, C. J., Noda, K., Sembrat, J. C., Devonshire, K., Hannan, S. J., Snyder, M. E., Pilewski, J. M., Sanchez, P. G., Chandra, D., Mallampalli, R. K., Alder, J. K., … McDyer, J. F. (2022). Cross-Regulation of F-Box Protein FBXL2 with T-bet and TNF-α during Acute and Chronic Lung Allograft Rejection. The Journal of Immunology, 209(9), 1788–1795. https://doi.org/10.4049/jimmunol.2200245
