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

Abstract

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.

• Authors: Shilong Yang, Yao Xiao, Di Kang, Jie Liu, Yuan Li, Eivind A B Undheim, Julie K Klint, Mingqiang Rong, Ren Lai, Glenn F King
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 43 Pg. 17534-9 (Oct 22 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 24082113 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, physiology)
• Neurons (drug effects, metabolism, physiology)
• Oocytes (drug effects, metabolism, physiology)
• Pain (physiopathology, prevention & control)
• Patch-Clamp Techniques
• Peptides (genetics, metabolism, pharmacology)
• Rats
• Xenopus laevis