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Venom Components Acting on the Hemostatic System: Structural and Mechanistic...
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Venom Components Acting on the Hemostatic System: Structural and Mechanistic Insights

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

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 17451

Special Issue Editors

Dr. Russolina Benedeta Zingali

E-Mail Website
Guest Editor
Laboratório de Hemostase e Venenos, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil
Interests: structure–activity relationship; proteomics; hemostasis; cancer; snake venom treatment
Dr. Robson Monteiro

E-Mail Website
Guest Editor
Laboratório de Trombose, Câncer e Inflamação, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21.941-902, Brazil
Interests: cancer; thrombosis; inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Venoms from different species of animals contain components, mainly proteins, and peptides, that can interfere with various physiopathological processes, including cancer, inflammation, neurotransmission, immune responses, cell growth, apoptosis, hemostasis, and others. The effects of crude venom from snakes on hemostasis have been recorded since the late 1700s. A large variety of molecules that interfere in the hemostatic process have been isolated, and their mechanisms of action characterized. For instance, molecules that perturb the hemostatic system can display pro or anticoagulant effects, activate or inhibit platelet aggregation, interfere in clot dissolution, and interfere with endothelial cells. This Special Issue focuses on the structural–activity relationship of some of these molecules and points to their mechanism of action.

Moreover, the applications of these molecules and derived analogs as tools for investigation, diagnosis, or use in drugs will also be presented and discussed.

Dr. Russolina Benedeta Zingali
Dr. Robson Monteiro
Guest Editors

Manuscript Submission Information

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Keywords

  • hemostasis
  • platelet
  • blood clotting
  • structure
  • mechanism of action
  • venom proteins
  • venom peptides
  • toxins
  • drug development
  • tools for diagnosis

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Published Papers (7 papers)

