Synthesis and evaluation of disulfide-rich cyclic α-conotoxin [S9A]TxID analogues as novel α3β4 nAChR antagonists

Bioorg Chem. 2021 Jul:112:104875. doi: 10.1016/j.bioorg.2021.104875. Epub 2021 Mar 29.

Abstract

Head-to-tail cyclization is an effective strategy to improve the biological stability of peptides. The α-conotoxin [S9A]TxID is a peptide that inhibits α3β4 nAChR with high activity and selectivity. Herein, we established a method for cyclizing and oxidative folding of [S9A]TxID, and six cyclic analogues of [S9A]TxID were chemically synthesized with various linker lengths. We used the electrophysiology assay to measure activity values of these cyclic analogues, and obtained the most potent analogue c[S9A]TxID-6, which was more stable than native [S9A]TxID against proteinase K.

Keywords: Conotoxins; Cyclization; Oxidative folding; nAChRs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Conotoxins / chemical synthesis
  • Conotoxins / chemistry
  • Conotoxins / pharmacology*
  • Disulfides / chemistry
  • Disulfides / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Nicotinic Antagonists / chemical synthesis
  • Nicotinic Antagonists / chemistry
  • Nicotinic Antagonists / pharmacology*
  • Receptors, Nicotinic / metabolism*
  • Structure-Activity Relationship

Substances

  • Conotoxins
  • Disulfides
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • nicotinic receptor alpha3beta4