General Peptide Information 41 min read January 28, 2026

t-CSM Peptide and NaV1.7 Channel Interaction in Research Models

## Voltage-Gated Sodium Channel NaV1.7 Controls Sensitivity to Pain. NaV1.7 sodium channels are nociceptors controlled by the SCN9A gene. A loss-of-function mutation in gene SCN9A reduces NaV1.7 nociceptor firing, causing CIP (Congenital Insensitivity to Pain) Disease. People born with this mutation are unable to feel most injuries, burns, et al. Conversely, there is a gain-of-function mutation in the SCN9A gene that causes NaV1.7 overactivity. It is associated with heightened pain sens

t-CSM Peptide and NaV1.7 Channel Interaction in Research Models

by Dr. Timothy J.

Voltage-Gated Sodium Channel NaV1.7 Controls Sensitivity to Pain.

NaV1.7 sodium channels are nociceptors controlled by the SCN9A gene. A loss-of-function mutation in gene SCN9A reduces NaV1.7 nociceptor firing, causing CIP (Congenital Insensitivity to Pain) Disease. People born with this mutation are unable to feel most injuries, burns, et al.

Conversely, there is a gain-of-function mutation in the SCN9A gene that causes NaV1.7 overactivity. It is associated with heightened pain sensitivity in neuropathic diseases like erythromelalgia.

Developing a NaV1.7 inhibitor capable of mimicking the insensitivity to pain seen in CIP disease has been a pivotal topic of research since the discovery was established 15 years ago. Finally finding a NaV1.7 blocker that completely avoids modulating all other NaV channels may represent a giant leap toward reducing the sensation of pain without abuse potential or overdose risk.

History of Why a Successful NaV1.7 Inhibitor Hasn’t Been Developed.

The main problem encountered in developing a NaV1.7 inhibitor: the NaV1.7 binding site is shaped too alike the other voltage-gated sodium channels (NaV1.1, 1.2, 1.3, 1.4. 1.5, 1.6, 1.8 or 1.9).

Inhibiting many NaV sodium channels causes intolerable toxicity due to their location in vital organs. NaV1.1-1.3 modulates CNS sodium, NaV1.4 supports muscle function, NaV1.5 controls sodium signaling in the heart, et al. [5] [6]

Direct NaV1.7 antagonists block NaV1.7 more than the other NaVs by a few hundred-fold, triggering off-target effects which limit the dosing scale needed to provide therapeutic benefit. Peptide t-CSM inhibits NaV1.7 sensitivity without binding to NaV1.7 directly. The t-CSM peptide binds to part of an endogenous protein-to-protein interaction (Ubc9-CRMP2) strictly governing NaV1.7 activity and current density. The binding spot on the protein-to-protein interaction that regulates NaV1.7 is unlike the shape of binding spots on all NaVs, providing a way to indirectly modulate NaV1.7 without accidently binding to other NaVs.

t-CSM Peptide’s Protein-to-Protein Interaction Avoids All Other NaV Channels.

No Effect on Other NaV channels: “We demonstrated that elimination of the CRMP2 SUMO modification site (i.e., K374) was sufficient to selectively decrease trafficking and therefore current density of NaV1.7, but not NaV1.1, 1.3, 1.5, 1.6, 1.8 or 1.9.” [1] [8] [9] [10]

No Effect on NaV1.5 (Cardiac NaV Channel): "Compared to the control, the t-CSM peptide did not affect the Nav1.5 sodium current. Identical results were obtained in HEK293-Nav1.5 cells with overexpression of UBC9. These data suggest that UBC9 does not affect the Nav1.5 function through the UBC9-CRMP2 interaction." [2]

No Effect on Calcium Channels: "Dialysis of t-CSM peptide reduced CRMP2 SUMOylation and blocked surface trafficking of NaV1.7 in rat sensory neurons. Fluorescence dye-based imaging in rat sensory neurons demonstrated calcium influx was unaffected. Finally, t-CSM effectively reversed persistent mechanical and thermal hypersensitivity induced by a spinal nerve injury, a model of neuropathic pain." [1]

CRMP2 SUMOylation Target Selectively Regulates NaV1.7 in Humans.

