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Marine Drugs
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Toxins as Marine-Based Drug Discovery
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Toxins as Marine-Based Drug Discovery

A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (20 November 2019) | Viewed by 31342

Special Issue Editor

Dr. Steve Peigneur

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Guest Editor
Toxicology and Pharmacology, Department Pharmaceutical Sciences, Catholic University Leuven, Herestraat 49 Box 922, 3000 Leuven, Belgium
Interests: peptide toxin; small molecules; voltage-gated ion channel; electrophysiology; pharmacology; venom; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Marine organisms can be seen as an untapped cocktail of biologically-active compounds, being increasingly recognized as new emerging source of therapeutics. Marine organisms have evolved the most sophisticated peptide chemistry and neuropharmacology for their own biological purposes by producing a structural and functional diversity of neurotoxins. These neurotoxins have shown to be highly selective ligands for a wide range of ion channels and receptors. Therefore, they represent interesting lead compounds for the development of, for example, analgesics, anti-cancer drugs, drugs for neurological disorders, such as multiple sclerosis, Parkinson disease, Alzheimer disease, etc.

This Special Issue of Marine Drugs aims to provide a comprehensive look at marine toxins and toxin inspired leads and will focus on the mechanism of action and structure-function of marine neurotoxins and their targets, including but not limited to, recent developments relating to the emergence of marine organisms as an underutilized source of highly evolved bioactive peptides and small molecules with clinical potential.

As Guest Editor, I invite colleagues working on marine bioactive peptides and compounds to contribute to this Special Issue of Marine Drugs with interesting papers showing significant advances within this field.

Sincerely,

Dr. Steve Peigneur
Guest Editor

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs 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 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurotoxins
  • marine natural compounds
  • sodium channels
  • potassium channels
  • calcium channels
  • chloride ion channels
  • TRP channels
  • ASIC channels
  • opiate receptors
  • acetylcholine receptors
  • NMDA receptors
  • antibiotics
  • antimicrobial peptides
  • gastropod venom peptides
  • sea anemone toxins

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Related Special Issues

Published Papers (7 papers)

