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

Journal Article


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.

UOW Authors


  •   Wan, Jingjing (external author)
  •   Huang, Johnny X. (external author)
  •   Vetter, Irina (external author)
  •   Mobli, Mehdi (external author)
  •   Lawson, Joshua (external author)
  •   Tae, Han Shen
  •   Abraham, Nikita (external author)
  •   Paul, Blessy (external author)
  •   Cooper, Matthew (external author)
  •   Adams, David
  •   Lewis, Richard J. (external author)
  •   Alewood, Paul F. (external author)

Publication Date


  • 2015

Citation


  • Wan, J., Huang, J. X., Vetter, I., Mobli, M., Lawson, J., Tae, H., Abraham, N., Paul, B., Cooper, M., Adams, D. J., Lewis, R. & Alewood, P. 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.

Scopus Eid


  • 2-s2.0-84924678243

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/589

Number Of Pages


  • 3

Start Page


  • 3209

End Page


  • 3212

Volume


  • 137

Issue


  • 9

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.

UOW Authors


  •   Wan, Jingjing (external author)
  •   Huang, Johnny X. (external author)
  •   Vetter, Irina (external author)
  •   Mobli, Mehdi (external author)
  •   Lawson, Joshua (external author)
  •   Tae, Han Shen
  •   Abraham, Nikita (external author)
  •   Paul, Blessy (external author)
  •   Cooper, Matthew (external author)
  •   Adams, David
  •   Lewis, Richard J. (external author)
  •   Alewood, Paul F. (external author)

Publication Date


  • 2015

Citation


  • Wan, J., Huang, J. X., Vetter, I., Mobli, M., Lawson, J., Tae, H., Abraham, N., Paul, B., Cooper, M., Adams, D. J., Lewis, R. & Alewood, P. 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.

Scopus Eid


  • 2-s2.0-84924678243

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/589

Number Of Pages


  • 3

Start Page


  • 3209

End Page


  • 3212

Volume


  • 137

Issue


  • 9