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Medically Relevant Snake Toxins, Current Antivenoms and the Development of...
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Medically Relevant Snake Toxins, Current Antivenoms and the Development of Next-Generation Antivenoms

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

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 17971

Special Issue Editors

Dr. Elda E. Sánchez

E-Mail Website
Guest Editor
National Natural Toxins Research Center, Texas A&M-University Kingsville
Dr. Montamas Suntravat

E-Mail Website
Guest Editor
National Natural Toxins Research Center, Texas A&M University-Kingsville, Kingsville, TX, USA
Interests: snake venom metalloproteinases; cysteine-rich secretary protein; disintegrin; pathophysiology; transcriptomes; recombinant protein; molecular mechanisms of action; envenomation; proteomics; vascular permeability
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Snake venoms are complex mixtures of numerous protein and polypeptide toxins belonging to only a few major molecular families. These toxin families include several classes of enzymes such as serine proteases, metalloproteases, phospholipases A2, and L-amino acid oxidases. Venom also contains numerous bioactive polypeptides that lack enzymatic activity, such as the three-finger toxins, myotoxins, disintegrins, C-type lectins, CRISP (cysteine-rich secretory protein) toxins, growth factors, and protease inhibitors, such as cystatin and Kunitz-type protease inhibitors. Snake envenoming can result in significant injury and in many cases death. A shortage of antivenoms is creating a global crisis that has encouraged health providers and researchers to take heed. The evolutionary relatedness among snake venom toxins and the high global morbidity and mortality has incited an interest in developing broad toxin class specificity antivenoms.
This Special Issue of Toxins aims to provide information on medically relevant snake toxins related to their chemical, pharmacological, pathophysiological, and immunological properties and their ability to be neutralized by current commercial antivenoms, including but not limited to the recent advancements of next-generation antivenom development and their ability to potentially alleviate this neglected tropical disease, snake envenoming.

Dr. Elda E. Sánchez
Dr. Montamas Suntravat
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

  • Snake venoms
  • toxins
  • disintegrins
  • phospholipases A2
  • metalloproteases
  • antivenoms
  • envenoming
  • next generation antivenoms
  • neglected tropical diseases

Published Papers (4 papers)

