title: α-Conotoxin dendrimers have enhanced potency and selectivity for homomeric nicotinic acetylcholine receptors.
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.
authors.affiliation: Institute of Molecular Bioscience, The University of Queensland , St Lucia Queensland 4072, Australia.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wan
authors.forename: Johnny X
authors.initials: JX
authors.lastname: Huang
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mobli
authors.forename: Joshua
authors.initials: J
authors.lastname: Lawson
authors.forename: Han-Shen
authors.initials: HS
authors.lastname: Tae
authors.forename: Nikita
authors.initials: N
authors.lastname: Abraham
authors.forename: Blessy
authors.initials: B
authors.lastname: Paul
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
mesh_terms: D001665:Binding Sites; D002460:Cell Line / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D002942:Circular Dichroism; D020916:Conotoxins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D061565:Cycloaddition Reaction; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D020349:Surface Plasmon Resonance; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020916:Conotoxins; D050091:Dendrimers; D064569:alpha7 Nicotinic Acetylcholine Receptor; C087686:alpha-conotoxin ImI