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Special Issue "Ion Channel Neurotoxins"

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A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (31 August 2014)

Special Issue Editor

Guest Editor
Dr. Jean-Marc Sabatier

Laboratory INSERM UMR 1097, Aix-Marseille University, 163, Parc Scientifique et Technologique de Luminy, Avenue de Luminy, Bâtiment TPR2, Case 939, Marseille 13288, France
Phone: +33 491 82 87 50
Fax: +33 491 83 09 26
Interests: chemical synthesis; peptide synthesis; structure-activity relationships; medicinal chemistry; candidate drugs; antivirals, antibacterials; antioxidants; toxins

Special Issue Information

Dear Colleagues,

Animal venoms (scorpions, snakes, cone snails, worms, sea anemones, frogs, wasps, etc.) are invaluable sources of pharmacologically-active compounds with various molecular targets. Among venom compounds, peptide toxins target the diverse ion channels (potassium, calcium, sodium and chloride channels). These molecules are often highly potent, more or less selective and, sometimes, have a potential therapeutic value depending on their cellular targets. Some peptide toxins are structurally optimized to be developed as candidate drugs to treat pain and specific human pathologies, such as autoimmune and neurological disorders. This special issue of ‘Toxins’ deals with all aspects of the venomous molecules, including structural properties, pharmacology, structure-activity relationships, toxin-based drug design, toxin engineering and development as chemotherapeutic drugs.

Dr. Jean-Marc Sabatier
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1400 CHF (Swiss Francs).

Keywords

  • venom
  • animal toxin
  • venomous animal
  • ion channel
  • ion channel modulator
  • drug design
  • toxin engineering
  • chemotherapeutic drug
  • therapy

Published Papers (6 papers)