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Research

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13 pages, 2482 KiB  
Article
Entomotoxic Activity of Prasiola crispa (Antarctic Algae) in Nauphoeta cinerea Cockroaches: Identification of Main Steroidal Compounds
by Graziela Holken Lorensi, Raquel Soares Oliveira, Allan P. Leal, Ana Paula Zanatta, Carlos Gabriel Moreira de Almeida, Yuri Correia Barreto, Maria Eduarda Rosa, Patrícia de Brum Vieira, Carlos José Brito Ramos, Filipe de Carvalho Victoria, Antônio Batista Pereira, Valéria LaneuvilleTeixeira and Cháriston André Dal Belo
Mar. Drugs 2019, 17(10), 573; https://doi.org/10.3390/md17100573 - 10 Oct 2019
Cited by 10 | Viewed by 3600
Abstract
Prasiola crispa is a macroscopic green algae found in abundance in Antarctica ice free areas. Prasiola crispan-hexaneextract (HPC) induced insecticidal activity in Nauphoeta cinerea cockroaches after 24 h of exposure. The chemical analysis of HPC revealed the presence of the followingphytosterols: β-sitosterol, [...] Read more.
Prasiola crispa is a macroscopic green algae found in abundance in Antarctica ice free areas. Prasiola crispan-hexaneextract (HPC) induced insecticidal activity in Nauphoeta cinerea cockroaches after 24 h of exposure. The chemical analysis of HPC revealed the presence of the followingphytosterols: β-sitosterol, campesterol and stigmasterol. The incubation of cockroach semi-isolated heart preparations with HPC caused a significant negative chronotropic activity in the heartbeats. HPC affected the insect neuromuscular function by inducing a complete inhibition of the cockroach leg-muscle twitch tension. When the isolated phytosterols were injected at in vivo cockroach neuromuscular preparations, there was a progressive inhibition of muscle twitches on the following order of potency: β-sitosterol > campesterol > stigmasterol. HPC also provoked significant behavioral alterations, characterized by the increase or decrease of cockroach grooming activity, depending on the dose assayed. Altogether, the results presented here corroborate the insecticide potential of Prasiola crispa Antarctic algae. They also revealed the presence of phytosterols and the involvement of these steroidal compounds in the entomotoxic activity of the algae, potentially by modulating octopaminergic-cholinergic pathways. Further phytochemical-combined bioguided analysis of the HPC will unveil novel bioactive compounds that might be an accessory to the insecticide activity of the algae. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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17 pages, 6886 KiB  
Article
Extremely Potent Block of Bacterial Voltage-Gated Sodium Channels by µ-Conotoxin PIIIA
by Rocio K. Finol-Urdaneta, Jeffrey R. McArthur, Vyacheslav S. Korkosh, Sun Huang, Denis McMaster, Robert Glavica, Denis B. Tikhonov, Boris S. Zhorov and Robert J. French
Mar. Drugs 2019, 17(9), 510; https://doi.org/10.3390/md17090510 - 29 Aug 2019
Cited by 12 | Viewed by 3803
Abstract
µ-Conotoxin PIIIA, in the sub-picomolar, range inhibits the archetypal bacterial sodium channel NaChBac (NavBh) in a voltage- and use-dependent manner. Peptide µ-conotoxins were first recognized as potent components of the venoms of fish-hunting cone snails that selectively inhibit voltage-gated skeletal muscle sodium channels, [...] Read more.
µ-Conotoxin PIIIA, in the sub-picomolar, range inhibits the archetypal bacterial sodium channel NaChBac (NavBh) in a voltage- and use-dependent manner. Peptide µ-conotoxins were first recognized as potent components of the venoms of fish-hunting cone snails that selectively inhibit voltage-gated skeletal muscle sodium channels, thus preventing muscle contraction. Intriguingly, computer simulations predicted that PIIIA binds to prokaryotic channel NavAb with much higher affinity than to fish (and other vertebrates) skeletal muscle sodium channel (Nav 1.4). Here, using whole-cell voltage clamp, we demonstrate that PIIIA inhibits NavBac mediated currents even more potently than predicted. From concentration-response data, with [PIIIA] varying more than 6 orders of magnitude (10−12 to 10−5 M), we estimated an IC50 = ~5 pM, maximal block of 0.95 and a Hill coefficient of 0.81 for the inhibition of peak currents. Inhibition was stronger at depolarized holding potentials and was modulated by the frequency and duration of the stimulation pulses. An important feature of the PIIIA action was acceleration of macroscopic inactivation. Docking of PIIIA in a NaChBac (NavBh) model revealed two interconvertible binding modes. In one mode, PIIIA sterically and electrostatically blocks the permeation pathway. In a second mode, apparent stabilization of the inactivated state was achieved by PIIIA binding between P2 helices and trans-membrane S5s from adjacent channel subunits, partially occluding the outer pore. Together, our experimental and computational results suggest that, besides blocking the channel-mediated currents by directly occluding the conducting pathway, PIIIA may also change the relative populations of conducting (activated) and non-conducting (inactivated) states. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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14 pages, 2753 KiB  
Article
Alanine-Scanning Mutagenesis of α-Conotoxin GI Reveals the Residues Crucial for Activity at the Muscle Acetylcholine Receptor
by Jiong Ning, Rui Li, Jie Ren, Dongting Zhangsun, Xiaopeng Zhu, Yong Wu and Sulan Luo
Mar. Drugs 2018, 16(12), 507; https://doi.org/10.3390/md16120507 - 13 Dec 2018
Cited by 21 | Viewed by 3914
Abstract
Recently, the muscle-type nicotinic acetylcholine receptors (nAChRs) have been pursued as a potential target of several diseases, including myogenic disorders, muscle dystrophies and myasthenia gravis, etc. α-conotoxin GI isolated from Conus geographus selectively and potently inhibited the muscle-type nAChRs which can be developed [...] Read more.
