Novel Small Molecule Inhibitors of CRMP2 SUMOylation That Regulate Nav1.7 to Treat Chronic PainTechnology #ua17-089
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- Reena Chawla Postdoctoral Research Associate I, BIO5 Institute
- Vijay Gokhale Senior Research Scientist, BIO5
- Rajesh Khanna Associate Professor, Pharmacology
- May Khanna Assistant Professor, Pharmacology
- Managed By
- Lisa Lin Licensing Manager (520) 626-6969
Title: Novel Small Molecule Inhibitors of CRMP2 SUMOylation that Regulate Nav1.7 to Treat Chronic Pain
Background: Approximately 1.5 billion people worldwide suffer from chronic pain. Opioids are currently the primary treatment option for chronic pain caused by severe trauma. However, opioids are encumbered with various side effects include constipation, nausea, respiratory depression, drowsiness, and addiction. Novel pain drug targets are necessary to provide multiple therapeutic options to patients to avoid addictions and tolerance to the drugs.
Invention: The invention describes compounds inhibiting CRMP2 SUMOylation, a post-translational modification that adds a small ubiquitin-like modifier (SUMO) tag, for indirect regulation of the voltage-gated sodium channel Nav1.7 channel. Nav1.7 is expressed in the peripheral nervous system within ganglia that are related to nociceptive pain. The Nav1.7 channel modulates current thresholds required to trigger action potentials, which are responsible for generating the sensations of pain. The decrease in SUMOylation of CMRP2 decreases Nav1.7 trafficking to the cell surface, resulting in pain reduction. The inventors at the University of Arizona have computationally and experimentally screened a chemical library and found several candidate compounds that decrease Nav1.7 current density on the surface and reduce pain in animal models. These compounds have never been used in pain indications before. They are also developing derivatives based on a structure-function analysis of these candidates.
• Use of these candidate compounds in pain reduction.
• Novel drug compounds for treating itchiness.
• No motor impairment or sedation.
• Higher potency and equivalent efficacy to opioids.
• Reduced potential for rewarding effect and reduced potential for abuse compared to opioids.
Dustrude ET, Wilson SM, Ju W, Xiao Y, Khanna R. CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking. J Biol Chem. 2013 Aug 23;288(34):24316-31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750134/
Erik T. Dustrudea, Aubin Moutala, Xiaofang Yanga, Yuying Wanga, May Khanna, and Rajesh Khanna. Hierarchical CRMP2 posttranslational modifications control Nav1.7 function. Proc Natl Acad Sci USA. 2016 Dec 27; 111(52): E8443-E8452. https://www.ncbi.nlm.nih.gov/pubmed/27940916