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Research

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Open AccessArticle Plectasin, First Animal Toxin-Like Fungal Defensin Blocking Potassium Channels through Recognizing Channel Pore Region
Toxins 2015, 7(1), 34-42; doi:10.3390/toxins7010034
Received: 7 November 2014 / Accepted: 24 December 2014 / Published: 5 January 2015
Cited by 8 | PDF Full-text (756 KB) | HTML Full-text | XML Full-text
Abstract
The potassium channels were recently found to be inhibited by animal toxin-like human β-defensin 2 (hBD2), the first defensin blocker of potassium channels. Whether there are other defensin blockers from different organisms remains an open question. Here, we reported the potassium channel-blocking [...] Read more.
The potassium channels were recently found to be inhibited by animal toxin-like human β-defensin 2 (hBD2), the first defensin blocker of potassium channels. Whether there are other defensin blockers from different organisms remains an open question. Here, we reported the potassium channel-blocking plectasin, the first defensin blocker from a fungus. Based on the similar cysteine-stabilized alpha-beta (CSαβ) structure between plectasin and scorpion toxins acting on potassium channels, we found that plectasin could dose-dependently block Kv1.3 channel currents through electrophysiological experiments. Besides Kv1.3 channel, plectasin could less inhibit Kv1.1, Kv1.2, IKCa, SKCa3, hERG and KCNQ channels at the concentration of 1 μΜ. Using mutagenesis and channel activation experiments, we found that outer pore region of Kv1.3 channel was the binding site of plectasin, which is similar to the interacting site of Kv1.3 channel recognized by animal toxin blockers. Together, these findings not only highlight the novel function of plectasin as a potassium channel inhibitor, but also imply that defensins from different organisms functionally evolve to be a novel kind of potassium channel inhibitors. Full article
(This article belongs to the Special Issue Ion Channel Neurotoxins)
Open AccessArticle Systematic Study of Binding of μ-Conotoxins to the Sodium Channel NaV1.4
Toxins 2014, 6(12), 3454-3470; doi:10.3390/toxins6123454
Received: 7 November 2014 / Revised: 1 December 2014 / Accepted: 10 December 2014 / Published: 18 December 2014
Cited by 2 | PDF Full-text (1984 KB) | HTML Full-text | XML Full-text
Abstract
Voltage-gated sodium channels (NaV) are fundamental components of the nervous system. Their dysfunction is implicated in a number of neurological disorders, such as chronic pain, making them potential targets for the treatment of such disorders. The prominence of the NaV channels in [...] Read more.
Voltage-gated sodium channels (NaV) are fundamental components of the nervous system. Their dysfunction is implicated in a number of neurological disorders, such as chronic pain, making them potential targets for the treatment of such disorders. The prominence of the NaV channels in the nervous system has been exploited by venomous animals for preying purposes, which have developed toxins that can block the NaV channels, thereby disabling their function. Because of their potency, such toxins could provide drug leads for the treatment of neurological disorders associated with NaV channels. However, most toxins lack selectivity for a given target NaV channel, and improving their selectivity profile among the NaV1 isoforms is essential for their development as drug leads. Computational methods will be very useful in the solution of such design problems, provided accurate models of the protein-ligand complex can be constructed. Using docking and molecular dynamics simulations, we have recently constructed a model for the NaV1.4-μ-conotoxin-GIIIA complex and validated it with the ample mutational data available for this complex. Here, we use the validated NaV1.4 model in a systematic study of binding other μ-conotoxins (PIIIA, KIIIA and BuIIIB) to NaV1.4. The binding mode obtained for each complex is shown to be consistent with the available mutation data and binding constants. We compare the binding modes of PIIIA, KIIIA and BuIIIB to that of GIIIA and point out the similarities and differences among them. The detailed information about NaV1.4-μ-conotoxin interactions provided here will be useful in the design of new NaV channel blocking peptides. Full article
(This article belongs to the Special Issue Ion Channel Neurotoxins)
Open AccessArticle Synthesis and Analgesic Effects of μ-TRTX-Hhn1b on Models of Inflammatory and Neuropathic Pain
Toxins 2014, 6(8), 2363-2378; doi:10.3390/toxins6082363
Received: 28 March 2014 / Revised: 17 July 2014 / Accepted: 18 July 2014 / Published: 13 August 2014
Cited by 2 | PDF Full-text (1126 KB) | HTML Full-text | XML Full-text
Abstract
μ-TRTX-Hhn1b (HNTX-IV) is a 35-amino acid peptide isolated from the venom of the spider, Ornithoctonus hainana. It inhibits voltage-gated sodium channel Nav1.7, which has been considered as a therapeutic target for pain. The goal of the present study is to elucidate [...] Read more.
μ-TRTX-Hhn1b (HNTX-IV) is a 35-amino acid peptide isolated from the venom of the spider, Ornithoctonus hainana. It inhibits voltage-gated sodium channel Nav1.7, which has been considered as a therapeutic target for pain. The goal of the present study is to elucidate the analgesic effects of synthetic μ-TRTX-Hhn1b on animal models of pain. The peptide was first synthesized and then successfully refolded/oxidized. The synthetic peptide had the same inhibitory effect on human Nav1.7 current transiently expressed in HEK 293 cells as the native toxin. Furthermore, the analgesic potentials of the synthetic peptide were examined on models of inflammatory pain and neuropathic pain. μ-TRTX-Hhn1b produced an efficient reversal of acute nociceptive pain in the abdominal constriction model, and significantly reduced the pain scores over the 40-min period in the formalin model. The efficiency of μ-TRTX-Hhn1b on both models was equivalent to that of morphine. In the spinal nerve model, the reversal effect of μ-TRTX-Hhn1b on allodynia was longer and higher than mexiletine. These results demonstrated that μ-TRTX-Hhn1b efficiently alleviated acute inflammatory pain and chronic neuropathic pain in animals and provided an attractive template for further clinical analgesic drug design. Full article
(This article belongs to the Special Issue Ion Channel Neurotoxins)
Open AccessArticle Binding Modes of Two Scorpion Toxins to the Voltage-Gated Potassium Channel Kv1.3 Revealed from Molecular Dynamics
Toxins 2014, 6(7), 2149-2161; doi:10.3390/toxins6072149
Received: 30 May 2014 / Revised: 8 July 2014 / Accepted: 10 July 2014 / Published: 22 July 2014
Cited by 4 | PDF Full-text (1369 KB) | HTML Full-text | XML Full-text
Abstract
Molecular dynamics (MD) simulations are used to examine the binding modes of two scorpion toxins, margatoxin (MgTx) and hongotoxin (HgTx), to the voltage gated K+ channel, Kv1.3. Using steered MD simulations, we insert either Lys28 or Lys35 of the toxins into [...] Read more.
Molecular dynamics (MD) simulations are used to examine the binding modes of two scorpion toxins, margatoxin (MgTx) and hongotoxin (HgTx), to the voltage gated K+ channel, Kv1.3. Using steered MD simulations, we insert either Lys28 or Lys35 of the toxins into the selectivity filter of the channel. The MgTx-Kv1.3 complex is stable when the side chain of Lys35 from the toxin occludes the channel filter, suggesting that Lys35 is the pore-blocking residue for Kv1.3. In this complex, Lys28 of the toxin forms one additional salt bridge with Asp449 just outside the filter of the channel. On the other hand, HgTx forms a stable complex with Kv1.3 when the side chain of Lys28 but not Lys35 protrudes into the filter of the channel. A survey of all the possible favorable binding modes of HgTx-Kv1.3 is carried out by rotating the toxin at 3° intervals around the channel axis while the position of HgTx-Lys28 relative to the filter is maintained. We identify two possible favorable binding modes: HgTx-Arg24 can interact with either Asp433 or Glu420 on the vestibular wall of the channel. The dissociation constants calculated from the two binding modes of HgTx-Kv1.3 differ by approximately 20 fold, suggesting that the two modes are of similar energetics. Full article
(This article belongs to the Special Issue Ion Channel Neurotoxins)
Open AccessArticle Recombinant Expression and Functional Characterization of Martentoxin: A Selective Inhibitor for BK Channel (α + β4)
Toxins 2014, 6(4), 1419-1433; doi:10.3390/toxins6041419
Received: 18 February 2014 / Revised: 27 March 2014 / Accepted: 1 April 2014 / Published: 22 April 2014
Cited by 5 | PDF Full-text (1505 KB) | HTML Full-text | XML Full-text
Abstract
Martentoxin (MarTX), a 37-residue peptide purified from the venom of East-Asian scorpion (Buthus martensi Karsch), was capable of blocking large-conductance Ca2+-activated K+ (BK) channels. Here, we report an effective expression and purification approach for this toxin. The cDNA [...] Read more.
Martentoxin (MarTX), a 37-residue peptide purified from the venom of East-Asian scorpion (Buthus martensi Karsch), was capable of blocking large-conductance Ca2+-activated K+ (BK) channels. Here, we report an effective expression and purification approach for this toxin. The cDNA encoding martentoxin was expressed by the prokaryotic expression system pGEX-4T-3 which was added an enterokinase cleavage site by PCR. The fusion protein (GST-rMarTX) was digested by enterokinase to release hetero-expressed toxin and further purified via reverse-phase HPLC. The molecular weight of the hetero-expressed rMarTX was 4059.06 Da, which is identical to that of the natural peptide isolated from scorpion venom. Functional characterization through whole-cell patch clamp showed that rMarTX selectively and potently inhibited the currents of neuronal BK channels (α + β4) (IC50 = 186 nM), partly inhibited mKv1.3, but hardly having any significant effect on hKv4.2 and hKv3.1a even at 10 μM. Successful expression of martentoxin lays basis for further studies of structure-function relationship underlying martentoxin or other potassium-channel specific blockers. Full article
(This article belongs to the Special Issue Ion Channel Neurotoxins)