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Research

17 pages, 4981 KiB  
Article
Structural Insight into Integrin Recognition and Anticancer Activity of Echistatin
by Yi-Chun Chen, Yao-Tsung Chang, Chiu-Yueh Chen, Jia-Hau Shiu, Chun-Ho Cheng, Chun-Hao Huang, Ju-Fei Chen and Woei-Jer Chuang
Toxins 2020, 12(11), 709; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12110709 - 09 Nov 2020
Cited by 4 | Viewed by 2329
Abstract
Echistatin (Ech) is a short disintegrin with a long 42NPHKGPAT C-terminal tail. We determined the 3-D structure of Ech by X-ray crystallography. Superimposition of the structures of chains A and B showed conformational differences in their RGD loops and C-termini. The chain [...] Read more.
Echistatin (Ech) is a short disintegrin with a long 42NPHKGPAT C-terminal tail. We determined the 3-D structure of Ech by X-ray crystallography. Superimposition of the structures of chains A and B showed conformational differences in their RGD loops and C-termini. The chain A structure is consistent with our NMR analysis that the GPAT residues of the C-terminus cannot be observed due to high flexibility. The hydrogen bond patterns of the RGD loop and between the RGD loop and C-terminus in Ech were the same as those of the corresponding residues in medium disintegrins. The mutant with C-terminal HKGPAT truncation caused 6.4-, 7.0-, 11.7-, and 18.6-fold decreases in inhibiting integrins αvβ3, αIIbβ3, αvβ5, and α5β1. Mutagenesis of the C-terminus showed that the H44A mutant caused 2.5- and 4.4-fold increases in inhibiting αIIbβ3 and α5β1, and the K45A mutant caused a 2.6-fold decrease in inhibiting αIIbβ3. We found that Ech inhibited VEGF-induced HUVEC proliferation with an IC50 value of 103.2 nM and inhibited the migration of A375, U373MG, and Panc-1 tumor cells with IC50 values of 1.5, 5.7, and 154.5 nM. These findings suggest that Ech is a potential anticancer agent, and its C-terminal region can be optimized to improve its anticancer activity. Full article
(This article belongs to the Special Issue Medically Relevant Snake Toxins, Current Antivenoms and the Development of Next-Generation Antivenoms)
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20 pages, 3279 KiB  
Article
Isolation of an Anti–tumour Disintegrin: Dabmaurin–1, a Peptide Lebein–1–like, from Daboia mauritanica Venom
by Florence Chalier, Laura Mugnier, Marion Tarbe, Soioulata Aboudou, Claude Villard, Hervé Kovacic, Didier Gigmes, Pascal Mansuelle, Harold de Pomyers, José Luis and Kamel Mabrouk
Toxins 2020, 12(2), 102; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12020102 - 05 Feb 2020
Cited by 8 | Viewed by 2578
Abstract
In the soft treatment of cancer tumours, consequent downregulation of the malignant tissue angiogenesis constitutes an efficient way to stifle tumour development and metastasis spreading. As angiogenesis requires integrin–promoting endothelial cell adhesion, migration, and vessel tube formation, integrins represent potential targets of new [...] Read more.
In the soft treatment of cancer tumours, consequent downregulation of the malignant tissue angiogenesis constitutes an efficient way to stifle tumour development and metastasis spreading. As angiogenesis requires integrin–promoting endothelial cell adhesion, migration, and vessel tube formation, integrins represent potential targets of new therapeutic anti–angiogenic agents. Our work is a contribution to the research of such therapeutic disintegrins in animal venoms. We report isolation of one peptide, named Dabmaurin–1, from the hemotoxic venom of snake Daboia mauritanica, and we evaluate its potential anti–tumour activity through in vitro inhibition of the human vascular endothelial cell HMECs functions involved in tumour angiogenesis. Dabmaurin–1 altered, in a dose–dependent manner, without any significant cytotoxicity, HMEC proliferation, adhesion, and their mesenchymal migration onto various extracellular matrix proteins, as well as formation of capillary–tube mimics on MatrigelTM. Via experiments involving HMEC or specific cancers cells integrins, we demonstrated that the above Dabmaurin–1 effects are possibly due to some anti–integrin properties. Dabmaurin–1 was demonstrated to recognize a broad panel of prooncogenic integrins (αvβ6, αvβ3 or αvβ5) and/or particularly involved in control of angiogenesis (α5β1, α6β4, αvβ3 or αvβ5). Furthermore, mass spectrometry and partial N–terminal sequencing of this peptide revealed, it is close to Lebein–1, a known anti–β1 disintegrin from Macrovipera lebetina venom. Therefore, our results show that if Dabmaurin–1 exhibits in vitro apparent anti–angiogenic effects at concentrations lower than 30 nM, it is likely because it acts as an anti–tumour disintegrin. Full article
(This article belongs to the Special Issue Medically Relevant Snake Toxins, Current Antivenoms and the Development of Next-Generation Antivenoms)
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16 pages, 6888 KiB  
Article
Antivenom Neutralization of Coagulopathic Snake Venom Toxins Assessed by Bioactivity Profiling Using Nanofractionation Analytics
by Chunfang Xie, Julien Slagboom, Laura-Oana Albulescu, Ben Bruyneel, Kristina B. M. Still, Freek J. Vonk, Govert W. Somsen, Nicholas R. Casewell and Jeroen Kool
