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

Proceedings of the National Academy of Sciences of the United States of America (2013-10-02)
Shilong Yang, Yao Xiao, Di Kang, Jie Liu, Yuan Li, Eivind A B Undheim, Julie K Klint, Mingqiang Rong, Ren Lai, Glenn F King
RÉSUMÉ

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.

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Description du produit

Supelco
Morphine solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Sigma-Aldrich
Morphine sulfate salt pentahydrate
Supelco
Morphine solution, 100 μg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Supelco
Morphine sulfate salt solution, 1.0 mg/mL in methanol, drug standard