Structure-Activity Studies of Cysteine-Rich [alpha]-Conotoxins that Inhibit High-Voltage-Activated Calcium Channels via GABAB Receptor Activation Reveal a Minimal Functional Motif

• Published in: Angewandte Chemie International Edition 2016-04, Vol.55 (15), p.4692
• Main Authors: Carstens, Bodil B, Berecki, Géza, Daniel, James T, Lee, Han Siean, Jackson, Kathryn A V, Tae, Han-Shen, Sadeghi, Mahsa, Castro, Joel, O'Donnell, Tracy, Deiteren, Annemie, Brierley, Stuart M, Craik, David J, Adams, David J, Clark, Richard J
• Format: Article
• Language: English
• Subjects: Calcium
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201600297

[alpha]-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several [alpha]-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABAB receptor (GABABR) agonists. These [alpha]-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of [alpha]-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to [alpha]-conotoxins known to inhibit high voltage-activated calcium channels via GABABR activation. Remarkably, all disulfide isomers of the active [alpha]-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs.