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Marine Drugs
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Toxins as Marine-Based Drug Discovery, 2nd Edition
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Toxins as Marine-Based Drug Discovery, 2nd Edition

A special issue of Marine Drugs (ISSN 1660-3397). This special issue belongs to the section "Marine Toxins".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 7750

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,

Following the success of the Special Issue “Toxins as Marine-Based Drug Discovery”, we are delighted to launch a second edition on the same topic.

Marine organisms can be considered 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 diverse structural and functional neurotoxins. These neurotoxins are 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 and drugs for neurological disorders such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, etc.

This Special Issue of Marine Drugs aims to provide a comprehensive overview of marine toxins and toxin-inspired leads, focusing on the mechanisms 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 a clinical potential.

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

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 Issue

Published Papers (5 papers)

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Research

18 pages, 3803 KiB  
Article
A High-Throughput Biosensing Approach for Rapid Screening of Compounds Targeting the hNav1.1 Channel: Marine Toxins as a Case Study
by Huijing Shen, Yuxia Cui, Shiyuan Liang, Shuang Zhou, Yingji Li, Yongning Wu and Junxian Song
Mar. Drugs 2025, 23(3), 119; https://doi.org/10.3390/md23030119 - 9 Mar 2025
Viewed by 1011
Abstract
Voltage-gated sodium (Nav) channels play a crucial role in initiating and propagating action potentials throughout the heart, muscles and nervous systems, making them targets for a number of drugs and toxins. While patch-clamp electrophysiology is considered the gold standard for measuring ion channel [...] Read more.
Voltage-gated sodium (Nav) channels play a crucial role in initiating and propagating action potentials throughout the heart, muscles and nervous systems, making them targets for a number of drugs and toxins. While patch-clamp electrophysiology is considered the gold standard for measuring ion channel activity, its labor-intensive and time-consuming nature highlights the need for fast screening strategies to facilitate a preliminary selection of potential drugs or hazards. In this study, a high-throughput and cost-effective biosensing method was developed to rapidly identify specific agonists and inhibitors targeting the human Nav1.1 (hNav1.1) channel. It combines a red fluorescent dye sensitive to transmembrane potentials with CHO cells stably expressing the hNav1.1 α-subunit (hNav1.1-CHO). In the initial screening mode, the tested compounds were mixed with pre-equilibrated hNav1.1-CHO cells and dye to detect potential agonist effects via fluorescence enhancement. In cases where no fluorescence enhancement was observed, the addition of a known agonist veratridine allowed the indication of inhibitor candidates by fluorescence reduction, relative to the veratridine control without test compounds. Potential agonists or inhibitors identified in the initial screening were further evaluated by measuring concentration–response curves to determine EC50/IC50 values, providing semi-quantitative estimates of their binding strength to hNav1.1. This robust, high-throughput biosensing assay was validated through comparisons with the patch-clamp results and tested with 12 marine toxins, yielding consistent results. It holds promise as a low-cost, rapid, and long-term stable approach for drug discovery and non-target screening of neurotoxins. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery, 2nd Edition)
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30 pages, 5277 KiB  
Article
Sea Anemone Kunitz Peptide HCIQ2c1: Structure, Modulation of TRPA1 Channel, and Suppression of Nociceptive Reaction In Vivo
by Aleksandra N. Kvetkina, Sergey D. Oreshkov, Pavel A. Mironov, Maxim M. Zaigraev, Anna A. Klimovich, Yulia V. Deriavko, Aleksandr S. Menshov, Dmitrii S. Kulbatskii, Yulia A. Logashina, Yaroslav A. Andreev, Anton O. Chugunov, Mikhail P. Kirpichnikov, Ekaterina N. Lyukmanova, Elena V. Leychenko and Zakhar O. Shenkarev
Mar. Drugs 2024, 22(12), 542; https://doi.org/10.3390/md22120542 - 2 Dec 2024
Cited by 1 | Viewed by 1530
Abstract
