Structure-Activity Studies of Cysteine-Rich a-Conotoxins that Inhibit High-Voltage-Activated Calcium Channels via GABAB Receptor Activation Reveal a Minimal Functional Motif

Bodil Carstens, Geza Berecki, James Daniel, Han Lee, Kathryn Jackson, Han-Shen Tae, Mahsa Sadeghi, Joel Castro, Tracy O'Donnell, Annemie Deiteren, Stuart Brierley, David Craik, David Adams, Richard Clark

    Research output: Contribution to journalArticle

    36 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)4692-4696
    Number of pages5
    JournalAngewandte Chemie-International Edition
    Volume55
    Issue number15
    DOIs
    Publication statusPublished - 2016

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