1. Structure-Activity Studies of Cysteine-Rich α-Conotoxins that Inhibit High-Voltage-Activated Calcium Channels via GABAB Receptor Activation Reveal a Minimal Functional Motif.
- Author
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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., and Clark, Richard J.
- Subjects
CONOTOXIN structure ,PEPTIDE drugs ,ANALGESICS ,CYSTEINE ,CALCIUM channels ,GABA receptors ,VOLTAGE-gated ion channels - Abstract
α-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABA
B receptor (GABAB R) agonists. These α-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α-conotoxins known to inhibit high voltage-activated calcium channels via GABAB R activation. Remarkably, all disulfide isomers of the active α-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. [ABSTRACT FROM AUTHOR]- Published
- 2016
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