BIROn - Birkbeck Institutional Research Online

    The role of disulfide bond replacements in analogues of the Tarantula toxin ProTx-II and their effects on inhibition of the voltage-gated sodium ion channel Nav1.7

    Wright, Z.V.F. and McCarthy, S. and Dickman, R. and Reyes, F.E. and Sanchez-Martinez, S. and Cryar, Adam and Kilford, I. and Hall, A. and Takle, A.K. and Topf, Maya and Gonen, T. and Thalassinos, Konstantinos and Tabor, A.B. (2017) The role of disulfide bond replacements in analogues of the Tarantula toxin ProTx-II and their effects on inhibition of the voltage-gated sodium ion channel Nav1.7. Journal of the American Chemical Society 139 (37), pp. 13063-13075. ISSN 0002-7863.

    [img]
    Preview
    Text
    19732.pdf - Published Version of Record
    Available under License Creative Commons Attribution.

    Download (3MB) | Preview

    Abstract

    Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Nav1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues. We have also investigated the folding and disulfide bridging patterns arising from different methods of oxidation of the linear peptide precursor. Finally, we report the X-ray crystal structure of ProTx-II to atomic resolution; to our knowledge this is the first crystal structure of an ICK spider venom peptide not bound to a substrate.

    Metadata

    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Depositing User: Administrator
    Date Deposited: 18 Sep 2017 13:54
    Last Modified: 02 Aug 2023 17:35
    URI: https://eprints.bbk.ac.uk/id/eprint/19732

    Statistics

    Activity Overview
    6 month trend
    300Downloads
    6 month trend
    238Hits

    Additional statistics are available via IRStats2.

    Archive Staff Only (login required)

    Edit/View Item Edit/View Item