Recently, the muscle-type nicotinic acetylcholine receptors (nAChRs) have been pursued as a potential target of several diseases, including myogenic disorders, muscle dystrophies and myasthenia gravis, etc. α-conotoxin GI isolated from Conus geographus selectively and potently inhibited the muscle-type nAChRs which can be developed as a tool to study them. Herein, alanine scanning mutagenesis was used to reveal the structure–activity relationship (SAR) between GI and mouse α1β1δε nAChRs. The Pro5, Gly8, Arg9, and Tyr11 were proved to be the critical residues for receptor inhibiting as the alanine (Ala) replacement led to a significant potency loss on mouse α1β1δε nAChR. On the contrary, substituting Asn4, His10 and Ser12 with Ala respectively did not affect its activity. Interestingly, the [E1A] GI analogue exhibited a three-fold potency for mouse α1β1δε nAChR, whereas it obviously decreased potency at rat α9α10 nAChR compared to wildtype GI. Molecular dynamic simulations also suggest that loop2 of GI significantly affects the interaction with α1β1δε nAChR, and Tyr11 of GI is a critical residue binding with three hydrophobic amino acids of the δ subunit, including Leu93, Tyr95 and Leu103. Our research elucidates the interaction of GI and mouse α1β1δε nAChR in detail that will help to develop the novel analogues of GI. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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15 pages, 2562 KiB  
Article
A Strategy to Replace the Mouse Bioassay for Detecting and Identifying Lipophilic Marine Biotoxins by Combining the Neuro-2a Bioassay and LC-MS/MS Analysis
by Marcia Bodero, Arjen Gerssen, Liza Portier, Mirjam D. Klijnstra, Ron L. A. P. Hoogenboom, Leonardo Guzmán, Peter J. M. Hendriksen and Toine F. H. Bovee
Mar. Drugs 2018, 16(12), 501; https://doi.org/10.3390/md16120501 - 12 Dec 2018
Cited by 13 | Viewed by 4785
Abstract
Marine biotoxins in fish and shellfish can cause several symptoms in consumers, such as diarrhea, amnesia, or even death by paralysis. Monitoring programs are in place for testing shellfish on a regular basis. In some countries testing is performed using the so-called mouse [...] Read more.
Marine biotoxins in fish and shellfish can cause several symptoms in consumers, such as diarrhea, amnesia, or even death by paralysis. Monitoring programs are in place for testing shellfish on a regular basis. In some countries testing is performed using the so-called mouse bioassay, an assay that faces ethical concerns not only because of animal distress, but also because it lacks specificity and results in high amounts of false positives. In Europe, for lipophilic marine biotoxins (LMBs), a chemical analytical method using LC-MS/MS was developed as an alternative and is now the reference method. However, safety is often questioned when relying solely on such a method, and as a result, the mouse bioassay might still be used. In this study the use of a cell-based assay for screening, i.e., the neuro-2a assay, in combination with the official LC-MS/MS method was investigated as a new alternative strategy for the detection and quantification of LMBs. To this end, samples that had been tested previously with the mouse bioassay were analyzed in the neuro-2a bioassay and the LC-MS/MS method. The neuro-2a bioassay was able to detect all LMBs at the regulatory levels and all samples that tested positive in the mouse bioassay were also suspect in the neuro-2a bioassay. In most cases, these samples contained toxin levels (yessotoxins) that explain the outcome of the bioassay but did not exceed the established maximum permitted levels. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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13 pages, 3675 KiB  
Article
iTRAQ-Based Quantitative Proteomic Analysis of a Toxigenic Dinoflagellate Alexandrium catenella at Different Stages of Toxin Biosynthesis during the Cell Cycle
by Shu-Fei Zhang, Yong Zhang, Lin Lin and Da-Zhi Wang
Mar. Drugs 2018, 16(12), 491; https://doi.org/10.3390/md16120491 - 7 Dec 2018
Cited by 20 | Viewed by 3749
Abstract
Paralytic shellfish toxins (PSTs) are a group of potent neurotoxic alkaloids that are produced mainly by marine dinoflagellates. PST biosynthesis in dinoflagellates is a discontinuous process that is coupled to the cell cycle. However, little is known about the molecular mechanism underlying this [...] Read more.
Paralytic shellfish toxins (PSTs) are a group of potent neurotoxic alkaloids that are produced mainly by marine dinoflagellates. PST biosynthesis in dinoflagellates is a discontinuous process that is coupled to the cell cycle. However, little is known about the molecular mechanism underlying this association. Here, we compared global protein expression profiles of a toxigenic dinoflagellate, Alexandrium catenella, collected at four different stages of toxin biosynthesis during the cell cycle, using an isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomic approach. The results showed that toxin biosynthesis occurred mainly in the G1 phase, especially the late G1 phase. In total, 7232 proteins were confidently identified, and 210 proteins exhibited differential expression among the four stages. Proteins involved in protein translation and photosynthetic pigment biosynthesis were significantly upregulated during toxin biosynthesis, indicating close associations among the three processes. Nine toxin-related proteins were detected, and two core toxin biosynthesis proteins, namely, sxtA and sxtI, were identified for the first time in dinoflagellates. Among these proteins, sxtI and ompR were significantly downregulated when toxin biosynthesis stopped, indicating that they played important roles in the regulation of PST biosynthesis. Our study provides new insights into toxin biosynthesis in marine dinoflagellates: nitrogen balance among different biological processes regulates toxin biosynthesis, and that glutamate might play a key modulatory role. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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Review

