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Special Issue "Animal Toxins Targeting Ion Channels Involved in Pain"

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (30 June 2012)

Special Issue Editors

Guest Editor
Prof. Dr. Glenn F. King

Division of Chemistry & Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia
Website | E-Mail
Phone: 61733462025
Fax: +61 7 3346-2101
Interests: venoms-based drug discovery; venoms-based insecticide discovery; venom evolution; ion channel blockers; acid-sensing ion channels; voltage-gated sodium channels; chronic pain; stroke; NMR structural biology
Guest Editor
Dr. Lachlan Rash

Division of Chemistry & Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia
Website | E-Mail
Phone: +61 7 3346-2985

Special Issue Information

Dear Colleagues,

Normal pain is a key adaptive response that serves to limit our exposure to potentially damaging or life-threatening events. In contrast, aberrant long-lasting pain transforms this adaptive response into a debilitating and often poorly managed disease. In 2007, global sales of pain medications totalled $34 billion, highlighting the pervasive nature of this medical condition. Unfortunately, very few drugs are available for the treatment of chronic pain, and most of these have limited efficacy and undesirable side-effects.

A variety of ion channels and receptors are involved sensing pain, including voltage-gated sodium (NaV) channels, voltage-gated calcium (CaV) channels, transient receptor potential (TRP) channels, acid-sensing ion channels (ASICs), and GABAB, P2X, and nicotinic acetylcholine (nAChR) receptors. In many cases, peptides derived from animal venoms are the most potent and selective modulators of these channels and receptors. As a result, venom peptides have been used extensively for characterizing these channels and receptors, and for their validation as analgesic targets. Moreover, some of these venom peptides are being developed as therapeutics. One venom peptide (Prialt®) has been approved by the FDA for the treatment of chronic pain, while several others are undergoing clinical trials (Xen2174 and CBSB004) or are in various stages of preclinical development. The aim of this special edition of Toxins is to review the potential of venom-derived peptides as leads for the development of novel analgesics.

Articles for this special edition are by invitation only. Authors wishing to submit an article to the special edition should submit a synopsis of no more than 250 words to either of the guest editors for consideration. The article must be aligned with the topic and preference will be given to toxins with potential as therapeutics or as leads for therapeutic development, or toxins that have facilitated the validation of novel analgesic targets.

Prof. Glenn King
Dr. Lachlan Rash
Guest Editors

Keywords

  • chronic pain
  • cone snail
  • drug
  • inflammatory pain
  • neuropathic pain
  • nociception
  • pain
  • peptide
  • protein
  • scorpion
  • snake
  • spider
  • therapeutic
  • venom

Published Papers (4 papers)

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Research

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Open AccessArticle Developing a Comparative Docking Protocol for the Prediction of Peptide Selectivity Profiles: Investigation of Potassium Channel Toxins
Toxins 2012, 4(2), 110-138; doi:10.3390/toxins4020110
Received: 16 December 2011 / Revised: 6 January 2012 / Accepted: 14 January 2012 / Published: 6 February 2012
Cited by 14 | PDF Full-text (14527 KB) | HTML Full-text | XML Full-text
Abstract
During the development of selective peptides against highly homologous targets, a reliable tool is sought that can predict information on both mechanisms of binding and relative affinities. These tools must first be tested on known profiles before application on novel therapeutic candidates. We
[...] Read more.
During the development of selective peptides against highly homologous targets, a reliable tool is sought that can predict information on both mechanisms of binding and relative affinities. These tools must first be tested on known profiles before application on novel therapeutic candidates. We therefore present a comparative docking protocol in HADDOCK using critical motifs, and use it to “predict” the various selectivity profiles of several major αKTX scorpion toxin families versus Kv1.1, Kv1.2 and Kv1.3. By correlating results across toxins of similar profiles, a comprehensive set of functional residues can be identified. Reasonable models of channel-toxin interactions can be then drawn that are consistent with known affinity and mutagenesis. Without biological information on the interaction, HADDOCK reproduces mechanisms underlying the universal binding of αKTX-2 toxins, and Kv1.3 selectivity of αKTX-3 toxins. The addition of constraints encouraging the critical lysine insertion confirms these findings, and gives analogous explanations for other families, including models of partial pore-block in αKTX-6. While qualitatively informative, the HADDOCK scoring function is not yet sufficient for accurate affinity-ranking. False minima in low-affinity complexes often resemble true binding in high-affinity complexes, despite steric/conformational penalties apparent from visual inspection. This contamination significantly complicates energetic analysis, although it is usually possible to obtain correct ranking via careful interpretation of binding-well characteristics and elimination of false positives. Aside from adaptations to the broader potassium channel family, we suggest that this strategy of comparative docking can be extended to other channels of interest with known structure, especially in cases where a critical motif exists to improve docking effectiveness. Full article
(This article belongs to the Special Issue Animal Toxins Targeting Ion Channels Involved in Pain)
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Review