Toxins 2020, 12(1), 53; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12010053 - 16 Jan 2020
Cited by 19 | Viewed by 5662
Abstract
Venomous snakebite is one of the world’s most lethal neglected tropical diseases. Animal-derived antivenoms are the only standardized specific therapies currently available for treating snakebite envenoming, but due to venom variation, often this treatment is not effective in counteracting all clinical symptoms caused [...] Read more.
Venomous snakebite is one of the world’s most lethal neglected tropical diseases. Animal-derived antivenoms are the only standardized specific therapies currently available for treating snakebite envenoming, but due to venom variation, often this treatment is not effective in counteracting all clinical symptoms caused by the multitude of injected toxins. In this study, the coagulopathic toxicities of venoms from the medically relevant snake species Bothrops asper, Calloselasma rhodostoma, Deinagkistrodon acutus, Daboia russelii, Echis carinatus and Echis ocellatus were assessed. The venoms were separated by liquid chromatography (LC) followed by nanofractionation and parallel mass spectrometry (MS). A recently developed high-throughput coagulation assay was employed to assess both the pro- and anticoagulant activity of separated venom toxins. The neutralization capacity of antivenoms on separated venom components was assessed and the coagulopathic venom peptides and enzymes that were either neutralized or remained active in the presence of antivenom were identified by correlating bioassay results with the MS data and with off-line generated proteomics data. The results showed that most snake venoms analyzed contained both procoagulants and anticoagulants. Most anticoagulants were identified as phospholipases A2s (PLA2s) and most procoagulants correlated with snake venom metalloproteinases (SVMPs) and serine proteases (SVSPs). This information can be used to better understand antivenom neutralization and can aid in the development of next-generation antivenom treatments. Full article
(This article belongs to the Special Issue Medically Relevant Snake Toxins, Current Antivenoms and the Development of Next-Generation Antivenoms)
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20 pages, 8235 KiB  
Article
Venomous Landmines: Clinical Implications of Extreme Coagulotoxic Diversification and Differential Neutralization by Antivenom of Venoms within the Viperid Snake Genus Bitis
by Nicholas J. Youngman, Jordan Debono, James S. Dobson, Christina N. Zdenek, Richard J. Harris, Bianca op den Brouw, Francisco C. P. Coimbra, Arno Naude, Kristian Coster, Eric Sundman, Ralph Braun, Iwan Hendrikx and Bryan G. Fry
Toxins 2019, 11(7), 422; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11070422 - 19 Jul 2019
Cited by 26 | Viewed by 6913
Abstract
The genus Bitis comprises 18 species that inhabit Africa and the Arabian Peninsula. They are responsible for a significant proportion of snakebites in the region. The venoms of the two independent lineages of giant Bitis (B. arietans and again in the common ancestor [...] Read more.
The genus Bitis comprises 18 species that inhabit Africa and the Arabian Peninsula. They are responsible for a significant proportion of snakebites in the region. The venoms of the two independent lineages of giant Bitis (B. arietans and again in the common ancestor of the clade consisting of B. gabonica, B. nasicornis, B. parviocula and B. rhinoceros) induce an array of debilitating effects including anticoagulation, hemorrhagic shock and cytotoxicity, whilst the dwarf species B. atropos is known to have strong neurotoxic effects. However, the venom effects of the other species within the genus have not been explored in detail. A series of coagulation assays were implemented to assess the coagulotoxic venom effects of fourteen species within the genus. This study identified procoagulant venom as the ancestral condition, retained only by the basal dwarf species B. worthingtoni, suggesting anticoagulant venom is a derived trait within the Bitis genus and has been secondarily amplified on at least four occasions. A wide range of anticoagulant mechanisms were identified, such as pseudo-procoagulant and destructive activities upon fibrinogen in both giant and dwarf Bitis and the action of inhibiting the prothrombinase complex, which is present in a clade of dwarf Bitis. Antivenom studies revealed that while the procoagulant effects of B. worthingtoni were poorly neutralized, and thus a cause for concern, the differential mechanisms of anticoagulation in other species were all well neutralized. Thus, this study concludes there is a wide range of coagulotoxic mechanisms which have evolved within the Bitis genus and that clinical management strategies are limited for the procoagulant effects of B. worthingtoni, but that anticoagulant effects of other species are readily treated by the South African polyvalent antivenom. These results therefore have direct, real-work implications for the treatment of envenomed patients. Full article
(This article belongs to the Special Issue Medically Relevant Snake Toxins, Current Antivenoms and the Development of Next-Generation Antivenoms)
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