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Freek J. Vonk
Naturalis Biodiversity Center, Darwinweg 2, 2333CR Leiden, the Netherlands

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Journal article
Published: 23 April 2021 in Toxins
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Bites from elapid snakes typically result in neurotoxic symptoms in snakebite victims. Neurotoxins are, therefore, often the focus of research relating to understanding the pathogenesis of elapid bites. However, recent evidence suggests that some elapid snake venoms contain anticoagulant toxins which may help neurotoxic components spread more rapidly. This study examines the effects of venom from the West African black-necked spitting cobra (Naja nigricollis) on blood coagulation and identifies potential coagulopathic toxins. An integrated RPLC-MS methodology, coupled with nanofractionation, was first used to separate venom components, followed by MS, proteomics and coagulopathic bioassays. Coagulation assays were performed on both crude and nanofractionated N. nigricollis venom toxins as well as PLA2s and 3FTx purified from the venom. Assays were then repeated with the addition of either the phospholipase A2 inhibitor varespladib or the snake venom metalloproteinase inhibitor marimastat to assess whether either toxin inhibitor is capable of neutralizing coagulopathic venom activity. Subsequent proteomic analysis was performed on nanofractionated bioactive venom toxins using tryptic digestion followed by nanoLC-MS/MS measurements, which were then identified using Swiss-Prot and species-specific database searches. Varespladib, but not marimastat, was found to significantly reduce the anticoagulant activity of N. nigricollis venom and MS and proteomics analyses confirmed that the anticoagulant venom components mostly consisted of PLA2 proteins. We, therefore, conclude that PLA2s are the most likely candidates responsible for anticoagulant effects stimulated by N. nigricollis venom.

ACS Style

Taline Kazandjian; Arif Arrahman; Kristina Still; Govert Somsen; Freek Vonk; Nicholas Casewell; Mark Wilkinson; Jeroen Kool. Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib. Toxins 2021, 13, 302 .

AMA Style

Taline Kazandjian, Arif Arrahman, Kristina Still, Govert Somsen, Freek Vonk, Nicholas Casewell, Mark Wilkinson, Jeroen Kool. Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib. Toxins. 2021; 13 (5):302.

Chicago/Turabian Style

Taline Kazandjian; Arif Arrahman; Kristina Still; Govert Somsen; Freek Vonk; Nicholas Casewell; Mark Wilkinson; Jeroen Kool. 2021. "Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib." Toxins 13, no. 5: 302.

Journal article
Published: 02 October 2020 in Toxins
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Venomous snakes are important subjects of study in evolution, ecology, and biomedicine. Many venomous snakes have alpha-neurotoxins (α-neurotoxins) in their venom. These toxins bind the alpha-1 nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction, causing paralysis and asphyxia. Several venomous snakes and their predators have evolved resistance to α-neurotoxins. The resistance is conferred by steric hindrance from N-glycosylated asparagines at amino acids 187 or 189, by an arginine at position 187 that has been hypothesized to either electrostatically repulse positively charged neurotoxins or sterically interfere with α-neurotoxin binding, or proline replacements at positions 194 or 197 of the nAChR ligand-binding domain to inhibit α-neurotoxin binding through structural changes in the receptor. Here, we analyzed this domain in 148 vertebrate species, and assessed its amino acid sequences for resistance-associated mutations. Of these sequences, 89 were sequenced de novo. We find widespread convergent evolution of the N-glycosylation form of resistance in several taxa including venomous snakes and their lizard prey, but not in the snake-eating birds studied. We also document new lineages with the arginine form of inhibition. Using an in vivo assay in four species, we provide further evidence that N-glycosylation mutations reduce the toxicity of cobra venom. The nAChR is of crucial importance for normal neuromuscular function and is highly conserved throughout the vertebrates as a result. Our research shows that the evolution of α-neurotoxins in snakes may well have prompted arms races and mutations to this ancient receptor across a wide range of sympatric vertebrates. These findings underscore the inter-connectedness of the biosphere and the ripple effects that one adaption can have across global ecosystems.