“Because the modification of CRMP2 by SUMOylation to selectively regulate NaV1.7 membrane expression is conserved in human sensory neurons, finding a selective CRMP2 SUMOylation inhibitor would have a high likelihood of clinical translation.” [1]

t-CSM Peptide Prevents NaV1.7 Nociceptor Firing by 80% via Inhibition of CRMP2 SUMOylation.

Direct NaV1.7 antagonists with a 100 fold selectivity over other NaVs can’t reach 80% NaV1.7 inhibition without inducing intolerable side-effects, unlike t-CSM.

Immunofluorescence of NaV1.7 nociceptor firing with and without t-CSM peptide:

“Quantification from 30–45 cells revealed an ~80% reduction in surface NaV1.7.t-CSM related inhibition of CRMP2 SUMOylation prevents NaV1.7 from being targeted to the DRG neuronal membrane.” [1]

Peptide-Induced Pain Relief Without Sedation or Motor Impairment via NaV1.7 Inhibition: Supporting t-CSM’s Selectivity for NaV1.7 in Vivo.

“t-CSM peptide does not induce typical motor deficit or sedation in rats. Thus, using t-CSM in vivo is a safe strategy to target voltage-gated sodium channel NaV1.7 and reverse chronic pain.” [1]

_From:_ _The NaV1.7 sodium channel: from molecule to man_

"Importantly, this peptide reversed nerve injury-induced thermal and mechanical hypersensitivity in the SNI model, supporting the practicality of discovering pain drugs by indirectly targeting NaV1.7 via prevention of CRMP2 SUMOylation." [7]

Peripheral NaV1.7 Nociceptors Firing à Activates DRG Neurons in the CNS where the Excitatory Pain Mediators Glutamate, CGRP, and Substance P are Released.

_From:_ _Mining the Nav1.7 interactome: Opportunities for chronic pain therapeutics._

“t-CSM peptide reverses neuropathic pain by impeding membrane trafficking of NaV1.7 in DRG (Dorsal Root Ganglia) neurons… Because increased NaV1.7 following nerve injury influences the hyperexcitability of sensory neurons, which leads to neuropathic pain, here we tested whether the “decoy peptide” based on the CRMP2 SUMOylation motif would reverse SNI-induced mechanical allodynia. The spared nerve injury model resulted in significant mechanical and thermal hypersensitivity in both male and female rats on day 7 after injury.t-CSM (10μg/5μL) resulted in a significant long-lasting reversal of both thermal and mechanical hypersensitivity ( Fig. 10A, B) that returned to the injury baseline by 24 hrs.” [1]

CRMP2 is Upregulated Concurrently With NaV1.7 in Painful Diseases.

“Nav1.7 is upregulated and promotes ongoing pain in animal models of chronic peripheral inflammation and in peripheral nerve injury. Recently, we reported that ( _i_) NaV1.7 upregulation in chronic neuropathic pain is accompanied by a concomitant increase in CRMP2 SUMOylation, and ( _ii_) loss of CRMP2 SUMOylation, mimicked by expressing a non-SUMOylated mutant of CRMP2 (i.e., CRMP2 K374A) _in vivo_, reversed SNI-induced mechanical allodynia.” [1]

"That CRMP2 is implicated in neuropathic pain can be surmised from recent work which demonstrates that there is a substantial increase in the amount of SUMOylated CRMP2 in sensory neurons and spinal cord dorsal horn in rodent models of chronic pain. This finding is congruent with transcriptomic data demonstrating an enrichment of CRMP2 in nociceptors, further underscoring the importance of targeting CRMP2 under these conditions." [1]

SUMOylation Inhibition Against Ubc9-CRMP2 Interaction is a Non-Toxic Human Target: High Likelihood of Safety.

“All hitherto reported strategies are therapeutically impractical because targeting the SUMOylation machinery – either E1 or E2 – would generate non-selective antagonists of essential biological processes. Our study is the first to design a SUMOylation inhibitor (i.e., the t-CSM peptide) against a singular protein-protein interaction (i.e., Ubc9-CRMP2) that is expected to allosterically modulate NaV1.7 activity.

