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Toxins
Special Issues
Next-Generation Antivenoms: Discovery, Development, and Manufacturability
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Next-Generation Antivenoms: Discovery, Development, and Manufacturability

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

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 9023

Special Issue Editors

Dr. Timothy P. Jenkins

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Guest Editor
Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
Interests: next-generation antivenoms; recombinant antivenom; alternative protein scaffolds; therapeutic discovery; phage display; bioinformatics; droplet microfluidics; snakebite envenoming; biologics; antibody technologies; oligoclonal antibodies; biotech entrepreneurship and innovation; commercialization of life science.
Dr. Andreas Hougaard Laustsen

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Guest Editor
Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
Interests: antibody discovery; phage display; toxin neutralization; biologics; biotherapeutics; antibody technologies; oligoclonal antibodies; recombinant antivenom; toxicovenomics; snakebite envenoming; mamba venoms; toxin synergism; next-generation antivenoms; infectious diseases; biotech entrepreneurship; commercialization of life science; biotech innovation.
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Special Issue Information

Dear colleagues,

For a long time, animal envenomings have been an overlooked problem, despite the hundreds of thousands of deaths and disabilities caused by this disease each year. However, since envenomings predominantly affect the poor, an absence of research funding has been met with a similar lack of innovation. Fortunately, technological advances, alongside an increase in public funding, are now presenting a new horizon for envenoming therapeutics.

The dire scarcity of efficacious and affordable antivenoms necessitates a significant overhaul in how we approach envenoming therapeutics. A key paradigm shift lies in the change of focus from plasma-derived antivenoms to targeted therapeutic molecules neutralizing (only) medically relevant toxins. Indeed, recent advances have investigated therapeutic molecules, which are either inherently broadly specific against certain toxin (sub-)families (e.g., some enzymatic inhibitors) or scaffold molecules, which can be easily adapted to neutralize multiple targets (e.g., antibodies or similar scaffold proteins). Furthermore, efforts are being made to ensure that the discovery and development of such toxin-neutralizing molecules can be conducted in a parallelized high-throughput fashion and that manufacturability via standardized large-scale and low-cost production processes is ensured.

The focus of this Special Issue of Toxins will be on next-generation antivenoms. We invite you to submit original research articles and reviews on all aspects concerning the discovery, development, and manufacturability of such antivenoms. This includes novel screening approaches, in vitro functional assays, the discovery of new toxin binders and neutralizers, innovative strategies towards the production of antitoxins, and bioinformatic tools to aid these processes.

Dr. Timothy P. Jenkins
Dr. Andreas Hougaard Laustsen
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

  • Next-generation antivenoms
  • recombinant antivenoms
  • antivenom development
  • antivenom manufacture
  • small molecule toxin inhibitors
  • toxin neutralization
  • monoclonal antibodies
  • alternative protein scaffolds
  • toxicovenomics

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Published Papers (3 papers)

