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
; 110(43): 17534-9, 2013 Oct 22.
Article
em En
| MEDLINE
| ID: mdl-24082113
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 â¼25 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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Base de dados:
MEDLINE
Assunto principal:
Dor
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Peptídeos
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Venenos de Artrópodes
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Canal de Sódio Disparado por Voltagem NAV1.7
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Analgésicos
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Morfina
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article