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Toxins
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Toxinology and Pharmacology of Snake Venoms
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Toxinology and Pharmacology of Snake Venoms

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

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 22170

Special Issue Editor

Prof. Dr. Igor Križaj

E-Mail Website
Guest Editor
Department of Molecular and Biomedical Sciences at Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia
Interests: animal venoms; envenomation; neurotoxins; anticoagulants; procoagulants; antithrombotics; hemorrhagins; myotoxins; molecular mechanisms of action; toxin receptors; secreted phospholipases A2; venomics; proteomics; protein structure; structure–function relationships; venoms to drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Evolution endowed snakes with the ultimate weapon: the venom. With it, several hundred types of venomous snakes can kill or weaken their victims to prevent them from escape. Snakes get closer to humans and cause more harm and more deaths than any other venomous animal, including spiders and scorpions. Snake venoms can be especially dangerous for the circulatory, nervous, and muscular systems in humans. The increased sensitivity of analytical instruments and the development of new techniques such as transcriptomics and proteomics in the last two decades have permitted us to analyze the structures and functions of venom components of rare snake species and to identify novel minor snake venom constituents. As a result, the number of polypeptides identified in snake venoms is increasing dramatically. The unraveled biochemical composition, genomics, and proteomics of toxins and venoms have deepened our understanding of their interaction with organisms, most importantly with humans. Their modes of action are better understood, which opens the door to their eventual application as molecular tools and diagnostic or therapeutic agents, including the development of antidotes. Snake venom research influences various areas of life and biomedical sciences. It has deep linkages with biochemistry, molecular biology, genetics, pathophysiology, pharmacology, and the rapidly developing field of clinical toxinology. The latter deals with understanding and managing the medical effects of toxins on the human body. Given the huge impact of snake-venom-based deaths globally, and the potential of venoms in the generation of drugs against different diseases, this field of research is guaranteed to bloom. This Special Issue of Toxins welcomes articles addressing most aspects of biochemical, evolutionary, pathophysiological, and therapeutic research on snake venoms and envenomation, to provide readers with an updated and comprehensive picture of this exciting area of research.

Prof. Dr. Igor Križaj
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 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 venom
  • envenomation
  • venomics
  • toxin
  • molecular mechanism of action
  • evolution
  • drug discovery

Published Papers (7 papers)

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Editorial

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2 pages, 209 KiB  
Editorial
Toxinology and Pharmacology of Snake Venoms
by Igor Križaj
Toxins 2023, 15(3), 212; https://doi.org/10.3390/toxins15030212 - 10 Mar 2023
Cited by 1 | Viewed by 1252
Abstract
Evolution endowed snakes with the ultimate weapon: venom [...] Full article
(This article belongs to the Special Issue Toxinology and Pharmacology of Snake Venoms)

