Oral Presentation 5th Modern Solid Phase Peptide Synthesis Symposium 2015

Dicarba a–conotoxin Vc1.1 analogues with differential selectivity for nicotinic acetylcholine and GABAB receptors  (#10)

Alessia Belgi 1 , James V. Burnley 1 , Bianca V. van Lierop 1 , Samuel D. Robinson 2 , Sandeep Chhabra 2 , Shiva N. Kompella 3 , Peter Bartels 3 , Andrew Hung 3 , Christopher MacRaild 2 , David J. Adams 3 , Raymond S. Norton 2 , Andrea J. Robinson 1
  1. School of Chemistry, Monash University, Clayton, VIC, Australia
  2. Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
  3. Health Innovations Research Institute, RMIT University, Melbourne, VIC, Australia

The a-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 cystine bridges with the connectivity Cys2-Cys8, Cys3-Cys16 (2). It acts both as antagonist on the a9a10 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 recently generated a useful toolkit for the investigation of the possible mode of action of Vc1.1. 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.

We focused on the GABAB selective analogues and expanded our toolkit with the generation of a [2-8]-alkyne Vc1.1 analogue and a [2-8]-alkane Vc1.1 analogue via on-resin ring-closing alkyne metathesis (RCAM), using a solid support approach and tandem RCAM-hydrogenation methodology.

Selected dicarba analogues are currently being assessed in animal models of pain to gain further insights into their analgesic properties. These results will be presented in this paper.

  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., Robinson, S. D., Kompella, S. N., Belgi, A., McArthur, J. R., Hung, A., MacRaild, C., 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, Chemical Biology accepted for publication June 2013.
  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.