Premium
Re‐engineering the μ‐conotoxin SIIIA scaffold
Author(s) -
Akondi K. B.,
Lewis R. J.,
Alewood P. F.
Publication year - 2014
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22368
Subject(s) - pharmacophore , sodium channel , chemistry , conotoxin , potency , mutant , sodium channel blocker , ion channel , scaffold , biophysics , in vitro , pharmacology , sodium , stereochemistry , receptor , peptide , biochemistry , gene , biology , biomedical engineering , medicine , organic chemistry
Voltage‐gated sodium (Na v ) 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 Na v channel function and development of effective therapeutics. µ‐Conotoxin SIIIA is a potent mammalian Na v 1.2 channel blocker that exhibits analgesic activity in rodents. We undertook to reengineer loop 1 through 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) mutant with enhanced net positive charge showed a dramatic increase in its Na v 1.2 potency (IC 50 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 Na v channel interactions despite loop 2 and 3 residues constituting the pharmacophore. This minimal functional conotoxin scaffold may allow further development of selective Na V blockers. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 347–354, 2014.