Research

Jump to: Editorial

18 pages, 1520 KiB  
Article
The Middle Eastern Cousin: Comparative Venomics of Daboia palaestinae and Daboia russelii
by R. R. Senji Laxme, Suyog Khochare, Saurabh Attarde, Navneet Kaur, Priyanka Jaikumar, Naeem Yusuf Shaikh, Reuven Aharoni, Naftali Primor, Dror Hawlena, Yehu Moran and Kartik Sunagar
Toxins 2022, 14(11), 725; https://doi.org/10.3390/toxins14110725 - 23 Oct 2022
Cited by 3 | Viewed by 3651
Abstract
Among the medically most important snakes in the world, the species belonging to the genus Daboia have been attributed to the highest number of human envenomings, deaths and disabilities. Given their significant clinical relevance, the venoms of Russell’s vipers (D. russelii and [...] Read more.
Among the medically most important snakes in the world, the species belonging to the genus Daboia have been attributed to the highest number of human envenomings, deaths and disabilities. Given their significant clinical relevance, the venoms of Russell’s vipers (D. russelii and D. siamensis) have been the primary focus of research. In contrast, the composition, activity, ecology and evolution of venom of its congener, the Palestine viper (D. palaestinae), have remained largely understudied. Therefore, to unravel the factors responsible for the enhanced medical relevance of D. russelii in comparison to D. palaestinae, we comparatively evaluated their venom proteomes, biochemical activities, and mortality and morbidity inflicting potentials. Furthermore, the synthesis and regulation of venom in snakes have also remained underinvestigated, and the relative contribution of each venom gland remains unclear. We address this knowledge gap by sequencing the tissue transcriptomes of both venom glands of D. palaestinae, and comparatively evaluating their contribution to the secreted venom concoction. Our findings highlight the disparity in the venom composition, function and toxicities of the two Daboia species. We also show that toxin production is not partitioned between the two venom glands of D. palaestinae. Full article
(This article belongs to the Special Issue Toxinology and Pharmacology of Snake Venoms)
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12 pages, 3880 KiB  
Article
The Target Selects the Toxin: Specific Amino Acids in Snake-Prey Nicotinic Acetylcholine Receptors That Are Selectively Bound by King Cobra Venoms
by Uthpala Chandrasekara, Richard J. Harris and Bryan G. Fry
Toxins 2022, 14(8), 528; https://doi.org/10.3390/toxins14080528 - 01 Aug 2022
Cited by 4 | Viewed by 1960
Abstract
Snake venom is an adaptive ecological trait that has evolved primarily as a form of prey subjugation. Thus, the selection pressure for toxin diversification is exerted by the prey’s physiological targets, with this pressure being particularly acute for specialist feeders, such as the [...] Read more.
Snake venom is an adaptive ecological trait that has evolved primarily as a form of prey subjugation. Thus, the selection pressure for toxin diversification is exerted by the prey’s physiological targets, with this pressure being particularly acute for specialist feeders, such as the King Cobra species, all of which are snake-prey specialists. However, while extensive research has been undertaken to elucidate key amino acids that guide toxin structure–activity relationships, reciprocal investigations into the specific sites guiding prey-lineage selective effects have been lacking. This has largely been due to the lack of assay systems amenable to systematic amino acid replacements of targeted proteins in the prey’s physiological pathways. To fill this knowledge gap, we used a recently described approach based upon mimotope peptides corresponding to the orthosteric site of nicotinic acetylcholine receptor alpha-1 subunits, a major binding site for snake venom neurotoxins that cause flaccid paralysis. We investigated the venoms of four different types of King Cobra (Cambodian, Javan, Malaysian, and Thai). This approach allowed for the determination of the key amino acid positions in King Cobra snake prey that are selectively bound by the toxins, whereby replacing these amino acids in the snake-prey orthosteric site with those from lizards or rats resulted in a significantly lower level of binding by the venoms, while conversely replacing the lizard or rat amino acids with those from the snake at that position increased the binding. By doing such, we identified three negatively charged amino acids in the snake orthosteric site that are strongly bound by the positively charged neurotoxic three-finger toxins found in King Cobra venom. This study, thus, sheds light on the selection pressures exerted by a specialist prey item for the evolution of lineage-selective toxins. Full article
(This article belongs to the Special Issue Toxinology and Pharmacology of Snake Venoms)
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10 pages, 1961 KiB  
Article
The Effect of Australian and Asian Commercial Antivenoms in Reversing the Post-Synaptic Neurotoxicity of O. hannah, N. naja and N. kaouthia Venoms In Vitro
by Tam M. Huynh, Wayne C. Hodgson, Geoffrey K. Isbister and Anjana Silva
