Rapid Fire & Poster Presentation 7th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2019

Novel dicarba α–conotoxin Vc1.1 analogues with selectivity for the GABAB receptor (#22)

Alessia Belgi 1 , Fei Yue Zhao 2 , David Spanswick 2 3 , Andrea Robinson 1
  1. School of Chemistry, Monash University, Clayton, VIC, Australia
  2. NeuroSolutions Ltd, University of Warwick, Coventry, United Kingdom
  3. Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia

The α-conotoxin Vc1.1 is a peptide extracted from the venom of the cone snail Conus victoriae (1). Specifically, Vc1.1 is a 16-residue peptide with an amidated C-terminus and four cysteine residues which form two disulfide bridges with the connectivity Cys2-Cys8, Cys3-Cys16 (2). It acts both as antagonist on the α9α10 subtype of nicotinic acetylcholine receptors (nAChRs) and as an agonist on γ–aminobutyric acid (GABAB) G protein-coupled receptors showing a potent analgesic activity (3, 4). The mechanism by which Vc1.1 exerts its analgesic effect has not been fully elucidated yet.

We used olefin metathesis to replace each of the disulfide bridges with dicarba bridges. The generated Vc1.1 dicarba analogues were found to be selectively active on one receptor over the other depending on which disulfide bridge was replaced. The Cys2-Cys8 replacement generated analogues only active on GABAB receptor whereas the Cys3-Cys16 replacement generated analogues only active on nAChRs.(3)

We focused on the GABAB selective analogues and generated a [2-8]-alkyne Vc1.1 analogue and a [2-8]-alkane Vc1.1 analogue via on-resin ring-closing alkyne metathesis (RCAM) and tandem RCAM-hydrogenation.

A second generation of dicarba analogues was recently produced which showed enhanced activity on GABAB receptor and could be used to further the understanding of the mode of action of Vc1.1 in analgesia.

This talk will discuss the synthesis and the in vitro and in vivo assessment of these novel dicarba analogues of Vc1.1.

  1. Sandall, D. W., Satkunanathan, N., Keays, D. A., Polidano, M. A., Liping, X., Pham, V., Down, J. G., Khalil, Z., Livett, B. G., and Gayler, K. R. (2003) A Novel α-Conotoxin Identified by Gene Sequencing Is Active in Suppressing the Vascular Response to Selective Stimulation of Sensory Nerves in Vivo, Biochemistry 42, 6904-6911.
  2. Clark, R. J., Fischer, H., Nevin, S. T., Adams, D. J., and Craik, D. J. (2006) The Synthesis, Structural Characterization, and Receptor Specificity of the α-Conotoxin Vc1.1, J. Biol. Chem. 281, 23254-23263.
  3. van Lierop, B. J., Robinson, S. D., Kompella, S. N., Belgi, A., McArthur, J. R., Hung, A., MacRaild, C. A., Adams, D. J., Norton, R. S., and Robinson, A. J. (2013) Dicarba α-Conotoxin Vc1.1 Analogues with Differential Selectivity for Nicotinic Acetylcholine and GABAB Receptors, ACS Chemical Biology 8, 1815-1821.
  4. Yu, R., Kompella, S. N., Adams, D. J., Craik, D. J., and Kaas, Q. (2013) Determination of the α-Conotoxin Vc1.1 Binding Site on the α9α10 Nicotinic Acetylcholine Receptor, J. Med. Chem. 56, 3557-3567.