α-Conotoxin dendrimers have enhanced potency and selectivity for homomeric nicotinic acetylcholine receptors

Wan, Jingjing, Huang, Johnny X., Vetter, Irina, Mobli, Mehdi, Lawson, Joshua, Tae, Han-Shen, Abraham, Nikita, Paul, Blessy, Cooper, Matthew A., Adams, David J., Lewis, Richard J. and Alewood, Paul F. (2015) α-Conotoxin dendrimers have enhanced potency and selectivity for homomeric nicotinic acetylcholine receptors. Journal of the American Chemical Society, 137 9: 3209-3212. doi:10.1021/jacs.5b00244


Author Wan, Jingjing
Huang, Johnny X.
Vetter, Irina
Mobli, Mehdi
Lawson, Joshua
Tae, Han-Shen
Abraham, Nikita
Paul, Blessy
Cooper, Matthew A.
Adams, David J.
Lewis, Richard J.
Alewood, Paul F.
Title α-Conotoxin dendrimers have enhanced potency and selectivity for homomeric nicotinic acetylcholine receptors
Journal name Journal of the American Chemical Society   Check publisher's open access policy
ISSN 1520-5126
0002-7863
Publication date 2015-01-01
Sub-type Article (original research)
DOI 10.1021/jacs.5b00244
Volume 137
Issue 9
Start page 3209
End page 3212
Total pages 4
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2016
Language eng
Abstract Covalently attached peptide dendrimers can enhance binding affinity and functional activity. Homogenous di- and tetravalent dendrimers incorporating the α7-nicotinic receptor blocker α-conotoxin ImI (α-ImI) with polyethylene glycol spacers were designed and synthesized via a copper-catalyzed azide-alkyne cycloaddition of azide-modified α-ImI to an alkyne-modified polylysine dendron. NMR and CD structural analysis confirmed that each α-ImI moiety in the dendrimers had the same 3D structure as native α-ImI. The binding of the α-ImI dendrimers to binding protein Ac-AChBP was measured by surface plasmon resonance and revealed enhanced affinity. Quantitative electrophysiology showed that α-ImI dendrimers had ∼100-fold enhanced potency at hα7 nAChRs (IC50 = 4 nM) compared to native α-ImI (IC50 = 440 nM). In contrast, no significant potency enhancement was observed at heteromeric hα3β2 and hα9α10 nAChRs. These findings indicate that multimeric ligands can significantly enhance conotoxin potency and selectivity at homomeric nicotinic ion channels.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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