Interactions of disulfide‐deficient selenocysteine analogs of μ‐conotoxin BuIIIB with the α‐subunit of the voltage‐gated sodium channel subtype 1.3

• DOI: 10.1111/febs.12835
• Publication Date: 2014-05-11T12:40:44Z
• Authors: Brad R. Green; Min‐Min Zhang; Sandeep Chhabra; Samuel D. Robinson; Michael J. Wilson; Addison Redding; Baldomero M. Olivera; Doju Yoshikami; Grzegorz Bulaj; Raymond S. Norton
• Keywords: Conotoxin

Inhibitors of the α‐subunit voltage‐gated sodium channel subtype 1.3 (Na V 1.3) are interest as pharmacological tools for study neuropathic pain associated with spinal cord injury and have potential therapeutic applications. The recently described μ‐conotoxin Bu IIIB (μ‐Bu ) from Conus bullatus was shown to block Na submicromolar potency ( K d = 0.2 μ m ), making it one most potent peptidic inhibitors this date. However, oxidative folding μ‐Bu results in numerous isoforms, difficult obtain sufficient quantities active form peptide detailed structure–activity studies. In present study, we report synthesis characterization analogs incorporating a disulfide‐deficient, diselenide‐containing scaffold designed simplify facilitate studies directed at identifying amino acid residues involved blockade. Our indicate that, similar other μ‐conotoxins, C‐terminal (Trp16, Arg18 His20) crucial 1 At N‐terminus, replacement Glu3 by Ala resulted an analog increased 0.07 implicating position site modification and/or selectivity. Further examination showed that negative charge, through γ‐carboxyglutamate replacement, decreased 0.33 whereas positively‐charged 2,4‐diamonobutyric 0.036 ). These provide foundation design ‐based against 1.3.