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Research

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21 pages, 5340 KiB  
Article
Importance of the Cysteine-Rich Domain of Snake Venom Prothrombin Activators: Insights Gained from Synthetic Neutralizing Antibodies
by Laetitia E. Misson Mindrebo, Jeffrey T. Mindrebo, Quoc Tran, Mark C. Wilkinson, Jessica M. Smith, Megan Verma, Nicholas R. Casewell, Gabriel C. Lander and Joseph G. Jardine
Toxins 2024, 16(8), 361; https://doi.org/10.3390/toxins16080361 - 15 Aug 2024
Cited by 1 | Viewed by 2262
Abstract
Snake venoms are cocktails of biologically active molecules that have evolved to immobilize prey, but can also induce a severe pathology in humans that are bitten. While animal-derived polyclonal antivenoms are the primary treatment for snakebites, they often have limitations in efficacy and [...] Read more.
Snake venoms are cocktails of biologically active molecules that have evolved to immobilize prey, but can also induce a severe pathology in humans that are bitten. While animal-derived polyclonal antivenoms are the primary treatment for snakebites, they often have limitations in efficacy and can cause severe adverse side effects. Building on recent efforts to develop improved antivenoms, notably through monoclonal antibodies, requires a comprehensive understanding of venom toxins. Among these toxins, snake venom metalloproteinases (SVMPs) play a pivotal role, particularly in viper envenomation, causing tissue damage, hemorrhage and coagulation disruption. One of the current challenges in the development of neutralizing monoclonal antibodies against SVMPs is the large size of the protein and the lack of existing knowledge of neutralizing epitopes. Here, we screened a synthetic human antibody library to isolate monoclonal antibodies against an SVMP from saw-scaled viper (genus Echis) venom. Upon characterization, several antibodies were identified that effectively blocked SVMP-mediated prothrombin activation. Cryo-electron microscopy revealed the structural basis of antibody-mediated neutralization, pinpointing the non-catalytic cysteine-rich domain of SVMPs as a crucial target. These findings emphasize the importance of understanding the molecular mechanisms of SVMPs to counter their toxic effects, thus advancing the development of more effective antivenoms. Full article
(This article belongs to the Special Issue Venom Components Acting on the Hemostatic System: Structural and Mechanistic Insights)
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18 pages, 3583 KiB  
Article
Blood Lines: Intraspecific and Interspecific Variations in Anticoagulant Actions of Agkistrodon Viperid Venoms
by Francisco C. P. Coimbra, Elda E. Sanchez, Bruno Lomonte, José María Gutiérrez, Juan J. Calvete and Bryan G. Fry
Toxins 2024, 16(7), 291; https://doi.org/10.3390/toxins16070291 - 26 Jun 2024
Cited by 2 | Viewed by 1953
Abstract
This study investigated the intraspecific and interspecific variability in the venom effects of Agkistrodon viperid snake species and subspecies (eleven venoms total) on plasma clotting times, fibrinogen levels, and fibrin clot strength. Significant delays in plasma clotting time were observed for A. conanti [...] Read more.
This study investigated the intraspecific and interspecific variability in the venom effects of Agkistrodon viperid snake species and subspecies (eleven venoms total) on plasma clotting times, fibrinogen levels, and fibrin clot strength. Significant delays in plasma clotting time were observed for A. conanti, A. contortrix mokasen, A. contortrix phaeogaster, A. howardgloydi, A. piscivorus leucostoma, and A. piscivorus piscivorus. Notably, the phylogenetically disjunct lineages A. conanti, A. contortrix mokasen, and A. howardgloydi exhibited the most potent anticoagulant effects, indicating the independent amplification of a basal trait. Inhibition assays with the activated clotting enzymes Factors XIa, IXa, Xa, and IIa (thrombin) revealed that FXa inhibition is another basal trait amplified independently on multiple occasions within the genus, but with A. howardgloydi, notably more potent than all others. Phospholipid degradation and zymogen destruction were identified as mechanisms underlying the variability in venom effects observed experimentally and in previous clinical reports. Thromboelastography demonstrated that the venoms did not clot fibrinogen directly but affected fibrin clot strength by damaging fibrinogen and that thrombin was subsequently only able to cleave into weak, unstable clots. The ability to activate Protein C, an endogenous anticoagulant enzyme, varied across species, with some venoms exceeding that of A. contortrix contortrix, which previously yielded the protein diagnostic agent Protac®. Phylogenetic analysis suggested that both fibrinogen degradation and Protein C activation were each amplified multiple times within the genus, albeit with negative correlation between these two modes of action. This study highlights the evolutionary, clinical, and biodiscovery implications of venom variability in the Agkistrodon species, underscoring their dynamic evolution, emphasising the need for tailored clinical approaches, and highlighting the potential for novel diagnostic and therapeutic developments inspired by the unique properties of snake venoms. Full article
(This article belongs to the Special Issue Venom Components Acting on the Hemostatic System: Structural and Mechanistic Insights)
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24 pages, 4815 KiB  
Article
The Clot Thickens: Differential Coagulotoxic and Cardiotoxic Activities of Anguimorpha Lizard Venoms
by James Dobson, Abhinandan Chowdhury, Jeremie Tai-A-Pin, Harold van der Ploeg, Amber Gillett and Bryan G. Fry
Toxins 2024, 16(6), 283; https://doi.org/10.3390/toxins16060283 - 20 Jun 2024
Cited by 4 | Viewed by 2256
Abstract
Despite their evolutionary novelty, lizard venoms are much less studied in comparison to the intense research on snake venoms. While the venoms of helodermatid lizards have long been assumed to be for defensive purposes, there is increasing evidence of toxic activities more useful [...] Read more.
Despite their evolutionary novelty, lizard venoms are much less studied in comparison to the intense research on snake venoms. While the venoms of helodermatid lizards have long been assumed to be for defensive purposes, there is increasing evidence of toxic activities more useful for predation than defence (such as paralytic neurotoxicity). This study aimed to ascertain the effects of Heloderma, Lanthanotus, and Varanus lizard venoms on the coagulation and cardiovascular systems. Anticoagulant toxicity was demonstrated for the Varanus species studied, with the venoms prolonging clotting times in human and bird plasma due to the destructive cleavage of fibrinogen. In contrast, thromboelastographic analyses on human and bird plasmas in this study demonstrated a procoagulant bioactivity for Heloderma venoms. A previous study on Heloderma venom using factor-depleted plasmas as a proxy model suggested a procoagulant factor was present that activated either Factor XI or Factor XII, but could not ascertain the precise target. Our activation studies using purified zymogens confirmed FXII activation. Comparisons of neonate and adult H. exasperatum, revealed the neonates to be more potent in the ability to activate FXII, being more similar to the venom of the smaller species H. suspectum than the adult H. exasperatum. This suggests potent FXII activation a basal trait in the genus, present in the small bodied last common ancestor. This also indicates an ontogenetic difference in prey preferences in the larger Heloderma species paralleing the change in venom biochemistry. In addition, as birds lack Factor XII, the ability to clot avian plasma suggested an additional procoagulant site of action, which was revealed to be the activation of Factor VII, with H. horridum being the most potent. This study also examined the effects upon the cardiovascular system, including the liberation of kinins from kininogen, which contributes to hypotension induction. This form of toxicity was previously described for Heloderma venoms, and was revealed in this study was to also be a pathophysiological effect of Lanthanotus and Varanus venoms. This suggests that this toxic activity was present in the venom of the last common ancestor of the anguimorph lizards, which is consistent with kallikrein enzymes being a shared toxin trait. This study therefore uncovered novel actions of anguimorph lizard venoms, not only contributing to the evolutionary biology body of knowledge but also revealing novel activities to mine for drug design lead compounds. Full article
(This article belongs to the Special Issue Venom Components Acting on the Hemostatic System: Structural and Mechanistic Insights)
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17 pages, 5158 KiB  
Article
Isolation and Functional Characterization of Erythrofibrase: An Alfa-Fibrinogenase Enzyme from Trimeresurus erythrurus Venom of North-East India
by Susmita Thakur, Rafika Yasmin, Anita Malhotra, Hmar Tlawmte Lalremsanga, Vishal Santra, Surajit Giri and Robin Doley
Toxins 2024, 16(4), 201; https://doi.org/10.3390/toxins16040201 - 22 Apr 2024
Viewed by 1973
Abstract
Green pit viper bites induce mild toxicity with painful local swelling, blistering, cellulitis, necrosis, ecchymosis and consumptive coagulopathy. Several bite cases of green pit vipers have been reported in several south-east Asian countries including the north-eastern region of India. The present study describes [...] Read more.
Green pit viper bites induce mild toxicity with painful local swelling, blistering, cellulitis, necrosis, ecchymosis and consumptive coagulopathy. Several bite cases of green pit vipers have been reported in several south-east Asian countries including the north-eastern region of India. The present study describes isolation and characterization of a haemostatically active protein from Trimeresurus erythrurus venom responsible for coagulopathy. Using a two-step chromatographic method, a snake venom serine protease erythrofibrase was purified to homogeneity. SDS-PAGE of erythrofibrase showed a single band of ~30 kDa in both reducing and non-reducing conditions. The primary structure of erythrofibrase was determined by ESI LC-MS/MS, and the partial sequence obtained showed 77% sequence similarity with other snake venom thrombin-like enzymes (SVTLEs). The partial sequence obtained had the typical 12 conserved cysteine residues, as well as the active site residues (His57, Asp102 and Ser195). Functionally, erythrofibrase showed direct fibrinogenolytic activity by degrading the Aα chain of bovine fibrinogen at a slow rate, which might be responsible for causing hypofibrinogenemia and incoagulable blood for several days in envenomated patients. Moreover, the inability of Indian polyvalent antivenom (manufactured by Premium Serum Pvt. Ltd., Maharashtra, India) to neutralize the thrombin-like and plasmin-like activity of erythrofibrase can be correlated with the clinical inefficacy of antivenom therapy. This is the first study reporting an α-fibrinogenase enzyme erythrofibrase from T. erythrurus venom, which is crucial for the pathophysiological manifestations observed in envenomated victims. Full article
(This article belongs to the Special Issue Venom Components Acting on the Hemostatic System: Structural and Mechanistic Insights)
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21 pages, 2990 KiB  
Article
Analytical Size Exclusion Chromatography Coupled with Mass Spectrometry in Parallel with High-Throughput Venomics and Bioassaying for Venom Profiling
by Sedef Terzioglu, Mátyás A. Bittenbinder, Julien Slagboom, Bas van de Velde, Nicholas R. Casewell and Jeroen Kool
Toxins 2023, 15(9), 552; https://doi.org/10.3390/toxins15090552 - 5 Sep 2023
Cited by 2 | Viewed by 2191
Abstract
Modern analytical size exclusion chromatography (SEC) is a suitable technique to separate venom toxin families according to their size characteristics. In this study, a method was developed to separate intact venom toxins from Bungarus multicinctus and Daboia russelii venoms via analytical SEC using [...] Read more.
Modern analytical size exclusion chromatography (SEC) is a suitable technique to separate venom toxin families according to their size characteristics. In this study, a method was developed to separate intact venom toxins from Bungarus multicinctus and Daboia russelii venoms via analytical SEC using volatile, non-salt-containing eluents for post-column mass spectrometry, coagulation bioassaying and high-throughput venomics. Two venoms were used to demonstrate the method developed. While the venom of Bungaurs multicinctus is known to exert anticoagulant effects on plasma, in this study, we showed the existence of both procoagulant toxins and anticoagulant toxins. For Daboia russelii venom, the method revealed characteristic procoagulant effects, with a 90 kDa mass toxin detected and matched with the Factor X-activating procoagulant heterotrimeric glycoprotein named RVV-X. The strong procoagulant effects for this toxin show that it was most likely eluted from size exclusion chromatography non-denatured. In conclusion, the separation of snake venom by size gave the opportunity to separate some specific toxin families from each other non-denatured, test these for functional bioactivities, detect the eluting mass on-line via mass spectrometry and identify the eluted toxins using high-throughput venomics. Full article
(This article belongs to the Special Issue Venom Components Acting on the Hemostatic System: Structural and Mechanistic Insights)
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Review