Review

Jump to: Research

Open AccessReview Chlorotoxin: A Helpful Natural Scorpion Peptide to Diagnose Glioma and Fight Tumor Invasion
Toxins 2015, 7(4), 1079-1101; doi:10.3390/toxins7041079
Received: 12 November 2014 / Revised: 22 December 2014 / Accepted: 20 February 2015 / Published: 27 March 2015
Cited by 12 | PDF Full-text (730 KB) | HTML Full-text | XML Full-text
Abstract
Chlorotoxin is a small 36 amino-acid peptide identified from the venom of the scorpion Leiurus quinquestriatus. Initially, chlorotoxin was used as a pharmacological tool to characterize chloride channels. While studying glioma-specific chloride currents, it was soon discovered that chlorotoxin possesses targeting [...] Read more.
Chlorotoxin is a small 36 amino-acid peptide identified from the venom of the scorpion Leiurus quinquestriatus. Initially, chlorotoxin was used as a pharmacological tool to characterize chloride channels. While studying glioma-specific chloride currents, it was soon discovered that chlorotoxin possesses targeting properties towards cancer cells including glioma, melanoma, small cell lung carcinoma, neuroblastoma and medulloblastoma. The investigation of the mechanism of action of chlorotoxin has been challenging because its cell surface receptor target remains under questioning since two other receptors have been claimed besides chloride channels. Efforts on chlorotoxin-based applications focused on producing analogues helpful for glioma diagnosis, imaging and treatment. These efforts are welcome since gliomas are very aggressive brain cancers, close to impossible to cure with the current therapeutic arsenal. Among all the chlorotoxin-based strategies, the most promising one to enhance patient mean survival time appears to be the use of chlorotoxin as a targeting agent for the delivery of anti-tumor agents. Finally, the discovery of chlorotoxin has led to the screening of other scorpion venoms to identify chlorotoxin-like peptides. So far several new candidates have been identified. Only detailed research and clinical investigations will tell us if they share the same anti-tumor potential as chlorotoxin. Full article
(This article belongs to the Special Issue Ion Channel Neurotoxins)

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