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Toxins
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Animal Poisons and Venoms in Drug Discovery
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Animal Poisons and Venoms in Drug Discovery

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

Deadline for manuscript submissions: closed (30 December 2022) | Viewed by 24996

Special Issue Editors

Dr. Antonio Garcia Soares

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Guest Editor
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA
Interests: Pharmacology; Toxicology; Ion channels; Electrophysiology; Kidney diseases, Hypertension, Cardiovascular function
Dr. Tarek Mohamed Abd El-Aziz

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Guest Editor
1. Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA
2. Zoology Department, Faculty of Science, Minia University, El-Minia 61519, Egypt
Interests: animal venoms and toxins; drug discovery; ion channels and membrane receptors; electrophysiology; pharmacology; snakebite; antivenom production

Special Issue Information

Dear Colleagues,

The development of new drugs represents one of the biggest challenging activities of the pharmaceutical industry. Since the middle of the 20th century, a growing number of potential therapeutic agents have been extracted and isolated from plants, animal venoms, and microorganism toxins. While the preliminary effort with regard to animal poisons and venoms was to understand the effects of snake and spider bites and scorpion stings on humans and to elaborate the action of the toxins, toxins from animal poisons and venoms display wide-ranging pharmacological activities, targeting mainly ion channels, membrane receptors, and components of the hemostatic system with high selectivity and affinity. Animal poisons and venoms are complex chemical mixtures of biologically active proteins. Animal venom components were also understood to be medical tools for thousands of years in Ayurveda, homeopathy, and traditional/folk medicine for the treatment of a variety of pathophysiological conditions.

In the past few decades, several potential drugs in use or in clinical trials have been isolated or derived from animal venoms. Since 1981, 10 toxin-based molecules have received FDA approval, five from snakes (Captopril, Tirofiban, Eptifibatide, Batroxobin, and Cobratide), two from lizards (Exenatide and Lixisenatide), two from leeches (Bivalirudin and Desirudin), and one from cone snails (Ziconotide). Many additional animal venom components are also currently in different clinical stages as therapeutic drugs.

This Special Issue of Toxins on “Animal Poisons and Venoms in Drug Discovery” aims to provide a comprehensive view not only of snake venom but also several other animal toxins having therapeutic potential for drug discovery. We welcome all research including original research articles, reviews, and short communications focused on the characterization, pharmacology, and therapeutic applications of animal poisons and venoms and their subcomponents. We hope that researchers will share their valuable studies using snake venoms for drug development.

Dr. Antonio Garcia Soares
Dr. Tarek Mohamed Abd El-Aziz
Guest Editors

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 double-blind 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 2700 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

  • Animal poisons and venoms
  • Bioactive proteins and peptides
  • Drug discovery
  • Pharmacology
  • Therapeutic applications
  • Ion channels
  • Membrane proteins
  • Antimicrobial agents

Published Papers (7 papers)

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Research

Jump to: Review

12 pages, 2185 KiB  
Article
Screening of TNFR1 Binding Peptides from Deinagkistrodon acutus Venom through Phage Display
by Kangran Zhang, Yang Liu and Yezhong Tang
Toxins 2022, 14(2), 155; https://doi.org/10.3390/toxins14020155 - 19 Feb 2022
Cited by 3 | Viewed by 2396
Abstract
The venomous species Deinagkistrodon acutus has been used as anti-inflammatory medicine in China for a long time. It has been proven to have anti-inflammatory activity, but its specific anti-inflammatory components have not yet been fully elucidated. Tumor necrosis factor receptor-1 (TNFR1), which participates [...] Read more.
The venomous species Deinagkistrodon acutus has been used as anti-inflammatory medicine in China for a long time. It has been proven to have anti-inflammatory activity, but its specific anti-inflammatory components have not yet been fully elucidated. Tumor necrosis factor receptor-1 (TNFR1), which participates in important intracellular signaling pathways, mediates apoptosis, and functions as a regulator of inflammation, is often used as the target to develop anti-inflammatory drugs. The small peptides of snake venom have the advantages of weak immunogenicity and strong activity. To obtain the specific TNFR1 binding peptides, we constructed a T7 phage library of D. acutus venom glands, and then performed biopanning against TNFR1 on the constructed library. After biopanning three times, several sequences with potential binding capacity were obtained and one 41-amino acid peptide was selected through a series of biological analyses including sequence length, solubility, and simulated affinity, named DAvp-1. After synthesis, the binding capacity of DAvp-1 and TNFR1 was verified using surface plasmon resonance technology (SPR). Conclusively, by applying phage display technology, this work depicts the successful screening of a promising peptide DAvp-1 from D. acutus venom that binds to TNFR1. Additionally, our study emphasizes the usefulness of phage display technology for studies on screening natural product components. Full article
(This article belongs to the Special Issue Animal Poisons and Venoms in Drug Discovery)
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13 pages, 10325 KiB  
Article
Characterization of the Composition and Biological Activity of the Venom from Vespa bicolor Fabricius, a Wasp from South China
by Yong-Hua Wu, Yu Zhang, Dan-Qiao Fang, Jing Chen, Jing-An Wang, Lin Jiang and Zhu-Fen Lv
Toxins 2022, 14(1), 59; https://doi.org/10.3390/toxins14010059 - 14 Jan 2022
Cited by 3 | Viewed by 2462
Abstract
We analyzed, for the first time, the major components and biological properties of the venom of Vespa bicolor, a wasp from South China. Using HPLC and SDS-PAGE, combined with LC–MS/MS, MALDI-TOF-MS, and NMR data to analyze V. bicolor venom (VBV), we found [...] Read more.
We analyzed, for the first time, the major components and biological properties of the venom of Vespa bicolor, a wasp from South China. Using HPLC and SDS-PAGE, combined with LC–MS/MS, MALDI-TOF-MS, and NMR data to analyze V. bicolor venom (VBV), we found that VBV contains three proteins (hyaluronidase A, phospholipase A1 (two isoforms), and antigen 5 protein) with allergenic activity, two unreported proteins (proteins 5 and 6), and two active substances with large quantities (mastoparan-like peptide 12a (Vb-MLP 12a), and 5-hydroxytryptamine (5-HT)). In addition, the antimicrobial activity of VBV was determined, and results showed that it had a significant effect against anaerobic bacteria. The minimum inhibitory concentration and minimum bactericidal concentration for Propionibacterium acnes were 12.5 µg/mL. Unsurprisingly, VBV had strong antioxidant activity because of the abundance of 5-HT. Contrary to other Vespa venom, VBV showed significant anti-inflammatory activity, even at low concentrations (1 µg/mL), and we found that Vb-MLP 12a showed pro-inflammatory activity by promoting the proliferation of RAW 264.7 cells. Cytotoxicity studies showed that VBV had similar antiproliferative effects against all tested tumor cell lines (HepG2, Hela, MCF-7, A549, and SASJ-1), with HepG2 being the most susceptible. Overall, this study on VBV has high clinical importance and promotes the development of Vespa bicolor resources. Full article
(This article belongs to the Special Issue Animal Poisons and Venoms in Drug Discovery)
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18 pages, 3263 KiB  
Article
Antinociceptive and Anti-Inflammatory Effects of Recombinant Crotamine in Mouse Models of Pain
by Jong Yeon Park, Bich Hang Do, Ju-Seung Lee, Hyun Cheol Yang, Anh Ngoc Nguyen, Martin Krupa, Chong Jai Kim, Yeon Jin Jang and Han Choe
Toxins 2021, 13(10), 707; https://doi.org/10.3390/toxins13100707 - 6 Oct 2021
Cited by 6 | Viewed by 2038
Abstract
Crotamine, a toxin found in the venom of the South American rattlesnake Crotalus durissus terrificus, has been reported to have antinociceptive effects. We purified recombinant crotamine expressed in Escherichia coli and investigated its antinociceptive and anti-inflammatory effects using the hot-plate test, acetic-acid-induced [...] Read more.
Crotamine, a toxin found in the venom of the South American rattlesnake Crotalus durissus terrificus, has been reported to have antinociceptive effects. We purified recombinant crotamine expressed in Escherichia coli and investigated its antinociceptive and anti-inflammatory effects using the hot-plate test, acetic-acid-induced writhing method, and formalin test in mice. Recombinant crotamine was administered intraperitoneally (0.04–1.2 mg kg−1) or intraplantarly (0.9–7.5 μg 10 μL−1) before the tests. The paw volume was measured with a plethysmometer. To evaluate the antagonistic and anti-inflammatory effects of naloxone, subcutaneous naloxone (4 mg kg−1) or intraplantar naloxone (5 μg 10 μL−1) was administered before recombinant crotamine. For tumor necrosis factor (TNF)-α assays, blood was drawn 3 h after formalin injection and measured using enzyme-linked immunosorbent assay. Intraperitoneal and intraplantar recombinant crotamine had antinociceptive and anti-inflammatory effects, neither of which were affected by pre-treatment with naloxone. The mean serum TNF-α levels were significantly lower in the intraperitoneal recombinant crotamine (0.4 and 1.2 mg kg−1) or intraplantar (2.5 and 7.5 μg 10 μL−1) recombinant crotamine groups than in the saline group and were not affected by naloxone pre-treatment. In conclusion, recombinant crotamine possesses significant antinociceptive and anti-inflammatory effects that do not appear to be related to the opioid receptor. The antinociceptive and anti-inflammatory effects of intraperitoneal or intraplantar recombinant crotamine are related to TNF-α. Full article
(This article belongs to the Special Issue Animal Poisons and Venoms in Drug Discovery)
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16 pages, 5132 KiB  
Article
Phosphoproteomics Identifies Significant Biomarkers Associated with the Proliferation and Metastasis of Prostate Cancer
