Peptide-based inhibitor for treating chronic viral and autoimmune inflammatory diseases
Inventors: Jonathan Kagan
Invention Types: Therapeutics
Research Areas: Immunology, Infectious Disease
Keywords: Small Molecule/DrugFor More Information Contact: Meyer, Abbie
Dr. Kagan's lab has developed a novel peptide-based inhibitor of Rig-I-like receptor (RLR)-mediated signal transduction that could serve as a good molecular candidate for therapeutic modulation of the immune response. RLRs have emerged as critical sentinels of viral infection, surveying the cytosol of all mammalian cell types for the presence of viruses containing RNA genomes. In addition to sensing viral RNAs, RLRs are important regulators of a growing list of non-infectious immunopathologies that may result from an inappropriate host response to self RNA. RLR-mediated detection of viral RNA results in the mitochondrial antiviral signaling protein (MAVS)-dependent activation of antiviral signaling pathways that result in the expression of cytokines, interferons (IFNs) and interferon stimulated genes (ISGs). While these responses are critical for clearing viral infections, they are also deleterious in the context of autoimmunity. The reason for this is that many of the factors induced by RLRs are responsible for activating autoreactive T-cells. Thus, depending on the clinical symptoms, some patients may benefit from inhibition of the RLR/MAVS signaling pathways (e.g. T1D patients) whereas others may benefit from activating these pathways (HCV patients).
Building off of Dr. Kagan's knowledge of the various antiviral pathways that function in mammals, they created a peptide inhibitor of RLR-mediated signal transduction. This inhibitor provides the first molecular tool available to disrupt the functions of this family in human cells, and may also be applicable for manipulating RLR pathways in mouse models of infection/autoimmunity. Moreover, the strategy used to design these RLR inhibitors may be adapted to generate peptides that activate the RLR pathways. Peptide activators of RLR signaling may prove particularly useful in treating chronic viral infections such as Hepatitis C Virus (HCV), as these viruses function to block antiviral signaling pathways.
Peptide therapeutic to treat:
• Rheumatoid arthritis
• Inflammatory bowel disease
• Crohn's disease
• Ulcerative colitis
• Therapeutic to treat inflammatory autoimmune diseases that are caused by inappropriate activation of antiviral responses. No other treatment currently exists to accomplish these goals.
• May improve disease outcomes while reducing the general and long term side effects of TNF-a antagonists.
• This inhibitor provides the first molecular tool available to disrupt the functions of this family in human cells, and may also be applicable for manipulating RLR pathways in mouse models of infection/autoimmunity.
Ferreira AR, et al. Hepatitis C virus NS3-4A inhibits the peroxizomal MAVS-dependent antiviral signaling response. J Cell Mol Med. 2016 Apr;20(4):750-7.
Dixit E, et al. Peroxisomes are signaling platforms for antiviral innate immunity. Cell. 2010 May 14;141(4):668-81.