Toxins 2022, 14(4), 277; https://doi.org/10.3390/toxins14040277 - 13 Apr 2022
Cited by 2 | Viewed by 2604
Abstract
Despite antivenoms being the only established specific treatment for neuromuscular paralysis arising from snake envenoming, their ability to reverse the post-synaptic neurotoxicity in snake envenoming is poorly understood. We investigated the ability of five commercial antivenoms i.e., King cobra monovalent, Thai cobra monovalent, [...] Read more.
Despite antivenoms being the only established specific treatment for neuromuscular paralysis arising from snake envenoming, their ability to reverse the post-synaptic neurotoxicity in snake envenoming is poorly understood. We investigated the ability of five commercial antivenoms i.e., King cobra monovalent, Thai cobra monovalent, Thai neuro polyvalent, Indian polyvalent and Australian polyvalent antivenoms to reverse neurotoxicity induced by the venoms of King cobra (Ophiophagus hannah, 3 µg/mL), Indian cobra (Naja naja, 5 µg/mL) and Thai cobra (Naja kaouthia, 3 µg/mL) using the in vitro chick-biventer cervicis nerve–muscle preparation. All three venoms displayed post-synaptic neurotoxicity, which was prevented by all tested antivenoms (40 µL/mL) added to the bath prior to venom. All antivenoms partially reversed the established post-synaptic neuromuscular block after the addition of the three venoms during a 180 min observation period, but to varying degrees and at different rates. The neurotoxic effects of O. hannah venom recovered to a greater magnitude (based on twitch height restoration) and faster than the neurotoxicity of N. kaouthia venom, which recovered to a lower magnitude more slowly. The recovery of post-synaptic neurotoxicity by N. naja venom was hindered due to the likely presence of cytotoxins in the venom, which cause direct muscle damage. The observations made in this study provide further evidence that the commercial antivenoms are likely to actively reverse established α-neurotoxin-mediated neuromuscular paralysis in snake envenoming, and there is cross-neutralisation with different antivenoms. Full article
(This article belongs to the Special Issue Toxinology and Pharmacology of Snake Venoms)
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21 pages, 6512 KiB  
Article
Genomic Confirmation of the P-IIIe Subclass of Snake Venom Metalloproteinases and Characterisation of Its First Member, a Disintegrin-Like/Cysteine-Rich Protein
by Kity Požek, Adrijana Leonardi, Jože Pungerčar, Weiqiao Rao, Zijian Gao, Siqi Liu, Andreas Hougaard Laustsen, Alenka Trampuš Bakija, Katarina Reberšek, Helena Podgornik and Igor Križaj
Toxins 2022, 14(4), 232; https://doi.org/10.3390/toxins14040232 - 23 Mar 2022
Cited by 6 | Viewed by 3369
Abstract
Disintegrin-like/cysteine-rich (DC) proteins have long been regarded just as products of proteolysis of P-III snake venom metalloproteinases (SVMPs). However, here we demonstrate that a DC protein from the venom of Vipera ammodytes (Vaa; nose-horned viper), VaaMPIII-3, is encoded per se by [...] Read more.
Disintegrin-like/cysteine-rich (DC) proteins have long been regarded just as products of proteolysis of P-III snake venom metalloproteinases (SVMPs). However, here we demonstrate that a DC protein from the venom of Vipera ammodytes (Vaa; nose-horned viper), VaaMPIII-3, is encoded per se by a P-III SVMP-like gene that has a deletion in the region of the catalytic metalloproteinase domain and in part of the non-catalytic disintegrin-like domain. In this way, we justify the proposal of the introduction of a new subclass P-IIIe of SVMP-derived DC proteins. We purified VaaMPIII-3 from the venom of Vaa in a series of chromatographic steps. A covalent chromatography step based on thiol-disulphide exchange revealed that VaaMPIII-3 contains an unpaired Cys residue. This was demonstrated to be Cys6 in about 90% and Cys19 in about 10% of the VaaMPIII-3 molecules. We further constructed a three-dimensional homology model of VaaMPIII-3. From this model, it is evident that both Cys6 and Cys19 can pair with Cys26, which suggests that the intramolecular thiol-disulphide exchange has a regulatory function. VaaMPIII-3 is an acidic 21-kDa monomeric glycoprotein that exists in at least six N-glycoforms, with isoelectric points ranging from pH 4.5 to 5.1. Consistent with the presence of an integrin-binding motif in its sequence, SECD, VaaMPIII-3 inhibited collagen-induced platelet aggregation. It also inhibited ADP- and arachidonic-acid-induced platelet aggregation, but not ristocetin-induced platelet agglutination and the blood coagulation cascade. Full article
(This article belongs to the Special Issue Toxinology and Pharmacology of Snake Venoms)
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15 pages, 1837 KiB  
Article
Intravenous Vipera berus Venom-Specific Fab Fragments and Intramuscular Vipera ammodytes Venom-Specific F(ab’)2 Fragments in Vipera ammodytes-Envenomed Patients
by Tihana Kurtović, Svjetlana Karabuva, Damjan Grenc, Mojca Dobaja Borak, Igor Križaj, Boris Lukšić, Beata Halassy and Miran Brvar
Toxins 2021, 13(4), 279; https://doi.org/10.3390/toxins13040279 - 14 Apr 2021
Cited by 3 | Viewed by 2374
Abstract
