PUBLICATION

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

Authors
Giribaldi, J., Haufe, Y., Evans, E.R.J., Amar, M., Durner, A., Schmidt, C., Faucherre, A., Moha Ou Maati, H., Enjalbal, C., Molgó, J., Servent, D., Wilson, D.T., Daly, N.L., Nicke, A., Dutertre, S.
ID
ZDB-PUB-201020-35
Date
2020
Source
Journal of medicinal chemistry   63(21): 12682-12692 (Journal)
Registered Authors
Faucherre, Adele
Keywords
none
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Conotoxins/chemistry
  • Cyclization
  • Larva/drug effects
  • Larva/physiology
  • Ligands*
  • Locomotion/drug effects
  • Mice
  • Muscle Contraction/drug effects
  • Muscles/metabolism*
  • Neurons/metabolism*
  • Nicotinic Antagonists/chemistry*
  • Nicotinic Antagonists/metabolism
  • Nicotinic Antagonists/pharmacology
  • Peptides/chemistry*
  • Peptides/metabolism
  • Peptides/pharmacology
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Nicotinic/chemistry
  • Receptors, Nicotinic/metabolism*
  • Venoms/metabolism*
  • Zebrafish/growth & development
  • Zebrafish/physiology
PubMed
33063995 Full text @ J. Med. Chem.
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 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 (IC50 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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping