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Title: 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

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.

Authors:
 [1];  [2];  [2];  [3];  [3];  [4];  [5];  [5];  [5];  [6];  [3];  [4]; ORCiD logo [2]
+ Show Author Affiliations
  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
Publication Date:
Research Org.:
Univ. College London (UCL) (United Kingdom)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1395186
Alternate Identifier(s):
OSTI ID: 1508270; OSTI ID: 1508271
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Published Article
Journal Name:
Journal of the American Chemical Society
Additional Journal Information:
Journal Name: Journal of the American Chemical Society Journal Volume: 139 Journal Issue: 37; Journal ID: ISSN 0002-7863
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Wright, Zoë V. F., McCarthy, Stephen, Dickman, Rachael, Reyes, Francis E., Sanchez-Martinez, Silvia, Cryar, Adam, Kilford, Ian, Hall, Adrian, Takle, Andrew K., Topf, Maya, Gonen, Tamir, Thalassinos, Konstantinos, and Tabor, Alethea B. 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. United States: N. p., 2017. Web. doi:10.1021/jacs.7b06506.
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Wright, Zoë V. F., McCarthy, Stephen, Dickman, Rachael, Reyes, Francis E., Sanchez-Martinez, Silvia, Cryar, Adam, Kilford, Ian, Hall, Adrian, Takle, Andrew K., Topf, Maya, Gonen, Tamir, Thalassinos, Konstantinos, & Tabor, Alethea B. 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. United States. https://doi.org/10.1021/jacs.7b06506
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Wright, Zoë V. F., McCarthy, Stephen, Dickman, Rachael, Reyes, Francis E., Sanchez-Martinez, Silvia, Cryar, Adam, Kilford, Ian, Hall, Adrian, Takle, Andrew K., Topf, Maya, Gonen, Tamir, Thalassinos, Konstantinos, and Tabor, Alethea B. Thu . "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". United States. https://doi.org/10.1021/jacs.7b06506.
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@article{osti_1395186,
title = {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},
author = {Wright, Zoë V. F. and McCarthy, Stephen and Dickman, Rachael and Reyes, Francis E. and Sanchez-Martinez, Silvia and Cryar, Adam and Kilford, Ian and Hall, Adrian and Takle, Andrew K. and Topf, Maya and Gonen, Tamir and Thalassinos, Konstantinos and Tabor, Alethea B.},
abstractNote = {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.},
doi = {10.1021/jacs.7b06506},
journal = {Journal of the American Chemical Society},
number = 37,
volume = 139,
place = {United States},
year = {Thu Sep 07 00:00:00 EDT 2017},
month = {Thu Sep 07 00:00:00 EDT 2017}
}
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https://doi.org/10.1021/jacs.7b06506
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