TRPA1 is a homotetrameric non-selective calcium-permeable channel. It contributes to chemical and temperature sensitivity, acute pain sensation, and development of inflammation. HCIQ2c1 is a peptide from the sea anemone Heteractis magnifica that inhibits serine proteases. Here, we showed that HCIQ2c1 significantly reduces AITC- [...] Read more.
TRPA1 is a homotetrameric non-selective calcium-permeable channel. It contributes to chemical and temperature sensitivity, acute pain sensation, and development of inflammation. HCIQ2c1 is a peptide from the sea anemone Heteractis magnifica that inhibits serine proteases. Here, we showed that HCIQ2c1 significantly reduces AITC- and capsaicin-induced pain and inflammation in mice. Electrophysiology recordings in Xenopus oocytes expressing rat TRPA1 channel revealed that HCIQ2c1 binds to open TRPA1 and prevents its transition to closed and inhibitor-insensitive ‘hyperactivated’ states. NMR study of the 15N-labeled recombinant HCIQ2c1 analog described a classical Kunitz-type structure and revealed two dynamic hot-spots (loops responsible for protease binding and regions near the N- and C-termini) that exhibit simultaneous mobility on two timescales (ps–ns and μs–ms). In modelled HCIQ2c1/TRPA1 complex, the peptide interacts simultaneously with one voltage-sensing-like domain and two pore domain fragments from different channel’s subunits, and with lipid molecules. The model explains stabilization of the channel in the open conformation and the restriction of ‘hyperactivation’, which are probably responsible for the observed analgetic activity. HCIQ2c1 is the third peptide ligand of TRPA1 from sea anemones and the first Kunitz-type ligand of this channel. HCIQ2c1 is a prototype of efficient analgesic and anti-inflammatory drugs. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery, 2nd Edition)
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20 pages, 5545 KiB  
Article
In Search of the Role of Three-Finger Starfish Proteins
by Ekaterina N. Lyukmanova, Maxim L. Bychkov, Andrei M. Chernikov, Ilya D. Kukushkin, Dmitrii S. Kulbatskii, Sergey V. Shabelnikov, Mikhail A. Shulepko, Ran Zhao, Wenxiao Guo, Mikhail P. Kirpichnikov, Zakhar O. Shenkarev and Alexander S. Paramonov
Mar. Drugs 2024, 22(11), 488; https://doi.org/10.3390/md22110488 - 30 Oct 2024
Cited by 1 | Viewed by 1191
Abstract
Three-finger proteins (TFPs), or Ly6/uPAR proteins, are characterized by the beta-structural LU domain containing three protruding “fingers” and stabilized by four conserved disulfide bonds. TFPs were initially characterized as snake alpha-neurotoxins, but later many studies showed their regulatory roles in different organisms. Despite [...] Read more.
Three-finger proteins (TFPs), or Ly6/uPAR proteins, are characterized by the beta-structural LU domain containing three protruding “fingers” and stabilized by four conserved disulfide bonds. TFPs were initially characterized as snake alpha-neurotoxins, but later many studies showed their regulatory roles in different organisms. Despite a known expression of TFPs in vertebrates, they are poorly studied in other taxa. The presence of TFPs in starfish was previously shown, but their targets and functional role still remain unknown. Here, we analyzed expression, target, and possible function of the Lystar5 protein from the Asterias rubens starfish using bioinformatics, qPCR, and immunoassay. First, the presence of Lystar5 homologues in all classes of echinoderms was demonstrated. qPCR revealed that mRNA of Lystar5 and LyAr2 are expressed mainly in coelomocytes and coelomic epithelium of Asterias, while mRNA of other TFPs, LyAr3, LyAr4, and LyAr5, were also found in a starfish body wall. Using anti-Lystar5 serum from mice immunized by a recombinant Lystar5, we confirmed that this protein is expressed on the surface of coelomocytes and coelomic epithelium cells. According to ELISA, a recombinant analogue of Lystar5 bound to the membrane fraction of coelomocytes and coelomic epithelium but not to the body wall or starfish arm tip. Analysis by LC-MALDI MS/MS suggested integrin α-8-like protein expressed in the coelomocytes and coelomic epithelium as a target of Lystar5. Thus, our insights propose the important role of TFPs in regulation of starfish physiology and show prospects for their further research. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery, 2nd Edition)
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16 pages, 5332 KiB  
Article
Single Amino Acid Substitution in Loop1 Switches the Selectivity of α-Conotoxin RegIIA towards the α7 Nicotinic Acetylcholine Receptor