ACS Style

Muzaffar A. Khan; Daniel Dashevsky; Harald Kerkkamp; Dušan Kordiš; Merijn A. G. De Bakker; Roel Wouters; Jory Van Thiel; Bianca Op Den Brouw; Freek J. Vonk; R. Manjunatha Kini; Jawad Nazir; Bryan G. Fry; Michael K. Richardson. Widespread Evolution of Molecular Resistance to Snake Venom α-Neurotoxins in Vertebrates. Toxins 2020, 12, 638 .

AMA Style

Muzaffar A. Khan, Daniel Dashevsky, Harald Kerkkamp, Dušan Kordiš, Merijn A. G. De Bakker, Roel Wouters, Jory Van Thiel, Bianca Op Den Brouw, Freek J. Vonk, R. Manjunatha Kini, Jawad Nazir, Bryan G. Fry, Michael K. Richardson. Widespread Evolution of Molecular Resistance to Snake Venom α-Neurotoxins in Vertebrates. Toxins. 2020; 12 (10):638.

Chicago/Turabian Style

Muzaffar A. Khan; Daniel Dashevsky; Harald Kerkkamp; Dušan Kordiš; Merijn A. G. De Bakker; Roel Wouters; Jory Van Thiel; Bianca Op Den Brouw; Freek J. Vonk; R. Manjunatha Kini; Jawad Nazir; Bryan G. Fry; Michael K. Richardson. 2020. "Widespread Evolution of Molecular Resistance to Snake Venom α-Neurotoxins in Vertebrates." Toxins 12, no. 10: 638.

Journal article
Published: 20 August 2020 in Biomedicines
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Animal-derived antivenoms are the only specific therapies currently available for the treatment of snake envenoming, but these products have a number of limitations associated with their efficacy, safety and affordability for use in tropical snakebite victims. Small molecule drugs and drug candidates are regarded as promising alternatives for filling the critical therapeutic gap between snake envenoming and effective treatment. In this study, by using an advanced analytical technique that combines chromatography, mass spectrometry and bioassaying, we investigated the effect of several small molecule inhibitors that target phospholipase A2 (varespladib) and snake venom metalloproteinase (marimastat, dimercaprol and DMPS) toxin families on inhibiting the activities of coagulopathic toxins found in Viperinae snake venoms. The venoms of Echis carinatus, Echis ocellatus, Daboia russelii and Bitis arietans, which are known for their potent haemotoxicities, were fractionated in high resolution onto 384-well plates using liquid chromatography followed by coagulopathic bioassaying of the obtained fractions. Bioassay activities were correlated to parallel recorded mass spectrometric and proteomics data to assign the venom toxins responsible for coagulopathic activity and assess which of these toxins could be neutralized by the inhibitors under investigation. Our results showed that the phospholipase A2-inhibitor varespladib neutralized the vast majority of anticoagulation activities found across all of the tested snake venoms. Of the snake venom metalloproteinase inhibitors, marimastat demonstrated impressive neutralization of the procoagulation activities detected in all of the tested venoms, whereas dimercaprol and DMPS could only partially neutralize these activities at the doses tested. Our results provide additional support for the concept that combinations of small molecules, particularly the combination of varespladib with marimastat, serve as a drug-repurposing opportunity to develop new broad-spectrum inhibitor-based therapies for snakebite envenoming.

ACS Style

Chunfang Xie; Laura-Oana Albulescu; Mátyás A. Bittenbinder; Govert W. Somsen; Freek J. Vonk; Nicholas R. Casewell; Jeroen Kool. Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins. Biomedicines 2020, 8, 297 .

AMA Style

Chunfang Xie, Laura-Oana Albulescu, Mátyás A. Bittenbinder, Govert W. Somsen, Freek J. Vonk, Nicholas R. Casewell, Jeroen Kool. Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins. Biomedicines. 2020; 8 (9):297.

Chicago/Turabian Style

Chunfang Xie; Laura-Oana Albulescu; Mátyás A. Bittenbinder; Govert W. Somsen; Freek J. Vonk; Nicholas R. Casewell; Jeroen Kool. 2020. "Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins." Biomedicines 8, no. 9: 297.