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Research

18 pages, 2079 KiB  
Article
Evaluation of Protection by Caffeic Acid, Chlorogenic Acid, Quercetin and Tannic Acid against the In Vitro Neurotoxicity and In Vivo Lethality of Crotalus durissus terrificus (South American Rattlesnake) Venom
by Isadora Caruso Fontana Oliveira, Edson Hideaki Yoshida, Murilo Melo Juste Dini, Ana Beatriz Olívio Paschoal, José Carlos Cogo, Maria Alice da Cruz-Höfling, Stephen Hyslop and Yoko Oshima-Franco
Toxins 2021, 13(11), 801; https://doi.org/10.3390/toxins13110801 - 13 Nov 2021
Cited by 2 | Viewed by 2268
Abstract
Systemic envenomation by Crotalus durissus terrificus (South American rattlesnake) can cause coagulopathy, rabdomyolysis, acute kidney injury, and peripheral neuromuscular blockade, the latter resulting in flaccid paralysis. Previous studies have shown that plant products such as tannic acid and theaflavin can protect against the [...] Read more.
Systemic envenomation by Crotalus durissus terrificus (South American rattlesnake) can cause coagulopathy, rabdomyolysis, acute kidney injury, and peripheral neuromuscular blockade, the latter resulting in flaccid paralysis. Previous studies have shown that plant products such as tannic acid and theaflavin can protect against the neuromuscular blockade caused by C. d. terrificus venom in vitro. In this work, we used mouse-isolated phrenic nerve-diaphragm preparations to examine the ability of caffeic acid, chlorogenic acid, and quercetin to protect against C. d. terrificus venom-induced neuromuscular blockade in vitro. In addition, the ability of tannic acid to protect against the systemic effects of severe envenomation was assessed in rats. Preincubation of venom with caffeic acid (0.5 mg/mL), chlorogenic acid (1 mg/mL), or quercetin (0.5 mg/mL) failed to protect against venom (10 μg/mL)-induced neuromuscular blockade. In rats, venom (6 mg kg−1, i.p.) caused death in ~8 h, which was prevented by preincubation of venom with tannic acid or the administration of antivenom 2 h post-venom, whereas tannic acid given 2 h post-venom prolonged survival (~18.5 h) but did not prevent death. Tannic acid (in preincubation protocols or given 2 h post-venom) had a variable effect on blood creatinine and urea and blood/urine protein levels and prevented venom-induced leukocytosis. Tannic acid attenuated the histological lesions associated with renal damage in a manner similar to antivenom. The protective effect of tannic acid appeared to be mediated by interaction with venom proteins, as assessed by SDS-PAGE. These findings suggest that tannic acid could be a potentially useful ancillary treatment for envenomation by C. d. terrificus. Full article
(This article belongs to the Special Issue Next-Generation Antivenoms: Discovery, Development, and Manufacturability)
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13 pages, 2553 KiB  
Article
Full Neutralization of Centruroides sculpturatus Scorpion Venom by Combining Two Human Antibody Fragments
by Lidia Riaño-Umbarila, José Alberto Romero-Moreno, Luis M. Ledezma-Candanoza, Timoteo Olamendi-Portugal, Lourival D. Possani and Baltazar Becerril
Toxins 2021, 13(10), 708; https://doi.org/10.3390/toxins13100708 - 6 Oct 2021
Cited by 7 | Viewed by 2671
Abstract
A fundamental issue of the characterization of single-chain variable fragments (scFvs), capable of neutralizing scorpion toxins, is their cross-neutralizing ability. This aspect is very important in Mexico because all scorpions dangerous to humans belong to the Centruroides genus, where toxin sequences show high [...] Read more.
A fundamental issue of the characterization of single-chain variable fragments (scFvs), capable of neutralizing scorpion toxins, is their cross-neutralizing ability. This aspect is very important in Mexico because all scorpions dangerous to humans belong to the Centruroides genus, where toxin sequences show high identity. Among toxin-neutralizing antibodies that were generated in a previous study, scFv 10FG2 showed a broad cross-reactivity against several Centruroides toxins, while the one of scFv LR is more limited. Both neutralizing scFvs recognize independent epitopes of the toxins. In the present work, the neutralization capacity of these two scFvs against two medically important toxins of the venom of Centruroides sculpturatus Ewing was evaluated. The results showed that these toxins are recognized by both scFvs with affinities between 1.8 × 10−9 and 6.1 × 10−11 M. For this reason, their ability to neutralize the venom was evaluated in mice, where scFv 10FG2 showed a better protective capacity. A combination of both scFvs at a molar ratio of 1:5:5 (toxins: scFv 10FG2: scFv LR) neutralized the venom without the appearance of any signs of intoxication. These results indicate a complementary activity of these two scFvs during venom neutralization. Full article
(This article belongs to the Special Issue Next-Generation Antivenoms: Discovery, Development, and Manufacturability)
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18 pages, 3563 KiB  
Article
A Novel Apilic Antivenom to Treat Massive, Africanized Honeybee Attacks: A Preclinical Study from the Lethality to Some Biochemical and Pharmacological Activities Neutralization
by Jhonatha Mota Teixeira-Cruz, Marcelo Abrahão Strauch, Marcos Monteiro-Machado, Matheus Silva Tavares-Henriques, João Alfredo de Moraes, Luís Eduardo Ribeiro da Cunha, Rui Seabra Ferreira, Jr., Benedito Barraviera, Luis Eduardo M. Quintas and Paulo A. Melo
Toxins 2021, 13(1), 30; https://doi.org/10.3390/toxins13010030 - 5 Jan 2021
Cited by 10 | Viewed by 2993
Abstract
Massive, Africanized honeybee attacks have increased in Brazil over the years. Humans and animals present local and systemic effects after envenomation, and there is no specific treatment for this potentially lethal event. This study evaluated the ability of a new Apilic antivenom, which [...] Read more.
Massive, Africanized honeybee attacks have increased in Brazil over the years. Humans and animals present local and systemic effects after envenomation, and there is no specific treatment for this potentially lethal event. This study evaluated the ability of a new Apilic antivenom, which is composed of F(ab’)2 fraction of specific immunoglobulins in heterologous and hyperimmune equine serum, to neutralize A. mellifera venom and melittin, in vitro and in vivo, in mice. Animal experiments were performed in according with local ethics committee license (UFRJ protocol no. DFBCICB072-04/16). Venom dose-dependent lethality was diminished with 0.25–0.5 μL of intravenous Apilic antivenom/μg honeybee venom. In vivo injection of 0.1–1 μg/g bee venom induced myotoxicity, hemoconcentration, paw edema, and increase of vascular permeability which were antagonized by Apilic antivenom. Cytotoxicity, assessed in renal LLC-PK1 cells and challenged with 10 μg/mL honeybee venom or melittin, was neutralized by preincubation with Apilic antivenom, as well the hemolytic activity. Apilic antivenom inhibited phospholipase and hyaluronidase enzymatic activities. In flow cytometry experiments, Apilic antivenom neutralized reduction of cell viability due to necrosis by honeybee venom or melittin. These results showed that this antivenom is effective inhibitor of honeybee venom actions. Thus, this next generation of Apilic antivenom emerges as a new promising immunobiological product for the treatment of massive, Africanized honeybee attacks. Full article
(This article belongs to the Special Issue Next-Generation Antivenoms: Discovery, Development, and Manufacturability)
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