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:
-
- Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom
- Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom
- Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, United States
- 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
- European Knowledge Centre, Eisai Limited, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, United Kingdom
- 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.
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
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.
@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}
}
https://doi.org/10.1021/jacs.7b06506
Web of Science
Works referenced in this record:
Characterization of Phosphorylated Peptides Using Traveling Wave-Based and Drift Cell Ion Mobility Mass Spectrometry
journal, January 2009
- Thalassinos, Konstantinos; Grabenauer, Megan; Slade, Susan E.
- Analytical Chemistry, Vol. 81, Issue 1
Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes Is a Prerequisite for Its Inhibition of Human Voltage-gated Sodium Channel NaV1.7
journal, August 2016
- Henriques, Sónia Troeira; Deplazes, Evelyne; Lawrence, Nicole
- Journal of Biological Chemistry, Vol. 291, Issue 33
N -Chlorosuccinimide, an Efficient Reagent for On-Resin Disulfide Formation in Solid-Phase Peptide Synthesis
journal, January 2013
- Postma, Tobias M.; Albericio, Fernando
- Organic Letters, Vol. 15, Issue 3
Synthesis and Activity of Thioether-Containing Analogues of the Complement Inhibitor Compstatin
journal, May 2011
- Knerr, Patrick J.; Tzekou, Apostolia; Ricklin, Daniel
- ACS Chemical Biology, Vol. 6, Issue 7
Optimization of oxidative folding methods for cysteine-rich peptides: a study of conotoxins containing three disulfide bridges
journal, September 2010
- Steiner, Andrew M.; Bulaj, Grzegorz
- Journal of Peptide Science, Vol. 17, Issue 1
Ziconotide: a clinical update and pharmacologic review
journal, March 2013
- Pope, Jason E.; Deer, Timothy R.
- Expert Opinion on Pharmacotherapy, Vol. 14, Issue 7
Ring-closing metathesis in peptides
journal, September 2016
- Gleeson, Ellen C.; Jackson, W. Roy; Robinson, Andrea J.
- Tetrahedron Letters, Vol. 57, Issue 39
Engineering Potent and Selective Analogues of GpTx-1, a Tarantula Venom Peptide Antagonist of the Na V 1.7 Sodium Channel
journal, February 2015
- Murray, Justin K.; Ligutti, Joseph; Liu, Dong
- Journal of Medicinal Chemistry, Vol. 58, Issue 5
An Overview of the Three Dimensional Structure ofs Short Spider Toxins
journal, January 2005
- Ferrat, G.; Darbon, H.
- Toxin Reviews, Vol. 24, Issue 3
Chemical Syntheses and Biological Activities of Lactam Analogues of α-Conotoxin SI ¶ , + , #
journal, December 2000
- Hargittai, Balazs; Solé, Núria A.; Groebe, Duncan R.
- Journal of Medicinal Chemistry, Vol. 43, Issue 25
Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain
journal, January 2014
- de Araujo, Aline Dantas; Mobli, Mehdi; Castro, Joel
- Nature Communications, Vol. 5, Issue 1
Pathway of Oxidative Folding of a 3-Disulfide α-Lactalbumin May Resemble Either BPTI Model or Hirudin Model
journal, May 2006
- Salamanca, Silvia; Chang, Jui-Yoa
- The Protein Journal, Vol. 25, Issue 4
Oxidation of Lanthionines Renders the Lantibiotic Nisin Inactive
journal, March 2009
- Wilson-Stanford, Shawanda; Kalli, Anastasia; Håkansson, Kristina
- Applied and Environmental Microbiology, Vol. 75, Issue 5
α-Conotoxin ImI Incorporating Stable Cystathionine Bridges Maintains Full Potency and Identical Three-Dimensional Structure
journal, October 2011
- Dekan, Zoltan; Vetter, Irina; Daly, Norelle L.