by Rongfang Xu, Yan Chen, Zijun Wang, Changxin Zhang, Xiaoping Dong, Yujie Yan, Ying Wang, Yong Zeng and Ping Chen
Toxins 2021, 13(8), 554; https://doi.org/10.3390/toxins13080554 - 9 Aug 2021
Cited by 2 | Viewed by 2764
Abstract
The spider peptide toxins HNTX-III and JZTX-I are a specific inhibitor and activator of TTX-S VGSCs, respectively. They play important roles in regulating MAT-LyLu cell metastasis in prostate cancer. In order to identify key biomarkers involved in the regulation of MAT-LyLu cell metastasis, [...] Read more.
The spider peptide toxins HNTX-III and JZTX-I are a specific inhibitor and activator of TTX-S VGSCs, respectively. They play important roles in regulating MAT-LyLu cell metastasis in prostate cancer. In order to identify key biomarkers involved in the regulation of MAT-LyLu cell metastasis, iTRAQ-based quantitative phosphoproteomics analysis was performed on cells treated with HNTX-III, JZTX-I and blank. A total of 554 unique phosphorylated proteins and 1779 distinct phosphorylated proteins were identified, while 55 and 36 phosphorylated proteins were identified as differentially expressed proteins in HNTX-III and JZTX-I treated groups compared with control groups. Multiple bioinformatics analysis based on quantitative phosphoproteomics data suggested that the differentially expressed phosphorylated proteins and peptides were significantly associated with the migration and invasion of prostate tumors. Specifically, the toxins HNTX-III and JZTX-I have opposite effects on tumor formation and metastasis by regulating the expression and phosphorylation level of causal proteins. Herein, we highlighted three key proteins EEF2, U2AF2 and FLNC which were down-regulated in HNTX-III treated cells and up-regulated in JZTX-I treated cells. They played significant roles in cancer related physiological and pathological processes. The differentially expressed phosphorylated proteins identified in this study may serve as potential biomarkers for precision medicine for prostate cancer in the near future. Full article
(This article belongs to the Special Issue Animal Poisons and Venoms in Drug Discovery)
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21 pages, 3485 KiB  
Article
Identification and Characterization of Novel Proteins from Arizona Bark Scorpion Venom That Inhibit Nav1.8, a Voltage-Gated Sodium Channel Regulator of Pain Signaling
by Tarek Mohamed Abd El-Aziz, Yucheng Xiao, Jake Kline, Harold Gridley, Alyse Heaston, Klaus D. Linse, Micaiah J. Ward, Darin R. Rokyta, James D. Stockand, Theodore R. Cummins, Luca Fornelli and Ashlee H. Rowe
Toxins 2021, 13(7), 501; https://doi.org/10.3390/toxins13070501 - 18 Jul 2021
Cited by 4 | Viewed by 4741
Abstract
The voltage-gated sodium channel Nav1.8 is linked to neuropathic and inflammatory pain, highlighting the potential to serve as a drug target. However, the biophysical mechanisms that regulate Nav1.8 activation and inactivation gating are not completely understood. Progress has been hindered by a lack [...] Read more.
The voltage-gated sodium channel Nav1.8 is linked to neuropathic and inflammatory pain, highlighting the potential to serve as a drug target. However, the biophysical mechanisms that regulate Nav1.8 activation and inactivation gating are not completely understood. Progress has been hindered by a lack of biochemical tools for examining Nav1.8 gating mechanisms. Arizona bark scorpion (Centruroides sculpturatus) venom proteins inhibit Nav1.8 and block pain in grasshopper mice (Onychomys torridus). These proteins provide tools for examining Nav1.8 structure–activity relationships. To identify proteins that inhibit Nav1.8 activity, venom samples were fractioned using liquid chromatography (reversed-phase and ion exchange). A recombinant Nav1.8 clone expressed in ND7/23 cells was used to identify subfractions that inhibited Nav1.8 Na+ current. Mass-spectrometry-based bottom-up proteomic analyses identified unique peptides from inhibitory subfractions. A search of the peptides against the AZ bark scorpion venom gland transcriptome revealed four novel proteins between 40 and 60% conserved with venom proteins from scorpions in four genera (Centruroides, Parabuthus, Androctonus, and Tityus). Ranging from 63 to 82 amino acids, each primary structure includes eight cysteines and a “CXCE” motif, where X = an aromatic residue (tryptophan, tyrosine, or phenylalanine). Electrophysiology data demonstrated that the inhibitory effects of bioactive subfractions can be removed by hyperpolarizing the channels, suggesting that proteins may function as gating modifiers as opposed to pore blockers. Full article
(This article belongs to the Special Issue Animal Poisons and Venoms in Drug Discovery)
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16 pages, 10501 KiB  
Article
Identification of a Novel Cathelicidin from the Deinagkistrodon acutus Genome with Antibacterial Activity by Multiple Mechanisms
by Lipeng Zhong, Jiye Liu, Shiyu Teng and Zhixiong Xie
Toxins 2020, 12(12), 771; https://doi.org/10.3390/toxins12120771 - 4 Dec 2020
Cited by 7 | Viewed by 2232
Abstract
The abuse of antibiotics and the consequent increase of drug-resistant bacteria constitute a serious threat to human health, and new antibiotics are urgently needed. Research shows that antimicrobial peptides produced by natural organisms are potential substitutes for antibiotics. Based on Deinagkistrodonacutus (known [...] Read more.
The abuse of antibiotics and the consequent increase of drug-resistant bacteria constitute a serious threat to human health, and new antibiotics are urgently needed. Research shows that antimicrobial peptides produced by natural organisms are potential substitutes for antibiotics. Based on Deinagkistrodonacutus (known as five-pacer viper) genome bioinformatics analysis, we discovered a new cathelicidin antibacterial peptide which was called FP-CATH. Circular dichromatic analysis showed a typical helical structure. FP-CATH showed broad-spectrum antibacterial activity. It has antibacterial activity to Gram-negative bacteria and Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). The results of transmission electron microscopy (TEM) and scanning electron microscopy (SEM) showed that FP-CATH could cause the change of bacterial cell integrity, having a destructive effect on Gram-negative bacteria and inducing Gram-positive bacterial surface formation of vesicular structure. FP-CATH could bind to LPS and showed strong binding ability to bacterial DNA. In vivo, FP-CATH can improve the survival rate of nematodes in bacterial invasion experiments, and has a certain protective effect on nematodes. To sum up, FP-CATH is likely to play a role in multiple mechanisms of antibacterial action by impacting bacterial cell integrity and binding to bacterial biomolecules. It is hoped that the study of FP-CATH antibacterial mechanisms will prove useful for development of novel antibiotics. Full article
(This article belongs to the Special Issue Animal Poisons and Venoms in Drug Discovery)
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Review

