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Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 12865

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Prof. Dr. Yuri N. Utkin

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Guest Editor

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
Interests: snake venoms; toxins; new proteins; isolation; properties; nicotinic acetylcholine receptor
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Prof. Dr. R. Manjunatha Kini

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Guest Editor

Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore
Interests: protein chemistry; structure-function relationships; protein–protein interaction; protein design and engineering
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Dear Colleagues,

In some animals, venoms have appeared as a means of defense and/or as a means of attack/hunting. Venoms may contain components of various chemical nature, commonly referred to as toxins. In the course of evolution, toxins have acquired the ability to selectively and effectively affect certain systems in the organism of the victim or predator. The development of methods for the identification and analysis of the chemical structure of organic compounds leads to the discovery of new toxins, for which it is necessary to establish the mechanisms of action. Moreover, new species of venomous animals are being discovered, for which it is also necessary to establish the molecular mechanisms of venom action. This understanding is very important for the effective treatment of intoxications, which still remain a serious problem in a number of regions of the planet. Currently, the most effective way to treat bites of venomous animals is the use of antisera obtained by immunizing large mammals (mainly horses) with small doses of venom. Although very effective, this method has a number of disadvantages, which requires the development of new treatments based on other molecular mechanisms. Since toxins are highly efficacious and selective for certain biological targets, they can serve as templates for drug development. Thus, the study of the molecular mechanisms of action of animal venoms, their toxins and new antitoxins is a very important task. The purpose of this Special Issue is to present the state of the art in the study of the molecular mechanisms underlying the action of animal venoms, their components and antitoxins.

Research articles, review articles as well as short communications are invited.

Please note that, for IJMS papers, theoretical studies should offer new insights into the understanding of experimental results or suggest new experimentally testable hypotheses.

Prof. Dr. Yuri N. Utkin
Prof. Dr. R. Manjunatha Kini
Guest Editors

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Keywords

venom
toxin
antitoxin
antivenom
neurotoxin
cytotoxin
hemotoxin
conotoxin
snake
scorpion
spider

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Published Papers (5 papers)

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29 pages, 7774 KiB

Open AccessArticle

A Russian Doll of Resistance: Nested Gains and Losses of Venom Immunity in Varanid Lizards

by Uthpala Chandrasekara, Marco Mancuso, Lorenzo Seneci, Lachlan Bourke, Dane F. Trembath, Joanna Sumner, Christina N. Zdenek and Bryan G. Fry

Int. J. Mol. Sci. 2024, 25(5), 2628; https://doi.org/10.3390/ijms25052628 - 23 Feb 2024

Viewed by 4987

Abstract

The interplay between predator and prey has catalyzed the evolution of venom systems, with predators honing their venoms in response to the evolving resistance of prey. A previous study showed that the African varanid species Varanus exanthematicus has heightened resistance to snake venoms compared to the Australian species V. giganteus, V. komodoensis, and V. mertensi, likely due to increased predation by sympatric venomous snakes on V. exanthematicus. To understand venom resistance among varanid lizards, we analyzed the receptor site targeted by venoms in 27 varanid lizards, including 25 Australian varanids. The results indicate an active evolutionary arms race between Australian varanid lizards and sympatric neurotoxic elapid snakes. Large species preying on venomous snakes exhibit inherited neurotoxin resistance, a trait potentially linked to their predatory habits. Consistent with the ‘use it or lose it’ aspect of venom resistance, this trait was secondarily reduced in two lineages that had convergently evolved gigantism (V. giganteus and the V. komodoensis/V. varius clade), suggestive of increased predatory success accompanying extreme size and also increased mechanical protection against envenomation due to larger scale osteoderms. Resistance was completely lost in the mangrove monitor V. indicus, consistent with venomous snakes not being common in their arboreal and aquatic niche. Conversely, dwarf varanids demonstrate a secondary loss at the base of the clade, with resistance subsequently re-evolving in the burrowing V. acanthurus/V. storri clade, suggesting an ongoing battle with neurotoxic predators. Intriguingly, within the V. acanthurus/V. storri clade, resistance was lost again in V. kingorum, which is morphologically and ecologically distinct from other members of this clade. Resistance was also re-evolved in V. glebopalma which is terrestrial in contrast to the arboreal/cliff dwelling niches occupied by the other members of its clade (V. glebopalma, V. mitchelli, V. scalaris, V. tristis). This ‘Russian doll’ pattern of venom resistance underscores the dynamic interaction between dwarf varanids and Australian neurotoxic elapid snakes. Our research, which included testing Acanthophis (death adder) venoms against varanid receptors as models for alpha-neurotoxic interactions, uncovered a fascinating instance of the Red Queen Hypothesis: some death adders have developed more potent toxins specifically targeting resistant varanids, a clear sign of the relentless predator–prey arms race. These results offer new insight into the complex dynamics of venom resistance and highlight the intricate ecological interactions that shape the natural world. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms 2.0)

