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

J Med Chem. 2020 Nov 12;63(21):12682-12692. doi: 10.1021/acs.jmedchem.0c00957. Epub 2020 Oct 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

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


  • Conotoxins
  • Ligands
  • Nicotinic Antagonists
  • Peptides
  • Receptors, Nicotinic
  • Venoms
  • nicotinic receptor alpha3beta2