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30 pages, 5107 KiB  
Review
The Search for Natural and Synthetic Inhibitors That Would Complement Antivenoms as Therapeutics for Snakebite Envenoming
by José María Gutiérrez, Laura-Oana Albulescu, Rachel H. Clare, Nicholas R. Casewell, Tarek Mohamed Abd El-Aziz, Teresa Escalante and Alexandra Rucavado
Toxins 2021, 13(7), 451; https://doi.org/10.3390/toxins13070451 - 29 Jun 2021
Cited by 38 | Viewed by 6491
Abstract
A global strategy, under the coordination of the World Health Organization, is being unfolded to reduce the impact of snakebite envenoming. One of the pillars of this strategy is to ensure safe and effective treatments. The mainstay in the therapy of snakebite envenoming [...] Read more.
A global strategy, under the coordination of the World Health Organization, is being unfolded to reduce the impact of snakebite envenoming. One of the pillars of this strategy is to ensure safe and effective treatments. The mainstay in the therapy of snakebite envenoming is the administration of animal-derived antivenoms. In addition, new therapeutic options are being explored, including recombinant antibodies and natural and synthetic toxin inhibitors. In this review, snake venom toxins are classified in terms of their abundance and toxicity, and priority actions are being proposed in the search for snake venom metalloproteinase (SVMP), phospholipase A2 (PLA2), three-finger toxin (3FTx), and serine proteinase (SVSP) inhibitors. Natural inhibitors include compounds isolated from plants, animal sera, and mast cells, whereas synthetic inhibitors comprise a wide range of molecules of a variable chemical nature. Some of the most promising inhibitors, especially SVMP and PLA2 inhibitors, have been developed for other diseases and are being repurposed for snakebite envenoming. In addition, the search for drugs aimed at controlling endogenous processes generated in the course of envenoming is being pursued. The present review summarizes some of the most promising developments in this field and discusses issues that need to be considered for the effective translation of this knowledge to improve therapies for tackling snakebite envenoming. Full article
(This article belongs to the Special Issue Animal Poisons and Venoms in Drug Discovery)
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