α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia

Adam C. Kennedy, Alessia Belgi, Benjamin W. Husselbee, David Spanswick, Raymond S. Norton, Andrea J. Robinson

Research output: Contribution to journalReview ArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets-nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABAB) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the N-terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca2+ channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions.

Original languageEnglish
Article number505
Number of pages25
JournalToxins
Volume12
Issue number8
DOIs
Publication statusPublished - 6 Aug 2020

Keywords

  • analgesia
  • conotoxins
  • dicarba peptides
  • disulfide
  • GABAB
  • nAChR.
  • peptides

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