Drug discovery targeting Na_v1.8: Structural insights and therapeutic potential

Voltage-gated sodium (Na_v) channels are crucial in transmitting action potentials in neurons. The tetrodotoxin-resistant subtype Na_v1.8 is predominantly expressed in the peripheral nervous system, offering a unique opportunity to design selective inhibitors for pain relief. A number of compounds have been reported to specifically block Na_v1.8. Among these, VX-548 is already in regulatory review for the treatment of moderate-to-severe acute pain and holds the promise to be the first non-opioid pain killer over the past twenty years. Recent structural studies using cryogenic electron microscopy (cryo-EM) and structure-based predictive modeling have provided unprecedented insights into the structural pharmacology of Na_v1.8. In this review, we summarize the latest developments in Na_v1.8-selective inhibitors, focusing on the druggable sites and mechanisms that confer subtype specificity. These structural insights highlight the potential for Na_v1.8 inhibitors to deliver non-addictive pain management, thus illuminating the avenue to next-generation analgesic development.