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Type: Journal article
Title: Structure-activity studies of cysteine-Rich α-conotoxins that inhibit high-voltage-activated calcium channels via GABAB receptor activation reveal a minimal functional motif
Other Titles: Structure-activity studies of cysteine-Rich alpha-conotoxins that inhibit high-voltage-activated calcium channels via GABAB receptor activation reveal a minimal functional motif
Author: Carstens, B.
Berecki, G.
Daniel, J.
Lee, H.
Jackson, K.
Tae, H.
Sadeghi, M.
Castro, J.
O'Donnell, T.
Deiteren, A.
Brierley, S.
Craik, D.
Adams, D.
Clark, R.
Citation: Angewandte Chemie International Edition, 2016; 55(15):4692-4696
Publisher: Wiley
Issue Date: 2016
ISSN: 1433-7851
Statement of
Bodil B. Carstens, Géza Berecki, James T. Daniel, Han Siean Lee, Kathryn A. V. Jackson, Han- Shen Tae, Mahsa Sadeghi, Joel Castro, Tracy O'Donnell, Annemie Deiteren, Stuart M. Brierley, David J. Craik, David J. Adams, and Richard J. Clark
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 (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.
Keywords: analgesics; calcium channel; drug design; peptides; structure-activity relationships
Description: Version of Record online: 7 MAR 2016
Rights: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.201600297
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