- Journal of the American Chemical Society, Vol. 133, Issue 40
Cysteine racemization during the Fmoc solid phase peptide synthesis of the Nav1.7-selective peptide - protoxin II: RACEMIZATION DURING LINEAR PROTOXIN II SYNTHESIS
journal, May 2012
- Park, Jae H.; Carlin, Kevin P.; Wu, Gang
- Journal of Peptide Science, Vol. 18, Issue 7
Distinct Disulfide Isomers of μ-Conotoxins KIIIA and KIIIB Block Voltage-Gated Sodium Channels
journal, November 2012
- Khoo, Keith K.; Gupta, Kallol; Green, Brad R.
- Biochemistry, Vol. 51, Issue 49
α-Selenoconotoxins, a New Class of Potent α7 Neuronal Nicotinic Receptor Antagonists
journal, May 2006
- Armishaw, Christopher J.; Daly, Norelle L.; Nevin, Simon T.
- Journal of Biological Chemistry, Vol. 281, Issue 20
Studies Examining the Relationship between the Chemical Structure of Protoxin II and Its Activity on Voltage Gated Sodium Channels
journal, July 2014
- Park, Jae H.; Carlin, Kevin P.; Wu, Gang
- Journal of Medicinal Chemistry, Vol. 57, Issue 15
Engineering Highly Potent and Selective Microproteins against Nav1.7 Sodium Channel for Treatment of Pain
journal, July 2016
- Shcherbatko, Anatoly; Rossi, Andrea; Foletti, Davide
- Journal of Biological Chemistry, Vol. 291, Issue 27
Divergent folding pathways of two homologous proteins, BPTI and tick anticoagulant peptide: Compartmentalization of folding intermediates and identification of kinetic traps
journal, May 2005
- Chang, Jui-Yoa; Li, Li
- Archives of Biochemistry and Biophysics, Vol. 437, Issue 1
No Gain, No Pain: Na V 1.7 as an Analgesic Target
journal, August 2014
- King, Glenn F.; Vetter, Irina
- ACS Chemical Neuroscience, Vol. 5, Issue 9
Lanthionine−Somatostatin Analogs: Synthesis, Characterization, Biological Activity, and Enzymatic Stability Studies
journal, July 1997
- Ösapay, George; Prokai, Laszlo; Kim, Ho-Seung
- Journal of Medicinal Chemistry, Vol. 40, Issue 14
Antimicrobial Leucocin Analogues with a Disulfide Bridge Replaced by a Carbocycle or by Noncovalent Interactions of Allyl Glycine Residues
journal, November 2006
- Derksen, Darren J.; Stymiest, Jake L.; Vederas, John C.
- Journal of the American Chemical Society, Vol. 128, Issue 44
The structure of spider toxin huwentoxin-II with unique disulfide linkage: Evidence for structural evolution
journal, February 2002
- Shu, Qin; Lu, Shan-Yun; Gu, Xiao-Cheng
- Protein Science, Vol. 11, Issue 2
Travelling wave ion mobility mass spectrometry studies of protein structure: biological significance and comparison with X-ray crystallography and nuclear magnetic resonance spectroscopy measurements
journal, October 2008
- Scarff, Charlotte A.; Thalassinos, Konstantinos; Hilton, Gillian R.
- Rapid Communications in Mass Spectrometry, Vol. 22, Issue 20
Recent advances in synthetic analogues of lantibiotics: What can we learn from these?
journal, August 2014
- Tabor, Alethea B.
- Bioorganic Chemistry, Vol. 55
On the use of PyAOP, a phosphonium salt derived from HOAt, in solid-phase peptide synthesis
journal, July 1997
- Albericio, Fernando; Cases, Marta; Alsina, Jordi
- Tetrahedron Letters, Vol. 38, Issue 27
Discovery, Synthesis, and Structure–Activity Relationships of Conotoxins
journal, April 2014
- Akondi, Kalyana B.; Muttenthaler, Markus; Dutertre, Sébastien
- Chemical Reviews, Vol. 114, Issue 11
ProTx-II, a Selective Inhibitor of Na V 1.7 Sodium Channels, Blocks Action Potential Propagation in Nociceptors
journal, August 2008
- Schmalhofer, William A.; Calhoun, Jeffrey; Burrows, Rachel
- Molecular Pharmacology, Vol. 74, Issue 5
Variable Substrate Preference among Phospholipase D Toxins from Sicariid Spiders
journal, April 2015
- Lajoie, Daniel M.; Roberts, Sue A.; Zobel-Thropp, Pamela A.
