Nav1.8
Nav 1.8
The voltage-gated sodium channel 1.8 (Nav1.8) is a transmembrane protein that regulates sodium transport across the cell membrane in response to electrical stimuli playing a crucial role in the generation and conduction of action potentials in neuronal cells.
Nav1.8 has emerged as a promising target for pain therapies due to its selective expression in peripheral sensory neurons involved in pain perception. This differentiates Nav1.8 from other Nav subtypes implicated in pain modulation such as Nav1.7 and Nav1.9, which are also expressed in the central nervous system (CNS). Nav1.8’s selective expression makes it an attractive target for developing analgesics that avoid CNS side effects, such as addictive potential, commonly associated with opioid pain medications.
The discovery of Nav1.8-selective blockers has proven challenging due to the high sequence homology with other Nav subtypes, making it difficult to achieve satisfactory selectivity. Most of the drug candidates (e.g., VX-150 and PF-06305591) failed phase II clinical trials mostly due to issues with efficacy or selectivity.
Recently, Vertex Pharmaceutical announced the FDA approval of suzetrigine, a first-in-class Nav1.8 inhibitor, marking a significant milestone in pain treatment. This is the first new class of non-opioid pain medicine approved in over 20 years. The pharmacology and mechanism of action of this drug were recently described, paving the way for the development of pain therapies with an alternative mode of action (ref).
Key insights in the novel mechanism of action
Below is the summary of key structural insights of the mechanism of action of the new drug:
In vitro analysis showed that suzetrigine inhibits Nav1.8 by binding the protein’s second voltage sensing domain (VSD2), stabilizing the closed resting state. This novel binding site and mode of action are distinct from previously characterized, non-selective Nav1.8 ligands (such as A-803467), which bind the pore channel region and block the sodium flux across the protein. Since this domain is located away from the pore, this represents an unprecedented allosteric mechanism.
Suzetrigine showed very high selectivity over all other Nav subtypes and 180 other targets. One contributing factor is that the specific region that the drug binds, contains a sequence unique to Nav1.8 (KKGS) located in the extracellular loop of the S3-S4 segment of the VSD2 domain, which is not observed in other Nav subtypes.
In vitro and in vivo safety assessment studies showed no significant side effects of the drug, in particular on the CNS and cardiovascular system. Phase 3 trials demonstrated no evidence of addictive potential upon administration of suzetrigine, while it proved efficacious in reducing moderate to severe acute pain.
While it is not yet fully understood how suzetrigine binding to VSD2 stabilizes the protein's closed state, it’s likely that the binding prevents the movement of this domain, thereby inhibiting the channel's opening. Given the limited structural knowledge of this target available in the public domain, further structural studies elucidating the molecular basis of inhibition would be highly beneficial. Such studies could pave the way for the development of other innovative modulators for this important, non-opioid pain drug target.
Reference:
Osteen JD, Immani S, Tapley TL, Indersmitten T, Hurst NW, Healey T, Aertgeerts K, Negulescu PA, Lechner SM. Pharmacology and Mechanism of Action of Suzetrigine, a Potent and Selective NaV1.8 Pain Signal Inhibitor for the Treatment of Moderate to Severe Pain. Pain Ther. 2025 Jan 8. doi: 10.1007/s40122-024-00697-0. Epub ahead of print. PMID: 39775738.