De novo protein design targeting voltage-gated sodium channel 1.7 using RFdiffusion and AlphaFold2

Voltage-gated sodium (NaV) channels—pore-forming transmembrane proteins regulating sodium flux across cell membranes—have been genetically and pre-clinically identified as a nociceptive drug target with limited addiction potential. In human sensory neurons, NaV subtypes hNaV1.7, hNaV1.8, and hNaV1.9 have been genetically and pre-clinically identified as promising pain targets. Small molecules typically bind non-selectively to other NaV subtypes and ion channel families, potentially leading to cardiac arrest, paralysis, and sedation.