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Structure–Activity Studies of Cysteine‐Rich α‐Conotoxins that Inhibit High‐Voltage‐Activated Calcium Channels via GABA B Receptor Activation Reveal a Minimal Functional Motif
Author(s) -
Carstens Bodil B.,
Berecki Géza,
Daniel James T.,
Lee Han Siean,
Jackson Kathryn A. V.,
Tae HanShen,
Sadeghi Mahsa,
Castro Joel,
O'Donnell Tracy,
Deiteren Annemie,
Brierley Stuart M.,
Craik David J.,
Adams David J.,
Clark Richard J.
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201600297
Subject(s) - conotoxin , chemistry , acetylcholine receptor , peptide , cysteine , voltage dependent calcium channel , receptor , calmodulin , calcium , nicotinic acetylcholine receptor , homology modeling , biochemistry , biophysics , biology , enzyme , organic chemistry
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 (GABA B 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 GABA B 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.