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20 pages, 3996 KiB  
Review
Research Progress in the Biosynthetic Mechanisms of Marine Polyether Toxins
by Xiukun Wan, Ge Yao, Yanli Liu, Jisheng Chen and Hui Jiang
Mar. Drugs 2019, 17(10), 594; https://doi.org/10.3390/md17100594 - 22 Oct 2019
Cited by 10 | Viewed by 3727
Abstract
Marine polyether toxins, mainly produced by marine dinoflagellates, are novel, complex, and diverse natural products with extensive toxicological and pharmacological effects. Owing to their harmful effects during outbreaks of marine red tides, as well as their potential value for the development of new [...] Read more.
Marine polyether toxins, mainly produced by marine dinoflagellates, are novel, complex, and diverse natural products with extensive toxicological and pharmacological effects. Owing to their harmful effects during outbreaks of marine red tides, as well as their potential value for the development of new drugs, marine polyether toxins have been extensively studied, in terms of toxicology, pharmacology, detection, and analysis, structural identification, as well as their biosynthetic mechanisms. Although the biosynthetic mechanisms of marine polyether toxins are still unclear, certain progress has been made. In this review, research progress and current knowledge on the biosynthetic mechanisms of polyether toxins are summarized, including the mechanisms of carbon skeleton deletion, pendant alkylation, and polyether ring formation, along with providing a summary of mined biosynthesis-related genes. Finally, future research directions and applications of marine polyether toxins are discussed. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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14 pages, 1803 KiB  
Review
Addressing the Issue of Tetrodotoxin Targeting
by Daria I. Melnikova, Yuri S. Khotimchenko and Timur Yu. Magarlamov
Mar. Drugs 2018, 16(10), 352; https://doi.org/10.3390/md16100352 - 26 Sep 2018
Cited by 24 | Viewed by 6830
Abstract
This review is devoted to the medical application of tetrodotoxin (TTX), a potent non-protein specific blocker of voltage-gated sodium (NaV) channels. The selectivity of action, lack of affinity with the heart muscle NaV channels, and the inability to penetrate the blood–brain barrier make [...] Read more.
This review is devoted to the medical application of tetrodotoxin (TTX), a potent non-protein specific blocker of voltage-gated sodium (NaV) channels. The selectivity of action, lack of affinity with the heart muscle NaV channels, and the inability to penetrate the blood–brain barrier make this toxin an attractive candidate for anesthetic and analgesic drug design. The efficacy of TTX was shown in neuropathic, acute and inflammatory pain models. The main emphasis of the review is on studies focused on the improvement of TTX efficacy and safety in conjunction with additional substances and drug delivery systems. A significant improvement in the effectiveness of the toxin was demonstrated when used in tandem with vasoconstrictors, local anesthetics and chemical permeation enhancers, with the best results obtained with the encapsulation of TTX in microparticles and liposomes conjugated to gold nanorods. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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