Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

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 Nav1.7

Journal Article · · Journal of the American Chemical Society
 [1];  [1];  [1];  [2];  [2];  [1];  [3];  [3];  [3];  [1];  [4];  [1]; ORCiD logo [1]
  1. Univ. College London (UCL) (United Kingdom)
  2. Howard Hughes Medical Inst., Ashburn, VA (United States)
  3. European Knowledge Centre, Hertfordshire (United Kingdom)
  4. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, United States
+ 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, Vol. 139, Issue 37; ISSN 0002-7863
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 37 works
Citation information provided by
Web of Science

References (58)

Peptide therapeutics: current status and future directions journal January 2015
Ziconotide: a clinical update and pharmacologic review journal March 2013
No Gain, No Pain: Na V 1.7 as an Analgesic Target journal August 2014
Toxins and drug discovery journal December 2014
α-Selenoconotoxins, a New Class of Potent α7 Neuronal Nicotinic Receptor Antagonists journal May 2006
Solving the α-Conotoxin Folding Problem: Efficient Selenium-Directed On-Resin Generation of More Potent and Stable Nicotinic Acetylcholine Receptor Antagonists journal February 2010
Structure and Activity of (2,8)-Dicarba-(3,12)-cystino α-ImI, an α-Conotoxin Containing a Nonreducible Cystine Analogue journal January 2009
Dicarba α-Conotoxin Vc1.1 Analogues with Differential Selectivity for Nicotinic Acetylcholine and GABA B Receptors journal June 2013
Diaminodiacid Bridges to Improve Folding and Tune the Bioactivity of Disulfide-Rich Peptides journal June 2015
Ring-closing metathesis in peptides journal September 2016
Chemical Syntheses and Biological Activities of Lactam Analogues of α-Conotoxin SI , + , # journal December 2000
α-Conotoxin ImI Incorporating Stable Cystathionine Bridges Maintains Full Potency and Identical Three-Dimensional Structure journal October 2011
Synthesis of Oxytocin Analogues with Replacement of Sulfur by Carbon Gives Potent Antagonists with Increased Stability journal September 2005
Antimicrobial Leucocin Analogues with a Disulfide Bridge Replaced by a Carbocycle or by Noncovalent Interactions of Allyl Glycine Residues journal November 2006
Synthesis and Activity of Thioether-Containing Analogues of the Complement Inhibitor Compstatin journal May 2011
Diaminodiacid-based synthesis of macrocyclic peptides using 1,2,3-triazole bridges as disulfide bond mimetics journal January 2017
Synthesis and conformational properties of the lanthionine-bridged opioid peptide [D-AlaL2,AlaL5]enkephalin as determined by NMR and computer simulations journal October 1992
Lanthionine−Somatostatin Analogs:  Synthesis, Characterization, Biological Activity, and Enzymatic Stability Studies journal July 1997
Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain journal January 2014
Orthogonally Protected Lanthionines:  Synthesis and Use for the Solid-Phase Synthesis of an Analogue of Nisin Ring C journal March 2005
The challenge of the lantibiotics: synthetic approaches to thioether-bridged peptides journal January 2011
Recent advances in synthetic analogues of lantibiotics: What can we learn from these? journal August 2014
Synthesis of the Lantibiotic Lactocin S Using Peptide Cyclizations on Solid Phase journal December 2009
Solid Supported Chemical Syntheses of Both Components of the Lantibiotic Lacticin 3147 journal September 2011
Two Tarantula Peptides Inhibit Activation of Multiple Sodium Channels † journal December 2002
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
Engineering Potent and Selective Analogues of GpTx-1, a Tarantula Venom Peptide Antagonist of the Na V 1.7 Sodium Channel journal February 2015
Engineering Highly Potent and Selective Microproteins against Nav1.7 Sodium Channel for Treatment of Pain journal July 2016
Discovery, Synthesis, and Structure–Activity Relationships of Conotoxins journal April 2014
An Overview of the Three Dimensional Structure ofs Short Spider Toxins journal January 2005
ProTx-II, a Selective Inhibitor of Na V 1.7 Sodium Channels, Blocks Action Potential Propagation in Nociceptors journal August 2008