by Jinpeng Yu, Junjie Xie, Yuting Ma, Pengcheng Wei, Panpan Zhang, Zepei Tang, Xiaopeng Zhu, Dongting Zhangsun and Sulan Luo
Mar. Drugs 2024, 22(9), 390; https://doi.org/10.3390/md22090390 - 29 Aug 2024
Viewed by 1359
Abstract
α-Conotoxins are disulfide-rich peptides obtained from the venom of cone snails, which are considered potential molecular probes and drug leads for nAChR-related disorders. However, low specificity towards different nAChR subtypes restricts the further application of many α-conotoxins. In this work, a series of [...] Read more.
α-Conotoxins are disulfide-rich peptides obtained from the venom of cone snails, which are considered potential molecular probes and drug leads for nAChR-related disorders. However, low specificity towards different nAChR subtypes restricts the further application of many α-conotoxins. In this work, a series of loop1 amino acid-substituted mutants of α-conotoxin RegIIA were synthesized, whose potency and selectivity were evaluated by an electrophysiological approach. The results showed that loop1 alanine scanning mutants [H5A]RegIIA and [P6A]RegIIA blocked rα7 nAChR with IC50s of 446 nM and 459 nM, respectively, while their inhibition against rα3β2 and rα3β4 subtypes was negligible, indicating the importance of the fifth and sixth amino acid residues for RegIIA’s potency and selectivity. Then, second-generation mutants were designed and synthesized, among which the analogues [H5V]RegIIA and [H5S]RegIIA showed significantly improved selectivity and comparable potency towards rα7 nAChR compared with the native RegIIA. Overall, these findings provide deep insights into the structure–activity relationship of RegIIA, as well as revealing a unique perspective for the further modification and optimization of α-conotoxins and other active peptides. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery, 2nd Edition)
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14 pages, 4811 KiB  
Article
Jellyfish Venom Peptides Targeting Human Potassium Channels Identified through Ligand Screening: Morphometric and Molecular Identification of the Species and Antibiotic Potential
by Edirisinghe Arachchige Hashini Wasthala Edirisinghe, Buddhima Nirmani Athukorala, Minoli Perera, Bothunga Arachchige Shamali Dilhara Abeywardana, Polgahawattage Sachini Tarushika Sigera, Pasindu Eranga, Kavindu Dinuhara Theekshana, Mohamad Boudjelal, Rizwan Ali and Dinithi Champika Peiris
Mar. Drugs 2024, 22(8), 333; https://doi.org/10.3390/md22080333 - 24 Jul 2024
Viewed by 2103
Abstract
The relative lack of marine venom could be attributed to the difficulty in dealing with venomous marine animals. Moreover, the venom of marine animals consists of various bioactive molecules, many of which are proteins with unique properties. In this study, we investigated the [...] Read more.
The relative lack of marine venom could be attributed to the difficulty in dealing with venomous marine animals. Moreover, the venom of marine animals consists of various bioactive molecules, many of which are proteins with unique properties. In this study, we investigated the potential toxic proteins of jellyfish collected for ligand screening to understand the mechanism of the toxic effects of jellyfish. Since taxonomic identification is problematic due to the lack of proper keys, we conducted morphological and molecular mitochondrial DNA sequencing from COI and ITS regions. The venom extract from nematocysts found along the bell margins was used for protein characterization using SDS-gel electrophoresis and nano-liquid chromatography-tandem mass spectrometry. Ligand screening for the most potent toxin and antibacterial and cytotoxicity assays were carried out. The phylogenetic tree showed distinct clustering from other Catostylus sp. The proteomic analysis revealed venom with many bioactive proteins. Only 13 venom proteins were identified with molecular weights ranging from 4318 to 184,923 Da, exhibiting the venom’s complexity. The overall toxin protein composition of Catostylus sp. venom was dominated by potassium channel toxin alpha-KTx. Molecular docking of toxin alpha-KTx 1.13 revealed high specificity towards the human voltage-gated potassium channel Kv3 with a high fitness score and a minimum energy barrier of −17.9 kcal/mol. Disc diffusion and cytotoxicity assays revealed potent antibacterial activity against Klebsiella pneumoniae with no cytotoxicity. Further studies on detailed characterization and therapeutic potentials are warranted. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery, 2nd Edition)
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