Re-engineering the mu-conotoxin SIIIA scaffold

Akondi, Kalyana B., Lewis, Richard J. and Alewood, Paul F. (2013) Re-engineering the mu-conotoxin SIIIA scaffold. Biopolymers, Accepted Article 1-21. doi:10.1002/bip.22368

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Author Akondi, Kalyana B.
Lewis, Richard J.
Alewood, Paul F.
Title Re-engineering the mu-conotoxin SIIIA scaffold
Formatted title
Re-engineering the μ-conotoxin SIIIA scaffold
Journal name Biopolymers   Check publisher's open access policy
ISSN 0006-3525
Publication date 2013-08-05
Sub-type Article (original research)
DOI 10.1002/bip.22368
Open Access Status
Volume Accepted Article
Start page 1
End page 21
Total pages 21
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Formatted abstract
Voltage-gated sodium (Nav) channels are responsible for generation and propagation of action potentials throughout the nervous system. Their malfunction causes several disorders and chronic conditions including neuropathic pain. Potent subtype specific ligands are essential for deciphering the molecular mechanisms of Nav channel function and development of effective therapeutics.μ-Conotoxin SIIIA is a potent mammalian Nav1.2 channel blocker that exhibits analgesic activity in rodents.We undertook to reengineer loop 1through a strategy involving charge alterations and truncations which led to the development of µ-SIIIA mimetics with novel selectivity profiles. A novel [N5K/D15A]SIIIA(3–20) mutantwith enhanced net positive charge showed a dramatic increase in its Nav1.2 potency (IC50 of 0.5 nM vs. 9.6 nM for native SIIIA) though further truncations led to loss of potency. Unexpectedly, it appears that SIIIA loop 1 significantly influences its Nav channel interactions despite loop 2 and 3 residues constituting the pharmacophore. This minimal functional conotoxin scaffold may allow further development of selective NaV blockers.
Keyword μ-Conotoxin
Voltage gated sodium channels
Structure activity relationships
NMR spectroscopy
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Running title: "μ-Conotoxin SIIIA loop 1 re-engineering leads to a highly potent novel scaffold". Accepted manuscript online: 5 AUG 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
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Created: Tue, 10 Dec 2013, 22:32:14 EST by Susan Allen on behalf of Institute for Molecular Bioscience