Titel
Two for the Price of One: Heterobivalent Ligand Design Targeting Two Binding Sites on Voltage-Gated Sodium Channels Slows Ligand Dissociation and Enhances Potency
Autor*in
Alicia Peschel
Institute for Molecular Bioscience, The University of Queensland
... show all
Abstract
Voltage-gated sodium (NaV) channels are pore-forming transmembrane proteins that play essential roles in excitable cells, and they are key targets for antiepileptic, antiarrhythmic, and analgesic drugs. We implemented a heterobivalent design strategy to modulate the potency, selectivity, and binding kinetics of NaV channel ligands. We conjugated μ-conotoxin KIIIA, which occludes the pore of the NaV channels, to an analogue of huwentoxin-IV, a spider-venom peptide that allosterically modulates channel gating. Bioorthogonal hydrazide and copper-assisted azide–alkyne cycloaddition conjugation chemistries were employed to generate heterobivalent ligands using polyethylene glycol linkers spanning 40–120 Å. The ligand with an 80 Å linker had the most pronounced bivalent effects, with a significantly slower dissociation rate and 4–24-fold higher potency compared to those of the monovalent peptides for the human NaV1.4 channel. This study highlights the power of heterobivalent ligand design and expands the repertoire of pharmacological probes for exploring the function of NaV channels.
Stichwort
DissociationKineticsLigandsMonomersPeptides and proteins
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
phaidra.univie.ac.at/o:2096308
Erschienen in
Titel
Journal of Medicinal Chemistry
Band
63
Ausgabe
21
ISSN
0022-2623
Erscheinungsdatum
2020
Seitenanfang
12773
Seitenende
12785
Publication
American Chemical Society (ACS)
Fördergeber
Europäische Union (alle Programme) — 714366
Erscheinungsdatum
2020
Zugänglichkeit
Rechte
Rechteangabe
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