Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17534-9. doi: 10.1073/pnas.1306285110. Epub 2013 Sep 30.


Loss-of-function mutations in the human voltage-gated sodium channel NaV1.7 result in a congenital indifference to pain. Selective inhibitors of NaV1.7 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 NaV1.7 with an IC50 of ∼25 nM. µ-SLPTX-Ssm6a has more than 150-fold selectivity for NaV1.7 over all other human NaV subtypes, with the exception of NaV1.2, 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 chemical-induced 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 NaV1.7, which might be suitable for treating a wide range of human pain pathologies.

Keywords: chronic pain; drug discovery; peptide therapeutic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Analgesics / pharmacology*
  • Animals
  • Arthropod Venoms / chemistry*
  • Arthropods / chemistry
  • Base Sequence
  • Dose-Response Relationship, Drug
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Molecular Sequence Data
  • Morphine / pharmacology*
  • NAV1.7 Voltage-Gated Sodium Channel / genetics
  • NAV1.7 Voltage-Gated Sodium Channel / physiology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / physiology
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Oocytes / physiology
  • Pain / physiopathology
  • Pain / prevention & control*
  • Patch-Clamp Techniques
  • Peptides / genetics
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Rats
  • Xenopus laevis


  • Analgesics
  • Arthropod Venoms
  • NAV1.7 Voltage-Gated Sodium Channel
  • Peptides
  • SCN9A protein, human
  • Morphine