- Journal of Biological Chemistry, Vol. 290, Issue 17
Diaminodiacid Bridges to Improve Folding and Tune the Bioactivity of Disulfide-Rich Peptides
journal, June 2015
- Guo, Ye; Sun, De-Meng; Wang, Feng-Liang
- Angewandte Chemie International Edition, Vol. 54, Issue 48
Diaminodiacid-based synthesis of macrocyclic peptides using 1,2,3-triazole bridges as disulfide bond mimetics
journal, January 2017
- Guo, Ye; Liu, Chao; Song, Hui
- RSC Advances, Vol. 7, Issue 4
Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor
journal, January 2017
- Flinspach, M.; Xu, Q.; Piekarz, A. D.
- Scientific Reports, Vol. 7, Issue 1
Orthogonally Protected Lanthionines: Synthesis and Use for the Solid-Phase Synthesis of an Analogue of Nisin Ring C
journal, March 2005
- Bregant, Sarah; Tabor, Alethea B.
- The Journal of Organic Chemistry, Vol. 70, Issue 7
High-throughput production of two disulphide-bridge toxins
journal, January 2014
- Upert, Grégory; Mourier, Gilles; Pastor, Alexandra
- Chem. Commun., Vol. 50, Issue 61
Synthesis of the Lantibiotic Lactocin S Using Peptide Cyclizations on Solid Phase
journal, December 2009
- Ross, Avena C.; Liu, Hongqiang; Pattabiraman, Vijaya R.
- Journal of the American Chemical Society, Vol. 132, Issue 2
Peptide therapeutics: current status and future directions
journal, January 2015
- Fosgerau, Keld; Hoffmann, Torsten
- Drug Discovery Today, Vol. 20, Issue 1
Dicarba α-Conotoxin Vc1.1 Analogues with Differential Selectivity for Nicotinic Acetylcholine and GABA B Receptors
journal, June 2013
- van Lierop, Bianca J.; Robinson, Samuel D.; Kompella, Shiva N.
- ACS Chemical Biology, Vol. 8, Issue 8
Two Tarantula Peptides Inhibit Activation of Multiple Sodium Channels †
journal, December 2002
- Middleton, Richard E.; Warren, Vivien A.; Kraus, Richard L.
- Biochemistry, Vol. 41, Issue 50
N,O-bisFmoc derivatives ofN-(2-hydroxy-4-methoxybenzyl)-amino acids: Useful intermediates in peptide synthesis
journal, January 1995
- Johnson, Tony; Quibell, Martin; Sheppard, Robert C.
- Journal of Peptide Science, Vol. 1, Issue 1
Synthesis of Oxytocin Analogues with Replacement of Sulfur by Carbon Gives Potent Antagonists with Increased Stability
journal, September 2005
- Stymiest, Jake L.; Mitchell, Bryan F.; Wong, Susan
- The Journal of Organic Chemistry, Vol. 70, Issue 20
Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a
journal, January 2017
- Deuis, Jennifer R.; Dekan, Zoltan; Wingerd, Joshua S.
- Scientific Reports, Vol. 7, Issue 1
An SCN9A channelopathy causes congenital inability to experience pain
journal, December 2006
- Cox, James J.; Reimann, Frank; Nicholas, Adeline K.
- Nature, Vol. 444, Issue 7121
Solving the α-Conotoxin Folding Problem: Efficient Selenium-Directed On-Resin Generation of More Potent and Stable Nicotinic Acetylcholine Receptor Antagonists
journal, February 2010
- Muttenthaler, Markus; Nevin, Simon T.; Grishin, Anton A.