Journal article
Published: 17 June 2020 in Biomedicines
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Phospholipase A2 (PLA2) enzymes are important toxins found in many snake venoms, and they can exhibit a variety of toxic activities including causing hemolysis and/or anticoagulation. In this study, the inhibiting effects of the small molecule PLA2 inhibitor varespladib on snake venom PLA2s was investigated by nanofractionation analytics, which combined chromatography, mass spectrometry (MS), and bioassays. The venoms of the medically important snake species Bothrops asper, Calloselasma rhodostoma, Deinagkistrodon acutus, Daboia russelii, Echis carinatus, Echis ocellatus, and Oxyuranus scutellatus were separated by liquid chromatography (LC) followed by nanofractionation and interrogation of the fractions by a coagulation assay and a PLA2 assay. Next, we assessed the ability of varespladib to inhibit the activity of enzymatic PLA2s and the coagulopathic toxicities induced by fractionated snake venom toxins, and identified these bioactive venom toxins and those inhibited by varespladib by using parallel recorded LC-MS data and proteomics analysis. We demonstrated here that varespladib was not only capable of inhibiting the PLA2 activities of hemotoxic snake venoms, but can also effectively neutralize the coagulopathic toxicities (most profoundly anticoagulation) induced by venom toxins. While varespladib effectively inhibited PLA2 toxins responsible for anticoagulant effects, we also found some evidence that this inhibitory molecule can partially abrogate procoagulant venom effects caused by different toxin families. These findings further emphasize the potential clinical utility of varespladib in mitigating the toxic effects of certain snakebites.

ACS Style

Chunfang Xie; Laura-Oana Albulescu; Kristina B. M. Still; Julien Slagboom; Yumei Zhao; Zhengjin Jiang; Govert W. Somsen; Freek J. Vonk; Nicholas R. Casewell; Jeroen Kool. Varespladib Inhibits the Phospholipase A2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes. Biomedicines 2020, 8, 165 .

AMA Style

Chunfang Xie, Laura-Oana Albulescu, Kristina B. M. Still, Julien Slagboom, Yumei Zhao, Zhengjin Jiang, Govert W. Somsen, Freek J. Vonk, Nicholas R. Casewell, Jeroen Kool. Varespladib Inhibits the Phospholipase A2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes. Biomedicines. 2020; 8 (6):165.

Chicago/Turabian Style

Chunfang Xie; Laura-Oana Albulescu; Kristina B. M. Still; Julien Slagboom; Yumei Zhao; Zhengjin Jiang; Govert W. Somsen; Freek J. Vonk; Nicholas R. Casewell; Jeroen Kool. 2020. "Varespladib Inhibits the Phospholipase A2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes." Biomedicines 8, no. 6: 165.

Preprint content
Published: 20 January 2020
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Many organisms, ranging from plants to mammals, contain phospholipase A2enzymes (PLA2s), which catalyze the production of lysophospholipids and fatty acid proinflammatory mediators. PLA2s are also common constituents of animal venoms, including bees, scorpions and snakes, and they cause a wide variety of toxic effects including neuro-, myo-, cyto-, and cardio-toxicity, anticoagulation and edema. The aim of this study was to develop a generic method for profiling enzymatically active PLA2s in snake venoms after chromatographic separation. For this, low-volume high-throughput assays for assessment of enzymatic PLA2activity were evaluated and optimized. Subsequently, the assays were incorporated into a nanofractionation platform that combines high-resolution fractionation of crude venoms by liquid chromatography (LC) with bioassaying in 384-well plate format, and parallel mass spectrometric (MS) detection for toxin identification. The miniaturized assays developed are based on absorbance or fluorescence detection (respectively, using cresol red or fluorescein as pH indicators) to monitor the pH drop associated with free fatty acid formation by enzymatically active PLA2s. The methodology was demonstrated for assessment of PLA2activity profiles of venoms from the snake speciesBothrops asper,Echis carinatus,Echis coloratus, Echis ocellatus,Oxyuranus scutellatusandDaboia russelii russelii.

ACS Style

Kristina B.M. Still; Julien R Slagboom; Sarah Kidwai; Chunfang Xie; Bastiaan Eisses; Freek J. Vonk; Govert W. Somsen; Nicholas R. Casewell; Jeroen Kool. Development of high-throughput screening assays for profiling snake venom Phospholipase A2activity after high-resolution chromatographic fractionation. 2020, 1 .