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30 pages, 3019 KiB  
Review
Potential Biotechnological Applications of Venoms from the Viperidae Family in Central America for Thrombosis
by Jorge Eduardo Chang Estrada, Taissa Nunes Guerrero, Daniel Fernando Reyes-Enríquez, Erica Santos Nardy, Roseane Guimarães Ferreira, Cristian José Ruiz Calderón, Irmgardt A. Wellmann, Kaio Murilo Monteiro Espíndola, Alejandro Ferraz do Prado, Andreimar Martins Soares, Marcos Roberto de Mattos Fontes, Marta Chagas Monteiro and Russolina Benedeta Zingali
Toxins 2024, 16(3), 142; https://doi.org/10.3390/toxins16030142 - 8 Mar 2024
Viewed by 3075
Abstract
Central America is home to one of the most abundant herpetofauna in the Americas, occupying only 7% of the continent’s total area. Vipers and lizards are among the most relevant venomous animals in medical practice due to the consequences of envenomation from the [...] Read more.
Central America is home to one of the most abundant herpetofauna in the Americas, occupying only 7% of the continent’s total area. Vipers and lizards are among the most relevant venomous animals in medical practice due to the consequences of envenomation from the bite of these animals. A great diversity of biomolecules with immense therapeutic and biotechnological value is contained in their venom. This paper describes the prominent leading representatives of the family Viperidae, emphasizing their morphology, distribution, habitat, feeding, and venom composition, as well as the biotechnological application of some isolated components from the venom of the animals from these families, focusing on molecules with potential anti-thrombotic action. We present the leading protein families that interfere with blood clotting, platelet activity, or the endothelium pro-thrombotic profile. In conclusion, Central America is an endemic region of venomous animals that can provide many molecules for biotechnological applications. Full article
(This article belongs to the Special Issue Venom Components Acting on the Hemostatic System: Structural and Mechanistic Insights)
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15 pages, 1430 KiB  
Review
The Role of Snake Venom Disintegrins in Angiogenesis
by Patricia Bianca Clissa, Maisa Splendore Della-Casa, Bianca Cestari Zychar and Sabri Saeed Sanabani
Toxins 2024, 16(3), 127; https://doi.org/10.3390/toxins16030127 - 1 Mar 2024
Cited by 7 | Viewed by 2746
Abstract
Angiogenesis, the formation of new blood vessels, plays a critical role in various physiological and pathological conditions. Snake venom disintegrins (SVDs) have been identified as significant regulators of this process. In this review, we explore the dual roles of SVD in angiogenesis, both [...] Read more.
Angiogenesis, the formation of new blood vessels, plays a critical role in various physiological and pathological conditions. Snake venom disintegrins (SVDs) have been identified as significant regulators of this process. In this review, we explore the dual roles of SVD in angiogenesis, both as antiangiogenic agents by inhibiting integrin binding and interfering with vascular endothelial growth factors and as proangiogenic agents by enhancing integrin binding, stimulating cell migration and proliferation, and inducing neoangiogenesis. Studies in vitro and in animal models have demonstrated these effects and offer significant therapeutic opportunities. The potential applications of SVD in diseases related to angiogenesis, such as cancer, ocular diseases, tissue regeneration, wound healing, and cardiovascular diseases, are also discussed. Overall, SVDs are promising potential therapeutics, and further advances in this field could lead to innovative treatments for diseases related to angiogenesis. Full article
(This article belongs to the Special Issue Venom Components Acting on the Hemostatic System: Structural and Mechanistic Insights)
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