We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Structure-Activity Studies of Cysteine-Rich α-Conotoxins that Inhibit High-Voltage-Activated Calcium Channels via GABA<sub>B</sub> Receptor Activation Reveal a Minimal Functional Motif.
- 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.
- 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 GABAB receptor (GABABR) 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 GABABR 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.
- Subjects
CONOTOXIN structure; DRUG design; STRUCTURE-activity relationships; CYSTEINE; CALCIUM channels; GABA receptors; PEPTIDE drugs
- Publication
Angewandte Chemie International Edition, 2016, Vol 55, Issue 15, p4692
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201600297