Vipera ammodytes (V. ammodytes) is the most venomous European viper. The aim of this study was to compare the clinical efficacy and pharmacokinetic values of intravenous Vipera berus venom-specific (paraspecific) Fab fragments (ViperaTAb) and intramuscular V. ammodytes venom-specific F(ab’)2 fragments [...] Read more.
Vipera ammodytes (V. ammodytes) is the most venomous European viper. The aim of this study was to compare the clinical efficacy and pharmacokinetic values of intravenous Vipera berus venom-specific (paraspecific) Fab fragments (ViperaTAb) and intramuscular V. ammodytes venom-specific F(ab’)2 fragments (European viper venom antiserum, also called “Zagreb” antivenom) in V.ammodytes-envenomed patients. This was a prospective study of V.ammodytes-envenomed patients that were treated intravenously with ViperaTAb or intramuscularly with European viper venom antiserum that was feasible only due to the unique situation of an antivenom shortage. The highest venom concentration, survival, length of hospital stay and adverse reactions did not differ between the groups. Patients treated with intravenous Fab fragments were sicker, with significantly more rhabdomyolysis and neurotoxicity. The kinetics of Fab fragments after one or more intravenous applications matched better with the venom concentration in the early phase of envenomation compared to F(ab’)2 fragments that were given intramuscularly only on admission. F(ab’)2 fragments given intramuscularly had 25-fold longer apparent total body clearance and 14-fold longer elimination half-time compared to Fab fragments given intravenously (2 weeks vs. 24 h, respectively). In V.ammodytes-envenomed patients, the intramuscular use of specific F(ab’)2 fragments resulted in a slow rise of antivenom serum concentration that demanded their early administration but without the need for additional doses for complete resolution of all clinical signs of envenomation. Intravenous use of paraspecific Fab fragments resulted in the immediate rise of antivenom serum concentration that enabled their use according to the clinical progress, but multiple doses might be needed for efficient therapy of thrombocytopenia due to venom recurrence, while the progression of rhabdomyolysis and neurotoxic effects of the venom could not be prevented. Full article
(This article belongs to the Special Issue Toxinology and Pharmacology of Snake Venoms)
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21 pages, 5427 KiB  
Article
Extensive Variation in the Activities of Pseudocerastes and Eristicophis Viper Venoms Suggests Divergent Envenoming Strategies Are Used for Prey Capture
by Bianca op den Brouw, Francisco C. P. Coimbra, Lachlan A. Bourke, Tam Minh Huynh, Danielle H. W. Vlecken, Parviz Ghezellou, Jeroen C. Visser, James S. Dobson, Manuel A. Fernandez-Rojo, Maria P. Ikonomopoulou, Nicholas R. Casewell, Syed A. Ali, Behzad Fathinia, Wayne C. Hodgson and Bryan G. Fry
Toxins 2021, 13(2), 112; https://doi.org/10.3390/toxins13020112 - 02 Feb 2021
Cited by 10 | Viewed by 5383
Abstract
Snakes of the genera Pseudocerastes and Eristicophis (Viperidae: Viperinae) are known as the desert vipers due to their association with the arid environments of the Middle East. These species have received limited research attention and little is known about their venom or ecology. [...] Read more.
Snakes of the genera Pseudocerastes and Eristicophis (Viperidae: Viperinae) are known as the desert vipers due to their association with the arid environments of the Middle East. These species have received limited research attention and little is known about their venom or ecology. In this study, a comprehensive analysis of desert viper venoms was conducted by visualising the venom proteomes via gel electrophoresis and assessing the crude venoms for their cytotoxic, haemotoxic, and neurotoxic properties. Plasmas sourced from human, toad, and chicken were used as models to assess possible prey-linked venom activity. The venoms demonstrated substantial divergence in composition and bioactivity across all experiments. Pseudocerastes urarachnoides venom activated human coagulation factors X and prothrombin and demonstrated potent procoagulant activity in human, toad, and chicken plasmas, in stark contrast to the potent neurotoxic venom of P. fieldi. The venom of E. macmahonii also induced coagulation, though this did not appear to be via the activation of factor X or prothrombin. The coagulant properties of P. fieldi and P. persicus venoms varied among plasmas, demonstrating strong anticoagulant activity in the amphibian and human plasmas but no significant effect in that of bird. This is conjectured to reflect prey-specific toxin activity, though further ecological studies are required to confirm any dietary associations. This study reinforces the notion that phylogenetic relatedness of snakes cannot readily predict venom protein composition or function. The significant venom variation between these species raises serious concerns regarding antivenom paraspecificity. Future assessment of antivenom is crucial. Full article
(This article belongs to the Special Issue Toxinology and Pharmacology of Snake Venoms)
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