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

Julien  Giribaldi; Yves  Haufe; Edward R. J.  EvansMuriel  AmarAnna  DurnerCasey  SchmidtAdèle  FaucherreHamid  Moha Ou MaatiChristine  EnjalbalJordi  MolgóDenis  ServentDavid T.  WilsonNorelle L.  DalyAnnette  NickeSébastien  Dutertre

首页> 外文期刊>Journal of Medicinal Chemistry >Backbone Cyclization Turns a Venom Peptide into a Stable and Equipotent Ligand at Both Muscle and Neuronal Nicotinic Receptors

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

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

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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 α-conotoxin CIA, a potent muscle nicotinic acetylcholine receptor (nAChR) blocker with a significantly lower affinity at the neuronal α3β2 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 α3β2 neuronal nAChR subtype (IC_(50) 1.3 nM). Comparison of nuclear magnetic resonance-derived structures revealed some differences that might explain the gain of potency at α3β2 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 α3β2 nAChR subtype to the train-of-four fade.

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《Journal of Medicinal Chemistry》 |2020年第21期|12682-12692|共11页
作者
Julien Giribaldi; Yves Haufe; Edward R. J. EvansMuriel AmarAnna DurnerCasey SchmidtAdèle FaucherreHamid Moha Ou MaatiChristine EnjalbalJordi MolgóDenis ServentDavid T. WilsonNorelle L. DalyAnnette NickeSébastien Dutertre;
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Institut des Biomolécules Max Mousseron, Université de Montpellier, CNRS, ENSCM;

Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich;

Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook UniversityDépartement Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, SIMoSDépartement de Physiologie, Institut de Génomique Fonctionnelle;

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

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