AMA Style

Kristina B.M. Still, Julien R Slagboom, Sarah Kidwai, Chunfang Xie, Bastiaan Eisses, Freek J. Vonk, Govert W. Somsen, Nicholas R. Casewell, Jeroen Kool. Development of high-throughput screening assays for profiling snake venom Phospholipase A2activity after high-resolution chromatographic fractionation. . 2020; ():1.

Chicago/Turabian Style

Kristina B.M. Still; Julien R Slagboom; Sarah Kidwai; Chunfang Xie; Bastiaan Eisses; Freek J. Vonk; Govert W. Somsen; Nicholas R. Casewell; Jeroen Kool. 2020. "Development of high-throughput screening assays for profiling snake venom Phospholipase A2activity after high-resolution chromatographic fractionation." , no. : 1.

Journal article
Published: 16 January 2020 in Toxins
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Venomous snakebite is one of the world’s most lethal neglected tropical diseases. Animal-derived antivenoms are the only standardized specific therapies currently available for treating snakebite envenoming, but due to venom variation, often this treatment is not effective in counteracting all clinical symptoms caused by the multitude of injected toxins. In this study, the coagulopathic toxicities of venoms from the medically relevant snake species Bothrops asper, Calloselasma rhodostoma, Deinagkistrodon acutus, Daboia russelii, Echis carinatus and Echis ocellatus were assessed. The venoms were separated by liquid chromatography (LC) followed by nanofractionation and parallel mass spectrometry (MS). A recently developed high-throughput coagulation assay was employed to assess both the pro- and anticoagulant activity of separated venom toxins. The neutralization capacity of antivenoms on separated venom components was assessed and the coagulopathic venom peptides and enzymes that were either neutralized or remained active in the presence of antivenom were identified by correlating bioassay results with the MS data and with off-line generated proteomics data. The results showed that most snake venoms analyzed contained both procoagulants and anticoagulants. Most anticoagulants were identified as phospholipases A2s (PLA2s) and most procoagulants correlated with snake venom metalloproteinases (SVMPs) and serine proteases (SVSPs). This information can be used to better understand antivenom neutralization and can aid in the development of next-generation antivenom treatments.

ACS Style

Chunfang Xie; Julien Slagboom; Laura-Oana Albulescu; Ben Bruyneel; Kristina B. M. Still; Freek J. Vonk; Govert W. Somsen; Nicholas R. Casewell; Jeroen Kool. Antivenom Neutralization of Coagulopathic Snake Venom Toxins Assessed by Bioactivity Profiling Using Nanofractionation Analytics. Toxins 2020, 12, 53 .

AMA Style

Chunfang Xie, Julien Slagboom, Laura-Oana Albulescu, Ben Bruyneel, Kristina B. M. Still, Freek J. Vonk, Govert W. Somsen, Nicholas R. Casewell, Jeroen Kool. Antivenom Neutralization of Coagulopathic Snake Venom Toxins Assessed by Bioactivity Profiling Using Nanofractionation Analytics. Toxins. 2020; 12 (1):53.

Chicago/Turabian Style

Chunfang Xie; Julien Slagboom; Laura-Oana Albulescu; Ben Bruyneel; Kristina B. M. Still; Freek J. Vonk; Govert W. Somsen; Nicholas R. Casewell; Jeroen Kool. 2020. "Antivenom Neutralization of Coagulopathic Snake Venom Toxins Assessed by Bioactivity Profiling Using Nanofractionation Analytics." Toxins 12, no. 1: 53.

Journal article
Published: 13 August 2019 in BMC Genomics
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Venom has evolved in parallel in multiple animals for the purpose of self-defense, prey capture or both. These venoms typically consist of highly complex mixtures of toxins: diverse bioactive peptides and/or proteins each with a specific pharmacological activity. Because of their specificity, they can be used as experimental tools to study cell mechanisms and develop novel medicines and drugs. It is therefore potentially valuable to explore the venoms of various animals to characterize their toxins and identify novel toxin-families. This study focuses on the annotation and exploration of the transcriptomes of six scorpion species from three different families. The transcriptomes were annotated with a custom-built automated pipeline, primarily consisting of Basic Local Alignment Search Tool searches against UniProt databases and filter steps based on transcript coverage. We annotated the transcriptomes of four scorpions from the family Buthidae, one from Iuridae and one from Diplocentridae using our annotation pipeline. We found that the four buthid scorpions primarily produce disulfide-bridged ion-channel targeting toxins, while the non-buthid scorpions have a higher abundance of non-disulfide-bridged toxins. Furthermore, analysis of the “unidentified” transcripts resulted in the discovery of six novel putative toxin families containing a total of 37 novel putative toxins. Additionally, 33 novel toxins in existing toxin-families were found. Lastly, 19 novel putative secreted proteins without toxin-like disulfide bonds were found. We were able to assign most transcripts to a toxin family and classify the venom composition for all six scorpions. In addition to advancing our fundamental knowledge of scorpion venomics, this study may serve as a starting point for future research by facilitating the identification of the venom composition of scorpions and identifying novel putative toxin families.

ACS Style

Dwin G. B. Grashof; Harald M. I. Kerkkamp; Sandra Afonso; John Archer; D. James Harris; Michael K. Richardson; Freek J. Vonk; Arie Van Der Meijden. Transcriptome annotation and characterization of novel toxins in six scorpion species. BMC Genomics 2019, 20, 1 -10.

AMA Style

Dwin G. B. Grashof, Harald M. I. Kerkkamp, Sandra Afonso, John Archer, D. James Harris, Michael K. Richardson, Freek J. Vonk, Arie Van Der Meijden. Transcriptome annotation and characterization of novel toxins in six scorpion species. BMC Genomics. 2019; 20 (1):1-10.

Chicago/Turabian Style

Dwin G. B. Grashof; Harald M. I. Kerkkamp; Sandra Afonso; John Archer; D. James Harris; Michael K. Richardson; Freek J. Vonk; Arie Van Der Meijden. 2019. "Transcriptome annotation and characterization of novel toxins in six scorpion species." BMC Genomics 20, no. 1: 1-10.

Journal article
Published: 03 June 2019 in Toxicology in Vitro
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Envenomations by venomous snake have major public health implications on a global scale. Despite its medical importance, snakebite has long been a neglected tropical disease by both governments and medical science. Many aspects of the resulting pathophysiology have been largely under-investigated. Most research on snake venom has focused on the neurological effects, with coagulotoxicity being relatively neglected, especially for venoms in the Elapidae snake family. In order to fill the knowledge gap regarding the coagulotoxic effects of elapid snake venoms, we performed functional activity tests to determine the fibrinogenolytic activity of 30 African and Asian elapid venoms across eight genera. The results of this study revealed that destructive (non-clotting) fibrinogenolytic activity is widespread across the African and Asian elapids. This trait evolved independently twice: once in the Hemachatus/Naja last common ancestor and again in Ophiophagus. Further, within Naja this trait was amplified on several independent occasions and possibly explains some of the clinical symptoms produced by these species. Species within the Hemachatus/Naja with fibrinogenolytic activity only cleaved the Aα-chain of fibrinogen, whereas Ophiophagus venoms degraded both the Aα- and the Bβ-chain of fibrinogen. All other lineages tested in this study lacked significant fibrinogenolytic effects. Our systematic research across Afro-Asian elapid snake venoms helps shed light on the various molecular mechanisms that are involved in coagulotoxicity within Elapidae.

ACS Style

Mátyás A. Bittenbinder; James S. Dobson; Christina N. Zdenek; Bianca Op Den Brouw; Arno Naude; Freek J. Vonk; Bryan G. Fry. Differential destructive (non-clotting) fibrinogenolytic activity in Afro-Asian elapid snake venoms and the links to defensive hooding behavior. Toxicology in Vitro 2019, 60, 330 -335.

AMA Style

Mátyás A. Bittenbinder, James S. Dobson, Christina N. Zdenek, Bianca Op Den Brouw, Arno Naude, Freek J. Vonk, Bryan G. Fry. Differential destructive (non-clotting) fibrinogenolytic activity in Afro-Asian elapid snake venoms and the links to defensive hooding behavior. Toxicology in Vitro. 2019; 60 ():330-335.

Chicago/Turabian Style

Mátyás A. Bittenbinder; James S. Dobson; Christina N. Zdenek; Bianca Op Den Brouw; Arno Naude; Freek J. Vonk; Bryan G. Fry. 2019. "Differential destructive (non-clotting) fibrinogenolytic activity in Afro-Asian elapid snake venoms and the links to defensive hooding behavior." Toxicology in Vitro 60, no. : 330-335.

