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Special Issue "Snakebite – From Science to Society. Selected papers"

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

Deadline for manuscript submissions: closed (31 December 2018)

Special Issue Editor

Guest Editor
Assoc. Prof. Bryan Grieg Fry

Venom Evolution Laboratory, School of Biological Sciences, University of Queensland, St. Lucia, QLD, 4072, Australia
Website | E-Mail
Phone: 61400193182
Interests: venom molecular evolution; phylogenetics and structure-function relationships; toxins

Special Issue Information

Dear Colleagues,

On 21 and 22 June, 2018, the Naturalis Biodiversity Center in Leiden, the Netherlands, is hosting an international multidisciplinary conference on the impact of snakebites. Our goal is to engage people from different backgrounds; medical, humanitarian, societal and technical fields, research, industry and policy, to discuss the issues surrounding the problem of snakebites and to co-create solutions.

During the two-day conference, experts from around the globe will focus on snakebite from different angles such as antivenom development and manufacturing, clinical issues, socio-economic burden, prevention, logistics and frontier technology. For more info on the conference, please see the conference webpage: snakebite.naturalis.nl.

The Special Issue aims to bring together active scholars and researchers to present their current scholarly work on all aspects relating to snakebite, ranging from basic research into snake venom evolution to clinical considerations. Review articles are particularly encouraged.

For manuscript submission guidelines, please see below. The guidelines refer to an article processing charge of 1500 Swiss Francs, but if your paper gets accepted, the costs for publication will be paid by Naturalis Biodiversity Center, organizer of the Conference Snakebite - from Science to Society.

With regards,

Assoc. Prof. Bryan Grieg Fry
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 papers will be 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 1800 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.

Published Papers (6 papers)

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Research

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Open AccessArticle Coagulotoxic Cobras: Clinical Implications of Strong Anticoagulant Actions of African Spitting Naja Venoms That Are Not Neutralised by Antivenom but Are by LY315920 (Varespladib)
Toxins 2018, 10(12), 516; https://doi.org/10.3390/toxins10120516
Received: 1 November 2018 / Revised: 27 November 2018 / Accepted: 1 December 2018 / Published: 4 December 2018
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Abstract
Snakebite is a global tropical disease that has long had huge implications for human health and well-being. Despite its long-standing medical importance, it has been the most neglected of tropical diseases. Reflective of this is that many aspects of the pathology have been [...] Read more.
Snakebite is a global tropical disease that has long had huge implications for human health and well-being. Despite its long-standing medical importance, it has been the most neglected of tropical diseases. Reflective of this is that many aspects of the pathology have been underinvestigated. Snakebite by species in the Elapidae family is typically characterised by neurotoxic effects that result in flaccid paralysis. Thus, while clinically significant disturbances to the coagulation cascade have been reported, the bulk of the research to date has focused upon neurotoxins. In order to fill the knowledge gap regarding the coagulotoxic effects of elapid snake venoms, we screened 30 African and Asian venoms across eight genera using in vitro anticoagulant assays to determine the relative inhibition of the coagulation function of thrombin and the inhibition of the formation of the prothrombinase complex through competitive binding to a nonenzymatic site on Factor Xa (FXa), thereby preventing FXa from binding to Factor Va (FVa). It was revealed that African spitting cobras were the only species that were potent inhibitors of either clotting factor, but with Factor Xa inhibited at 12 times the levels of thrombin inhibition. This is consistent with at least one death on record due to hemorrhage following African spitting cobra envenomation. To determine the efficacy of antivenom in neutralising the anticoagulant venom effects, for the African spitting cobras we repeated the same 8-point dilution series with the addition of antivenom and observed the shift in the area under the curve, which revealed that the antivenom performed extremely poorly against the coagulotoxic venom effects of all species. However, additional tests with the phospholipase A2 inhibitor LY315920 (trade name: varespladib) demonstrated a powerful neutralisation action against the coagulotoxic actions of the African spitting cobra venoms. Our research has important implications for the clinical treatment of cobra snakebites and also sheds light on the molecular mechanisms involved in coagulotoxicity within Naja. As the most coagulotoxic species are also those that produce characteristic extreme local tissue damage, future research should investigate potential synergistic actions between anticoagulant toxins and cytotoxins. Full article
(This article belongs to the Special Issue Snakebite – From Science to Society. Selected papers)
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Open AccessFeature PaperArticle Coagulotoxicity of Bothrops (Lancehead Pit-Vipers) Venoms from Brazil: Differential Biochemistry and Antivenom Efficacy Resulting from Prey-Driven Venom Variation
Toxins 2018, 10(10), 411; https://doi.org/10.3390/toxins10100411
Received: 18 September 2018 / Revised: 3 October 2018 / Accepted: 8 October 2018 / Published: 11 October 2018
Cited by 2 | PDF Full-text (7174 KB) | HTML Full-text | XML Full-text
Abstract
Lancehead pit-vipers (Bothrops genus) are an extremely diverse and medically important group responsible for the greatest number of snakebite envenomations and deaths in South America. Bothrops atrox (common lancehead), responsible for majority of snakebites and related deaths within the Brazilian Amazon, is [...] Read more.
Lancehead pit-vipers (Bothrops genus) are an extremely diverse and medically important group responsible for the greatest number of snakebite envenomations and deaths in South America. Bothrops atrox (common lancehead), responsible for majority of snakebites and related deaths within the Brazilian Amazon, is a highly adaptable and widely distributed species, whose venom variability has been related to several factors, including geographical distribution and habitat type. This study examined venoms from four B. atrox populations (Belterra and Santarém, PA; Pres. Figueiredo, AM and São Bento, MA), and two additional Bothrops species (B. jararaca and B. neuwiedi) from Southeastern region for their coagulotoxic effects upon different plasmas (human, amphibian, and avian). The results revealed inter– and intraspecific variations in coagulotoxicity, including distinct activities between the three plasmas, with variations in the latter two linked to ecological niche occupied by the snakes. Also examined were the correlated biochemical mechanisms of venom action. Significant variation in the relative reliance upon the cofactors calcium and phospholipid were revealed, and the relative dependency did not significantly correlate with potency. Relative levels of Factor X or prothrombin activating toxins correlated with prey type and prey escape potential. The antivenom was shown to perform better in neutralising prothrombin activation activity than neutralising Factor X activation activity. Thus, the data reveal new information regarding the evolutionary selection pressures shaping snake venom evolution, while also having significant implications for the treatment of the envenomed patient. These results are, therefore, an intersection between evolutionary biology and clinical medicine. Full article
(This article belongs to the Special Issue Snakebite – From Science to Society. Selected papers)
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Review

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Open AccessReview Toxin Neutralization Using Alternative Binding Proteins
Received: 15 December 2018 / Revised: 7 January 2019 / Accepted: 12 January 2019 / Published: 17 January 2019
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Abstract
Animal toxins present a major threat to human health worldwide, predominantly through snakebite envenomings, which are responsible for over 100,000 deaths each year. To date, the only available treatment against snakebite envenoming is plasma-derived antivenom. However, despite being key to limiting morbidity and [...] Read more.
Animal toxins present a major threat to human health worldwide, predominantly through snakebite envenomings, which are responsible for over 100,000 deaths each year. To date, the only available treatment against snakebite envenoming is plasma-derived antivenom. However, despite being key to limiting morbidity and mortality among snakebite victims, current antivenoms suffer from several drawbacks, such as immunogenicity and high cost of production. Consequently, avenues for improving envenoming therapy, such as the discovery of toxin-sequestering monoclonal antibodies against medically important target toxins through phage display selection, are being explored. However, alternative binding protein scaffolds that exhibit certain advantages compared to the well-known immunoglobulin G scaffold, including high stability under harsh conditions and low cost of production, may pose as possible low-cost alternatives to antibody-based therapeutics. There is now a plethora of alternative binding protein scaffolds, ranging from antibody derivatives (e.g., nanobodies), through rationally designed derivatives of other human proteins (e.g., DARPins), to derivatives of non-human proteins (e.g., affibodies), all exhibiting different biochemical and pharmacokinetic profiles. Undeniably, the high level of engineerability and potentially low cost of production, associated with many alternative protein scaffolds, present an exciting possibility for the future of snakebite therapeutics and merit thorough investigation. In this review, a comprehensive overview of the different types of binding protein scaffolds is provided together with a discussion on their relevance as potential modalities for use as next-generation antivenoms. Full article
(This article belongs to the Special Issue Snakebite – From Science to Society. Selected papers)
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Open AccessReview Global Availability of Antivenoms: The Relevance of Public Manufacturing Laboratories
Received: 16 November 2018 / Revised: 14 December 2018 / Accepted: 20 December 2018 / Published: 24 December 2018
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Abstract
Snakebite envenoming is a serious global public health problem, and international initiatives, under the coordination of the World Health Organization and its regional offices, are being developed to reduce the impact of this neglected tropical disease. The global availability of safe and effective [...] Read more.
Snakebite envenoming is a serious global public health problem, and international initiatives, under the coordination of the World Health Organization and its regional offices, are being developed to reduce the impact of this neglected tropical disease. The global availability of safe and effective antivenoms is one of the key aspects in this global strategy. This review discusses the role of public antivenom manufacturing laboratories for ensuring the supply of antivenoms. The difficulties faced by public laboratories are discussed, together with some tasks that need to be implemented for strengthening them. In addition, the concept of ‘redundancy’ in the supply of antivenoms is emphasized, as a way to cope with the risks associated with the provision of antivenoms by few manufacturers. In general, the public sector should play a leading role, in antivenom availability and other aspects as well, within the global struggle to reduce the mortality and morbidity caused by snakebite envenoming. Full article
(This article belongs to the Special Issue Snakebite – From Science to Society. Selected papers)
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Open AccessReview Innovative Immunization Strategies for Antivenom Development
Toxins 2018, 10(11), 452; https://doi.org/10.3390/toxins10110452
Received: 29 September 2018 / Revised: 29 October 2018 / Accepted: 30 October 2018 / Published: 2 November 2018
Cited by 2 | PDF Full-text (1770 KB) | HTML Full-text | XML Full-text
Abstract
Snakes, scorpions, and spiders are venomous animals that pose a threat to human health, and severe envenomings from the bites or stings of these animals must be treated with antivenom. Current antivenoms are based on plasma-derived immunoglobulins or immunoglobulin fragments from hyper-immunized animals. [...] Read more.
Snakes, scorpions, and spiders are venomous animals that pose a threat to human health, and severe envenomings from the bites or stings of these animals must be treated with antivenom. Current antivenoms are based on plasma-derived immunoglobulins or immunoglobulin fragments from hyper-immunized animals. Although these medicines have been life-saving for more than 120 years, opportunities to improve envenoming therapy exist. In the later decades, new biotechnological tools have been applied with the aim of improving the efficacy, safety, and affordability of antivenoms. Within the avenues explored, novel immunization strategies using synthetic peptide epitopes, recombinant toxins (or toxoids), or DNA strings as immunogens have demonstrated potential for generating antivenoms with high therapeutic antibody titers and broad neutralizing capacity. Furthermore, these approaches circumvent the need for venom in the production process of antivenoms, thereby limiting some of the complications associated with animal captivity and venom collection. Finally, an important benefit of innovative immunization approaches is that they are often compatible with existing antivenom manufacturing setups. In this review, we compile all reported studies examining venom-independent innovative immunization strategies for antivenom development. In addition, a brief description of toxin families of medical relevance found in snake, scorpion, and spider venoms is presented, as well as how biochemical, bioinformatic, and omics tools could aid the development of next-generation antivenoms. Full article
(This article belongs to the Special Issue Snakebite – From Science to Society. Selected papers)
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Other