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Open AccessReview Venom Peptides as a Rich Source of Cav2.2 Channel Blockers
Toxins 2013, 5(2), 286-314; doi:10.3390/toxins5020286
Received: 2 November 2012 / Revised: 7 January 2013 / Accepted: 25 January 2013 / Published: 4 February 2013
Cited by 10 | PDF Full-text (1170 KB) | HTML Full-text | XML Full-text
Abstract
Cav2.2 is a calcium channel subtype localized at nerve terminals, including nociceptive fibers, where it initiates neurotransmitter release. Cav2.2 is an important contributor to synaptic transmission in ascending pain pathways, and is up-regulated in the spinal cord in chronic
[...] Read more.
Cav2.2 is a calcium channel subtype localized at nerve terminals, including nociceptive fibers, where it initiates neurotransmitter release. Cav2.2 is an important contributor to synaptic transmission in ascending pain pathways, and is up-regulated in the spinal cord in chronic pain states along with the auxiliary α2δ1 subunit. It is therefore not surprising that toxins that inhibit Cav2.2 are analgesic. Venomous animals, such as cone snails, spiders, snakes, assassin bugs, centipedes and scorpions are rich sources of remarkably potent and selective Cav2.2 inhibitors. However, side effects in humans currently limit their clinical use. Here we review Cav2.2 inhibitors from venoms and their potential as drug leads. Full article
(This article belongs to the Special Issue Animal Toxins Targeting Ion Channels Involved in Pain)
Figures

Open AccessReview Conotoxins Targeting Neuronal Voltage-Gated Sodium Channel Subtypes: Potential Analgesics?
Toxins 2012, 4(11), 1236-1260; doi:10.3390/toxins4111236
Received: 10 October 2012 / Revised: 5 November 2012 / Accepted: 5 November 2012 / Published: 8 November 2012
Cited by 29 | PDF Full-text (402 KB) | HTML Full-text | XML Full-text
Abstract
Voltage-gated sodium channels (VGSC) are the primary mediators of electrical signal amplification and propagation in excitable cells. VGSC subtypes are diverse, with different biophysical and pharmacological properties, and varied tissue distribution. Altered VGSC expression and/or increased VGSC activity in sensory neurons is characteristic
[...] Read more.
Voltage-gated sodium channels (VGSC) are the primary mediators of electrical signal amplification and propagation in excitable cells. VGSC subtypes are diverse, with different biophysical and pharmacological properties, and varied tissue distribution. Altered VGSC expression and/or increased VGSC activity in sensory neurons is characteristic of inflammatory and neuropathic pain states. Therefore, VGSC modulators could be used in prospective analgesic compounds. VGSCs have specific binding sites for four conotoxin families: μ-, μO-, δ- and ί-conotoxins. Various studies have identified that the binding site of these peptide toxins is restricted to well-defined areas or domains. To date, only the μ- and μO-family exhibit analgesic properties in animal pain models. This review will focus on conotoxins from the μ- and μO-families that act on neuronal VGSCs. Examples of how these conotoxins target various pharmacologically important neuronal ion channels, as well as potential problems with the development of drugs from conotoxins, will be discussed. Full article
(This article belongs to the Special Issue Animal Toxins Targeting Ion Channels Involved in Pain)
Open AccessReview Animal Toxins Can Alter the Function of Nav1.8 and Nav1.9
Toxins 2012, 4(8), 620-632; doi:10.3390/toxins4080620
Received: 4 July 2012 / Revised: 24 July 2012 / Accepted: 27 July 2012 / Published: 14 August 2012
Cited by 16 | PDF Full-text (315 KB) | HTML Full-text | XML Full-text
Abstract
Human voltage-activated sodium (Nav) channels are adept at rapidly transmitting electrical signals across long distances in various excitable tissues. As such, they are amongst the most widely targeted ion channels by drugs and animal toxins. Of the nine isoforms, Nav1.8 and Nav1.9 are
[...] Read more.
Human voltage-activated sodium (Nav) channels are adept at rapidly transmitting electrical signals across long distances in various excitable tissues. As such, they are amongst the most widely targeted ion channels by drugs and animal toxins. Of the nine isoforms, Nav1.8 and Nav1.9 are preferentially expressed in DRG neurons where they are thought to play an important role in pain signaling. Although the functional properties of Nav1.8 have been relatively well characterized, difficulties with expressing Nav1.9 in established heterologous systems limit our understanding of the gating properties and toxin pharmacology of this particular isoform. This review summarizes our current knowledge of the role of Nav1.8 and Nav1.9 in pain perception and elaborates on the approaches used to identify molecules capable of influencing their function. Full article
(This article belongs to the Special Issue Animal Toxins Targeting Ion Channels Involved in Pain)

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