An SCN9A channelopathy causes congenital inability to experience pain journal December 2006
Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia journal March 2004
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
Studies Examining the Relationship between the Chemical Structure of Protoxin II and Its Activity on Voltage Gated Sodium Channels journal July 2014
Molecular Interactions of the Gating Modifier Toxin ProTx-II with Nav1.5 journal April 2007
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
Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor journal January 2017
Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a journal January 2017
Microwave heating in solid-phase peptide synthesis journal January 2012
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
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
On the use of PyAOP, a phosphonium salt derived from HOAt, in solid-phase peptide synthesis journal July 1997
Oxidation of Lanthionines Renders the Lantibiotic Nisin Inactive journal March 2009
N,O-bisFmoc derivatives ofN-(2-hydroxy-4-methoxybenzyl)-amino acids: Useful intermediates in peptide synthesis journal January 1995
N -Chlorosuccinimide, an Efficient Reagent for On-Resin Disulfide Formation in Solid-Phase Peptide Synthesis journal January 2013
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
Optimization of oxidative folding methods for cysteine-rich peptides: a study of conotoxins containing three disulfide bridges journal September 2010
Distinct Disulfide Isomers of μ-Conotoxins KIIIA and KIIIB Block Voltage-Gated Sodium Channels journal November 2012
The structure of spider toxin huwentoxin-II with unique disulfide linkage: Evidence for structural evolution journal February 2002
Characterization of Phosphorylated Peptides Using Traveling Wave-Based and Drift Cell Ion Mobility Mass Spectrometry journal January 2009
Traveling-Wave Ion Mobility Mass Spectrometry Analysis of Isomeric Modified Peptides Arising from Chemical Cross-Linking journal December 2010
Travelling wave ion mobility mass spectrometry studies of protein structure: biological significance and comparison with X-ray crystallography and nuclear magnetic resonance spectroscopy measurements
  • Scarff, Charlotte A.; Thalassinos, Konstantinos; Hilton, Gillian R.
  • Rapid Communications in Mass Spectrometry, Vol. 22, Issue 20 https://doi.org/10.1002/rcm.3737
journal October 2008
Thioether Analogues of Disulfide-Bridged Cyclic Peptides Targeting Death Receptor 5: Conformational Analysis, Dimerisation and Consequences for Receptor Activation journal December 2014
High-throughput production of two disulphide-bridge toxins journal January 2014
Pathway of Oxidative Folding of a 3-Disulfide α-Lactalbumin May Resemble Either BPTI Model or Hirudin Model journal May 2006
Divergent folding pathways of two homologous proteins, BPTI and tick anticoagulant peptide: Compartmentalization of folding intermediates and identification of kinetic traps journal May 2005
Variable Substrate Preference among Phospholipase D Toxins from Sicariid Spiders journal April 2015

Cited By (6)

Facile synthesis of macrocyclic peptide toxins of GpTx-1 and its analogue journal January 2018
Heterogeneous‐Backbone Foldamer Mimics of a Computationally Designed, Disulfide‐Rich Miniprotein journal November 2018
Non-reducible disulfide bond replacement implies that disulfide exchange is not required for hepcidin–ferroportin interaction journal January 2019
Structure–Function and Therapeutic Potential of Spider Venom-Derived Cysteine Knot Peptides Targeting Sodium Channels journal April 2019
GpTx-1 and [Ala 5 , Phe 6 , Leu 26 , Arg 28 ]GpTx-1, two peptide Na V 1.7 inhibitors: analgesic and tolerance properties at the spinal level: The spinal analgesia and tolerance of GpTx-1 and GpTx-1-71 journal September 2018
A Chemical Biology Approach to Understanding Molecular Recognition of Lipid II by Nisin(1–12): Synthesis and NMR Ensemble Analysis of Nisin(1–12) and Analogues journal October 2019

Similar Records

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY