Structure–Activity Studies of Cysteine‐Rich α‐Conotoxins that Inhibit High‐Voltage‐Activated Calcium Channels via GABAB Receptor Activation Reveal a Minimal Functional Motif. (7th March 2016)

• Record Type: Journal Article
• 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.
• Is Part Of: Angewandte Chemie. Volume 128:Number 15(2016)
• Page Start: 4770
• Page End: 4774
• Publication Date: 2016-03-07
• Subjects: Analgetika -- Calciumkanäle -- Peptide -- Struktur-Aktivitäts-Beziehungen -- Wirkstoffdesign; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201600297
• Languages: English
• ISSNs: 0044-8249

Abstract

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. Abstract : Verkleinerte Schlangenpeptide : Durch NMR‐Strukturstudien und funktionelle Assays wurde ein funktionelles Minimalepitop eines α‐Conotoxins entdeckt, das über einen GPCR‐vermittelten Mechanismus spannungsaktivierte Calciumströme hemmt. Diese verkleinerten Peptidtoxine sind vielversprechende Leitverbindungen für die Behandlung von Nervenschmerzen.