41: Novel Short Lipidated Peptidomimetic Targeting Nav1.8 Reduces Neuropathic Pain-like Behaviors

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Pharmacological interventions

Background and Aims: Neuropathic pain remains a major therapeutic challenge, with over 50% of patients responding inadequately to existing therapies (gabapentinoids, SNRIs, TCAs). Dorsal root ganglion (DRG) neurons serve as primary sites for injury-induced plasticity underlying painful peripheral pathophysiologies. Voltage-gated sodium channels (VGSC), specifically Nav1.8, are highly expressed in DRGs and are critical for nociception. Recently, suzetrigine, a Nav1.8-specifc blocker, received FDA approval for acute pain, validating Nav1.8 as a viable clinical target for pain. However, targeting Nav1.8 for neuropathic pain remains unclear. Therefore we aimed to develop a non-opioid analgesic targeting Nav1.8 for the treatment of chronic neuropathies.

Methods: We opted to target membrane delimited protein-protein interactions between scaffold proteins and Nav1.8. Therefore, we developed a short lipidated peptidomimetic (SLiP) based on a unique protein-binding domain found in Nav1.8. This SLiP (MM-3000), a tool compound, was designed to interrupt Nav1.8 binding to scaffold proteins at neuronal membrane. MM-3000 provided proof-of-concept and was further modified resulting in MM-3001, a SLiP with superior pharmacokinetic parameters. Techniques used include calcium imaging, whole cell patch clamp, and behavioral studies. In vitro experiments were conducted using mouse embryonic DRG neurons, human DRG neurons, and in vivo experiments were conducted in rodents and minipigs.

Results: In electrophysiology experiments, MM-3000 reduced total sodium current selectively in hyperexcitable neurons. This reduction was due to a specific reduction in Nav1.8-mediated sodium current. The action potentials of eDRG neurons that received MM-3000 were shorter and narrower, indicative of loss of Nav1.8. We also observed a significant reduction in action potential firing and increase in rheobase, while there was no observable change in resting membrane potential or action potential threshold. When tested in vivo, systemic administration of MM-3000 and MM-3001 produced a significant, dose-dependent reduction in neuropathic pain-like behaviors in multiple preclinical models.

Conclusions: These data suggest that Nav1.8-scaffold protein complexes play a critical role in regulating the intrinsic excitability of DRG neurons. By disrupting Nav1.8 binding to scaffold proteins with MM-3000 and MM-3001, we precipitated profound reductions in metrics associated with pain in vitro and in vivo. And by leveraging our SLiP platform, we have created a long-lasting preclinical drug-like molecule that highlights a new target for treating painful chronic neuropathies.

References: 1. Woolf, C. J. What is this thing called pain? J Clin Invest 120, 3742–3744 (2010).
2. Loeser, J. D. & Melzack, R. Pain: an overview. The Lancet 353, 1607–1609 (1999).
3. Ashburn, M. A. & Staats, P. S. Management of chronic pain. The Lancet 353, 1865–1869 (1999).
4. Campbell, J. N. & Meyer, R. A. Mechanisms of Neuropathic Pain. Neuron 52, 77–92 (2006).
5. Finnerup, N. B., Kuner, R. & Jensen, T. S. Neuropathic Pain: From Mechanisms to Treatment. Physiological Reviews 101, 259–301 (2021).
6. Huynh, V. et al. Supraspinal nociceptive networks in neuropathic pain after spinal cord injury. Hum Brain Mapp 42, 3733–3749 (2021).
7. Alsaloum, M., Vasylyev, D. & Waxman, S. G. Targeting sodium channels — challenges for acute pain and the leap to chronic pain. Nat Rev Neurol 21, 567–576 (2025).
8. Zeng, X., Powell, R. & Woolf, C. J. Mechanism-based nonopioid analgesic targets. J Clin Invest 135, e191346.
9. Cavalli, E., Mammana, S., Nicoletti, F., Bramanti, P. & Mazzon, E. The neuropathic pain: An overview of the current treatment and future therapeutic approaches. Int J Immunopathol Pharmacol 33, 2058738419838383 (2019).

Presenting Author: Rasheen Powell
Submitting Author: Rasheen Powell

Senior Author: Rasheen Powell

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• John Strumbos: Ph.D. - Mimetic Medicines
• Clifford Woolf: M.B., B.Ch., Ph.D. - Boston Children's Hospital