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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 Na v 1.7

Journal Article · · Journal of the American Chemical Society
DOI:https://doi.org/10.1021/jacs.7b06506· OSTI ID:1395186
 [1];  [2];  [2];  [3];  [3];  [4];  [5];  [5];  [5];  [6];  [3];  [4];  [2]
  1. Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom
  2. Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom
  3. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, United States
  4. Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, United Kingdom, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London WC1E 7HX, United Kingdom
  5. European Knowledge Centre, Eisai Limited, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, United Kingdom
  6. Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London WC1E 7HX, United Kingdom
+ Show Author Affiliations
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.
Research Organization:
Univ. College London (UCL) (United Kingdom)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1395186
Alternate ID(s):
OSTI ID: 1508270
OSTI ID: 1508271
Journal Information:
Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 37 Vol. 139; ISSN 0002-7863
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English

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