Discovery of a selective Na(V)1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

Yang, Shilong, Xiao, Yao, Kang, Di, Liu, Jie, Li, Yuan, Undheim, Eivind A. B., Klint, Julie K., Rong, Mingqiang, Lai, Ren and King, Glenn F. (2013) Discovery of a selective Na(V)1.7 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, 110 43: 17534-17539. doi:10.1073/pnas.1306285110


Author Yang, Shilong
Xiao, Yao
Kang, Di
Liu, Jie
Li, Yuan
Undheim, Eivind A. B.
Klint, Julie K.
Rong, Mingqiang
Lai, Ren
King, Glenn F.
Title Discovery of a selective Na(V)1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2013-10-01
Year available 2013
Sub-type Article (original research)
DOI 10.1073/pnas.1306285110
Open Access Status Not yet assessed
Volume 110
Issue 43
Start page 17534
End page 17539
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
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 Na V1.7 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 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 NaV1.7, which might be suitable for treating a wide range of human pain pathologies.
Keyword Chronic pain
Drug discovery
Peptide therapeutic
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 30830021
2010CB529800
2011CI139
DP110103129
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
 
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