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18 pages, 2114 KiB

Open AccessArticle

Acetylcholine-Binding Protein Affinity Profiling of Neurotoxins in Snake Venoms with Parallel Toxin Identification

by Giulia Palermo, Wietse M. Schouten, Luis Lago Alonso, Chris Ulens, Jeroen Kool and Julien Slagboom

Int. J. Mol. Sci. 2023, 24(23), 16769; https://doi.org/10.3390/ijms242316769 - 26 Nov 2023

Cited by 2 | Viewed by 1897

Abstract

Snakebite is considered a concerning issue and a neglected tropical disease. Three-finger toxins (3FTxs) in snake venoms primarily cause neurotoxic effects since they have high affinity for nicotinic acetylcholine receptors (nAChRs). Their small molecular size makes 3FTxs weakly immunogenic and therefore not appropriately targeted by current antivenoms. This study aims at presenting and applying an analytical method for investigating the therapeutic potential of the acetylcholine-binding protein (AChBP), an efficient nAChR mimic that can capture 3FTxs, for alternative treatment of elapid snakebites. In this analytical methodology, snake venom toxins were separated and characterised using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) and high-throughput venomics. By subsequent nanofractionation analytics, binding profiling of toxins to the AChBP was achieved with a post-column plate reader-based fluorescence-enhancement ligand displacement bioassay. The integrated method was established and applied to profiling venoms of six elapid snakes (Naja mossambica, Ophiophagus hannah, Dendroaspis polylepis, Naja kaouthia, Naja haje and Bungarus multicinctus). The methodology demonstrated that the AChBP is able to effectively bind long-chain 3FTxs with relatively high affinity, but has low or no binding affinity towards short-chain 3FTxs, and as such provides an efficient analytical platform to investigate binding affinity of 3FTxs to the AChBP and mutants thereof and to rapidly identify bound toxins. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms 2.0)

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23 pages, 4028 KiB

Open AccessArticle

Comparative Biochemical, Structural, and Functional Analysis of Recombinant Phospholipases D from Three Loxosceles Spider Venoms

by Hanna Câmara da Justa, Jorge Enrique Hernández González, Larissa Vuitika, Ricardo Barros Mariutti, Pedro Augusto Martinho Magnago, Fábio Rogério de Moraes, Andrea Senff-Ribeiro, Luiza Helena Gremski, Raghuvir Krishnaswamy Arni and Silvio Sanches Veiga

Int. J. Mol. Sci. 2023, 24(15), 12006; https://doi.org/10.3390/ijms241512006 - 26 Jul 2023

Cited by 2 | Viewed by 1489

Abstract

Spiders of Loxosceles genus are widely distributed and their venoms contain phospholipases D (PLDs), which degrade phospholipids and trigger inflammatory responses, dermonecrosis, hematological changes, and renal injuries. Biochemical, functional, and structural properties of three recombinant PLDs from L. intermedia, L. laeta, and L. gaucho, the principal species clinically relevant in South America, were analyzed. Sera against L. gaucho and L. laeta PLDs strongly cross-reacted with other PLDs, but sera against L. intermedia PLD mostly reacted with homologous molecules, suggesting underlying structural and functional differences. PLDs presented a similar secondary structure profile but distinct melting temperatures. Different methods demonstrated that all PLDs cleave sphingomyelin and lysophosphatidylcholine, but L. gaucho and L. laeta PLDs excelled. L. gaucho PLD showed greater “in vitro” hemolytic activity. L. gaucho and L. laeta PLDs were more lethal in assays with mice and crickets. Molecular dynamics simulations correlated their biochemical activities with differences in sequences and conformations of specific surface loops, which play roles in protein stability and in modulating interactions with the membrane. Despite the high similarity, PLDs from L. gaucho and L. laeta venoms are more active than L. intermedia PLD, requiring special attention from physicians when these two species prevail in endemic regions. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms 2.0)