Importantly, our approach does not target Ubc9, which is the necessary E2 conjugating enzyme for SUMOylation of several protein targets. Ubc9 knockout mice are embryonic lethal, and global decreases in SUMOylation are implicated in cognitive dysfunction. Thus, in an effort to find a selective “druggable” pocket in CRMP2 close to the SUMOylation site on residue K374, we generated an in-silico model of CRMP2 with Ubc9-SUMO.” [1]

_From:_ _Mining the Nav1.7 interactome: Opportunities for chronic pain therapeutics._

Computational Design Strategy of t-CSM Peptide:

“Using a rational design strategy, we identified a heptamer peptide harboring CRMP2’s SUMO motif that disrupted the CRMP2-Ubc9 interaction, inhibited CRMP2 SUMOylation, inhibited NaV1.7 membrane trafficking, and specifically inhibited NaV1.7 sodium influx in sensory neurons.” [7]

“We demonstrate that, of 3 sites predicted to be SUMOylated in CRMP2, only the lysine 374 site is a SUMOylation client. A reduction in NaV1.7 currents was the corollary of the loss of CRMP2 SUMOylation at this site.” [11]

"We generated a computational model of the CRMP2-Ubc9-SUMO interaction. We used the crystal structure of RanGAP1 with Ubc9–SUMO as a structural template, and replaced RanGAP1 with a CRMP2 crystal structure. Based on this computational model, we predicted two major points of contact: Arginine 440 of CRMP2 to Glutamate 132 of Ubc9, and Valine 371 of CRMP2 to Alanine 131 of Ubc9. In this manuscript, we map the interaction of CRMP2 to Ubc9 using [15 N- 1 H] heteronuclear single quantum correlation spectroscopy (HSQC) and demonstrate that several residues that we predicted were indeed perturbed by CRMP2 binding. This result was largely recapitulated using the CRMP2 SUMO decoy, i.e. the t-CSM peptide. Mutating one of the computationally predicted hot spot residues on CRMP2 – Arginine 440 to Alanine – inhibited CRMP2 binding to Ubc9." [7]

t-CSM Peptide Information:

t-CSM is a tat-conjugated cell-penetrating peptide containing the SUMOylation consensus site of CRMP2 fused to the transduction domain of the HIV-1 tat protein. [2]

Sequence: YGRKKRRQRRRGKMDENQ

_• “YGRKKRRQRRR” is the tat-conjugated cell-penetrating component at the start of the sequence._

_• "GKMDENQ" is the CRMP2 component affecting NaV1.7 sodium channels at the end of the sequence._

Effects Last 24 Hours:

“Delivery of t-CSM (10μg/5μL) resulted in a significant long-lasting reversal of both thermal and mechanical hypersensitivity that returned to the injury baseline by 24 hrs.”

References

[1] Inhibition of the Ubc9 E2 SUMO conjugating enzyme–CRMP2 interaction decreases NaV1.7 currents and reverses experimental neuropathic pain

[2] UBC9 regulates cardiac sodium channel Nav1.5 ubiquitination, degradation and sodium current density

[3] Inhibition of Ubc9-Induced CRMP2 SUMOylation Disrupts Glioblastoma Cell Proliferation

[4] The voltage-gated sodium channel Nav1.7 associated with endometrial cancer

[5] Mining the NaV1.7 interactome: Opportunities for chronic pain therapeutics. (CRMP2 - the road not yet taken for NaV1.7)

[6] Voltage-gated sodium channels: (NaV)igating the field to determine their contribution to visceral nociception (Overview of each NaV)

[7] Chemical shift perturbation mapping of the Ubc9-CRMP2 interface identifies a pocket in CRMP2 amenable for allosteric modulation of Nav1.7 channels

[8] CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking

[9] Hierarchical CRMP2 posttranslational modifications control NaV1.7 function

[10] CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking

[11] A single structurally conserved SUMOylation site in CRMP2 controls NaV1. 7 function.

[12] Inhibition of the Ubc9 E2 SUMO-conjugating enzyme-CRMP2 interaction decreases NaV1.7 currents and reverses experimental neuropathic pain

[13] Non-SUMOylated CRMP2 decreases NaV1.7 currents via the endocytic proteins Numb, Nedd4-2 and Eps15

Posted in: General Peptide Information

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