Backbone Cyclization Turns a Venom Peptide into a Stable and Equipotent Ligand at Both Muscle and Neuronal Nicotinic Receptors

Giribaldi, Julien; Haufe, Yves; Evans, Edward R. J.; Amar, Muriel; Durner, Anna; Schmidt, Casey; Faucherre, Adele; Maati, Hamid Moha Ou; Enjalbal, Christine; Molgo, Jordi; Servent, Denis; Wilson, David T.; Daly, Norelle L.; Nicke, Annette und Dutertre, Sebastien (2020): Backbone Cyclization Turns a Venom Peptide into a Stable and Equipotent Ligand at Both Muscle and Neuronal Nicotinic Receptors. In: Journal of Medicinal Chemistry, Bd. 63, Nr. 21: S. 12682-12692

Abstract

Venom peptides are promising drug leads, but their therapeutic use is often limited by stability and bioavailability issues. In this study, we designed cyclic analogues of alpha-conotoxin CIA, a potent muscle nicotinic acetylcholine receptor (nAChR) blocker with a significantly lower affinity at the neuronal alpha 3 beta 2 subtype. Remarkably, all analogues retained the low nanomolar activity of native CIA toward muscle-type nAChRs but showed greatly improved resistance to degradation in human serum and, surprisingly, displayed up to 52-fold higher potency for the alpha 3 beta 2 neuronal nAChR subtype (IC50 1.3 nM). Comparison of nuclear magnetic resonance-derived structures revealed some differences that might explain the gain of potency at alpha 3 beta 2 nAChRs. All peptides were highly paralytic when injected into adult zebrafish and bath-applied to zebrafish larvae, suggesting barrier-crossing capabilities and efficient uptake. Finally, these cyclic CIA analogues were shown to be unique pharmacological tools to investigate the contribution of the presynaptic alpha 3 beta 2 nAChR subtype to the train-of-four fade.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0022-2623
• Sprache: Englisch