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15 pages, 2107 KiB

Open AccessArticle

New Insights into Immunopathology Associated to Bothrops lanceolatus Snake Envenomation: Focus on PLA₂ Toxin

by Joel J. M. Gabrili, Giselle Pidde, Fabio Carlos Magnoli, Rafael Marques-Porto, Isadora Maria Villas-Boas, Carla Cristina Squaiella-Baptistão, Felipe Silva-de-França, François Burgher, Joël Blomet and Denise V. Tambourgi

Int. J. Mol. Sci. 2023, 24(12), 9931; https://doi.org/10.3390/ijms24129931 - 9 Jun 2023

Cited by 3 | Viewed by 1553

Abstract

The systemic increase in inflammatory mediator levels can induce diverse pathological disorders, including potentially thrombus formation, which may be lethal. Among the clinical conditions in which the formation of thrombi dictates the patient’s prognosis, envenomation by Bothrops lanceolatus should be emphasized, as it can evolve to stroke, myocardial infarction and pulmonary embolism. Despite their life-threatening potential, the immunopathological events and toxins involved in these reactions remain poorly explored. Therefore, in the present study, we examined the immunopathological events triggered by a PLA₂ purified from B. lanceolatus venom, using an ex vivo human blood model of inflammation. Our results showed that the purified PLA₂ from the venom of B. lanceolatus damages human erythrocytes in a dose dependent way. The cell injury was associated with a decrease in the levels of CD55 and CD59 complement regulators on the cell surface. Moreover, the generation of anaphylatoxins (C3a and C5a) and the soluble terminal complement complex (sTCC) indicates that human blood exposure to the toxin activates the complement system. Increased production of TNF-α, CXCL8, CCL2 and CCL5 followed complement activation. The venom PLA₂ also triggered the generation of lipid mediators, as evidenced by the detected high levels of LTB₄, PGE₂ and TXB₂. The scenario here observed of red blood cell damage, dysfunctions of the complement regulatory proteins, accompanied by an inflammatory mediator storm, suggests that B. lanceolatus venom PLA₂ contributes to the thrombotic disorders present in the envenomed individuals. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms 2.0)

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12 pages, 992 KiB

Open AccessHypothesis

Sodium Channel β Subunits—An Additional Element in Animal Tetrodotoxin Resistance?

by Lorenzo Seneci and Alexander S. Mikheyev

Int. J. Mol. Sci. 2024, 25(3), 1478; https://doi.org/10.3390/ijms25031478 - 25 Jan 2024

Cited by 1 | Viewed by 2266

Abstract

Tetrodotoxin (TTX) is a neurotoxic molecule used by many animals for defense and/or predation, as well as an important biomedical tool. Its ubiquity as a defensive agent has led to repeated independent evolution of tetrodotoxin resistance in animals. TTX binds to voltage-gated sodium channels (VGSC) consisting of α and β subunits. Virtually all studies investigating the mechanisms behind TTX resistance have focused on the α subunit of voltage-gated sodium channels, where tetrodotoxin binds. However, the possibility of β subunits also contributing to tetrodotoxin resistance was never explored, though these subunits act in concert. In this study, we present preliminary evidence suggesting a potential role of β subunits in the evolution of TTX resistance. We gathered mRNA sequences for all β subunit types found in vertebrates across 12 species (three TTX-resistant and nine TTX-sensitive) and tested for signatures of positive selection with a maximum likelihood approach. Our results revealed several sites experiencing positive selection in TTX-resistant taxa, though none were exclusive to those species in subunit β1, which forms a complex with the main physiological target of TTX (VGSC Na_v1.4). While experimental data validating these findings would be necessary, this work suggests that deeper investigation into β subunits as potential players in tetrodotoxin resistance may be worthwhile. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms 2.0)

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