CRMP2 SUMOylation Peptides Modulate Nav1.7 for Chronic Pain
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Solution Overview
Problem
Current pain management for chronic pain in veterans, particularly those with severe injuries, PTSD, and TBI, relies heavily on opioids which are ineffective long-term and come with severe side effects, necessitating the development of alternative non-opioid therapies.
Innovation Solution
Development of peptides that regulate voltage-gated sodium channels isoform 1.7 (Nav1.7) by preventing collapsin response mediator protein 2 (CRMP2)-small ubiquitin-like modifier (SUMO)ylation mediated trafficking, using specific amino acid sequences like GKMDENQ or WDKAVVTGKMDENQFVAV to modulate pain by decreasing Nav1.7 current density at the cell surface.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If opioids are used for chronic pain management, then pain relief is achieved, but severe side effects occur including respiratory depression, sedation, addiction, and tolerance
Solution Approach 1:
The patent uses CRMP2 as an intermediary protein to indirectly regulate Nav1.7 channel function. Instead of directly blocking the sodium channel (which would require high potency and risk side effects), the peptide mediates its effect through CRMP2 SUMOylation, providing a more selective and controllable mechanism for pain relief without activating opioid receptors and their associated side effects
Solution Approach 2:
The patent replaces the mechanical/receptor-binding approach of opioids with a biochemical modification approach. Rather than binding to opioid receptors and triggering downstream effects, the peptide directly modifies CRMP2 through SUMOylation, substituting a more specific biochemical mechanism for the broader pharmacological approach of opioids
2Duration of action of moving object
If opioids are prescribed for long-term pain management, then initial pain control is effective, but tolerance develops and addiction risk increases
Solution Approach 1:
The patent employs a self-regulating mechanism where CRMP2 SUMOylation dynamically controls Nav1.7 channel trafficking. The system inherently adjusts channel expression levels based on cellular needs, providing sustained pain relief without the tolerance development seen with opioids, as the mechanism responds to actual physiological states rather than delivering constant pharmacological pressure
3Reliability
If Nav1.7 current density is decreased at the cell surface, then nociception is reduced and pain is alleviated, but channel function must be sufficiently maintained to avoid neurological deficits
Solution Approach 1:
The patent employs dynamic regulation of Nav1.7 channels through CRMP2 SUMOylation, allowing the system to adjust channel surface expression levels flexibly. This dynamic control enables sufficient reduction of nociceptive signaling for pain relief while maintaining baseline channel function necessary for normal neurological operations, avoiding the static and absolute blockade that would cause deficits
Data Source
AI summary
Disclosed herein are isolated polypeptides capable of preventing collapsin response mediator protein 2 (CRMP2)-small ubiquitin-like modifier (SUMO)ylation mediated trafficking of voltage gated sodium channel 1.7 (Nav1.7) function. In some examples, the disclosed peptides comprise three to twenty amino acids and include the amino acid sequence KMD. Also disclosed are methods of decreasing nociception including administering an effective amount of one or more disclosed peptides to a subject in need thereof, such as a subject experiencing chronic pain.