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Open AccessCommentary Integrating Engineering, Manufacturing, and Regulatory Considerations in the Development of Novel Antivenoms
Received: 7 July 2018 / Revised: 23 July 2018 / Accepted: 27 July 2018 / Published: 31 July 2018
Cited by 3 | PDF Full-text (627 KB) | HTML Full-text | XML Full-text
Abstract
Snakebite envenoming is a neglected tropical disease that requires immediate attention. Conventional plasma-derived snakebite antivenoms have existed for more than 120 years and have been instrumental in saving thousands of lives. However, both a need and an opportunity exist for harnessing biotechnology and [...] Read more.
Snakebite envenoming is a neglected tropical disease that requires immediate attention. Conventional plasma-derived snakebite antivenoms have existed for more than 120 years and have been instrumental in saving thousands of lives. However, both a need and an opportunity exist for harnessing biotechnology and modern drug development approaches to develop novel snakebite antivenoms with better efficacy, safety, and affordability. For this to be realized, though, development approaches, clinical testing, and manufacturing must be feasible for any novel treatment modality to be brought to the clinic. Here, we present engineering, manufacturing, and regulatory considerations that need to be taken into account for any development process for a novel antivenom product, with a particular emphasis on novel antivenoms based on mixtures of monoclonal antibodies. We highlight key drug development challenges that must be addressed, and we attempt to outline some of the important shifts that may have to occur in the ways snakebite antivenoms are designed and evaluated. Full article
(This article belongs to the Special Issue Snakebite – From Science to Society. Selected papers)
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