- Journal of the American Chemical Society, Vol. 132, Issue 10
Microwave heating in solid-phase peptide synthesis
journal, January 2012
- Pedersen, Søren L.; Tofteng, A. Pernille; Malik, Leila
- Chem. Soc. Rev., Vol. 41, Issue 5
The challenge of the lantibiotics: synthetic approaches to thioether-bridged peptides
journal, January 2011
- Tabor, Alethea B.
- Organic & Biomolecular Chemistry, Vol. 9, Issue 22
Structure and Activity of (2,8)-Dicarba-(3,12)-cystino α-ImI, an α-Conotoxin Containing a Nonreducible Cystine Analogue
journal, January 2009
- MacRaild, Christopher A.; Illesinghe, Jayamini; Lierop, Bianca J. van
- Journal of Medicinal Chemistry, Vol. 52, Issue 3
Synthesis of Peptides Containing Overlapping Lanthionine Bridges on the Solid Phase: An Analogue of Rings D and E of the Lantibiotic Nisin
journal, August 2011
- Mothia, Begum; Appleyard, Antony N.; Wadman, Sjoerd
- Organic Letters, Vol. 13, Issue 16
Synthesis and conformational properties of the lanthionine-bridged opioid peptide [D-AlaL2,AlaL5]enkephalin as determined by NMR and computer simulations
journal, October 1992
- Polinsky, Alexander; Cooney, Michael G.; Toy-Palmer, Anna
- Journal of Medicinal Chemistry, Vol. 35, Issue 22
The Tarantula Toxins ProTx-II and Huwentoxin-IV Differentially Interact with Human Na v 1.7 Voltage Sensors to Inhibit Channel Activation and Inactivation
journal, September 2010
- Xiao, Yucheng; Blumenthal, Kenneth; Jackson, James O.
- Molecular Pharmacology, Vol. 78, Issue 6
Tarantula Huwentoxin-IV Inhibits Neuronal Sodium Channels by Binding to Receptor Site 4 and Trapping the Domain II Voltage Sensor in the Closed Configuration
journal, October 2008
- Xiao, Yucheng; Bingham, Jon-Paul; Zhu, Weiguo
- Journal of Biological Chemistry, Vol. 283, Issue 40
Solid Supported Chemical Syntheses of Both Components of the Lantibiotic Lacticin 3147
journal, September 2011
- Liu, Wei; Chan, Alice S. H.; Liu, Hongqiang
- Journal of the American Chemical Society, Vol. 133, Issue 36
Thioether Analogues of Disulfide-Bridged Cyclic Peptides Targeting Death Receptor 5: Conformational Analysis, Dimerisation and Consequences for Receptor Activation
journal, December 2014
- Pulka-Ziach, Karolina; Pavet, Valeria; Chekkat, Neila
- ChemBioChem, Vol. 16, Issue 2
Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia
journal, March 2004
- Yang, Y.
- Journal of Medical Genetics, Vol. 41, Issue 3
Molecular Interactions of the Gating Modifier Toxin ProTx-II with Nav1.5
journal, April 2007
- Smith, Jaime J.; Cummins, Theodore R.; Alphy, Sujith
- Journal of Biological Chemistry, Vol. 282, Issue 17
Traveling-Wave Ion Mobility Mass Spectrometry Analysis of Isomeric Modified Peptides Arising from Chemical Cross-Linking
journal, December 2010
- Santos, Luiz F. A.; Iglesias, Amadeu H.; Pilau, Eduardo J.
- Journal of the American Society for Mass Spectrometry, Vol. 21, Issue 12
Synthesis of Lipidated eNOS Peptides by Combining Enzymatic, Noble Metal- and Acid-Mediated Protecting Group Techniques with Solid Phase Peptide Synthesis and Fragment Condensation in Solution
journal, July 2001
- Machauer, Rainer; Waldmann, Herbert
- Chemistry - A European Journal, Vol. 7, Issue 13