Loss-of-function mutations in the human voltage-gated sodium channel Na V 1.7 result in a congenital indifference to pain. Selective inhibitors of Na V 1.7 are therefore likely to be powerful analgesics for treating a broad range of pain conditions. Herein we describe the identification of μ-SLPTX-Ssm6a, a unique 46-residue peptide from centipede venom that potently inhibits Na V 1.7 with an IC 50 of ∼25 nM. μ-SLPTX-Ssm6a has more than 150-fold selectivity for Na V 1.7 over all other human Na V subtypes, with the exception of Na V 1.2, for which the selectivity is 32-fold. μ-SLPTX-Ssm6a contains three disulfide bonds with a unique connectivity pattern, and it has no significant sequence homology with any previously characterized peptide or protein. μ-SLPTX-Ssm6a proved to be a more potent analgesic than morphine in a rodent model of chemicalinduced pain, and it was equipotent with morphine in rodent models of thermal and acid-induced pain. This study establishes μ-SPTX-Ssm6a as a promising lead molecule for the development of novel analgesics targeting Na V 1.7, which might be suitable for treating a wide range of human pain pathologies.chronic pain | drug discovery | peptide therapeutic

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