Journal article
Published: 04 December 2018 in Toxins
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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.

ACS Style

Mátyás A. Bittenbinder; Christina N. Zdenek; Bianca Op Den Brouw; Nicholas J. Youngman; James S. Dobson; Arno Naude; Freek J. Vonk; Bryan G. Fry. 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, 516 .

AMA Style

Mátyás A. Bittenbinder, Christina N. Zdenek, Bianca Op Den Brouw, Nicholas J. Youngman, James S. Dobson, Arno Naude, Freek J. Vonk, Bryan G. Fry. 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.

Chicago/Turabian Style

Mátyás A. Bittenbinder; Christina N. Zdenek; Bianca Op Den Brouw; Nicholas J. Youngman; James S. Dobson; Arno Naude; Freek J. Vonk; Bryan G. Fry. 2018. "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 10, no. 12: 516.

Journal article
Published: 01 August 2018 in Toxicon
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Currently, biological and organic substances are screened in order to find a new generation of therapeutics active against cancer. Previous research has identified promising candidate peptides in snake venom. In this study, venoms from different snake species (Naja annulifera, Naja kaouthia, Ophiophagus hannah and Echis carinatus) were screened for potential anti-cancer properties using pancreatic tumour cells as the assay system. The cells were incubated with venom and then subjected to the following analyses: (i) in vitro cell death (ii) in vitro migration (iii) in vivo dissemination and (iv) in vivo angiogenesis. For the in vivo assays, the cells, after incubation and labelling, were transplanted into the yolk sac of zebrafish embryos for motility and angiogenesis. The results showed strong effects in cells treated with venoms from Ophiophagus hannah and Echis carinatus in the in vitro assays. In the in vivo assays, venom derived from Ophiophagus hannah had the most potent effects with respect to angiogenesis. These venoms might therefore be considered as candidates for further studies.

ACS Style

Harald Kerkkamp; Christoph Bagowski; Jeroen Kool; Babette van Soolingen; Freek J. Vonk; Daniëlle Vlecken. Whole snake venoms: Cytotoxic, anti-metastatic and antiangiogenic properties. Toxicon 2018, 150, 39 -49.

AMA Style

Harald Kerkkamp, Christoph Bagowski, Jeroen Kool, Babette van Soolingen, Freek J. Vonk, Daniëlle Vlecken. Whole snake venoms: Cytotoxic, anti-metastatic and antiangiogenic properties. Toxicon. 2018; 150 ():39-49.

Chicago/Turabian Style

Harald Kerkkamp; Christoph Bagowski; Jeroen Kool; Babette van Soolingen; Freek J. Vonk; Daniëlle Vlecken. 2018. "Whole snake venoms: Cytotoxic, anti-metastatic and antiangiogenic properties." Toxicon 150, no. : 39-49.

Journal article
Published: 13 March 2017 in Toxins
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The cytotoxicity of the venom of 25 species of Old World elapid snake was tested and compared with the morphological and behavioural adaptations of hooding and spitting. We determined that, contrary to previous assumptions, the venoms of spitting species are not consistently more cytotoxic than those of closely related non-spitting species. While this correlation between spitting and non-spitting was found among African cobras, it was not present among Asian cobras. On the other hand, a consistent positive correlation was observed between cytotoxicity and utilisation of the defensive hooding display that cobras are famous for. Hooding and spitting are widely regarded as defensive adaptations, but it has hitherto been uncertain whether cytotoxicity serves a defensive purpose or is somehow useful in prey subjugation. The results of this study suggest that cytotoxicity evolved primarily as a defensive innovation and that it has co-evolved twice alongside hooding behavior: once in the Hemachatus + Naja and again independently in the king cobras (Ophiophagus). There was a significant increase of cytotoxicity in the Asian Naja linked to the evolution of bold aposematic hood markings, reinforcing the link between hooding and the evolution of defensive cytotoxic venoms. In parallel, lineages with increased cytotoxicity but lacking bold hood patterns evolved aposematic markers in the form of high contrast body banding. The results also indicate that, secondary to the evolution of venom rich in cytotoxins, spitting has evolved three times independently: once within the African Naja, once within the Asian Naja, and once in the Hemachatus genus. The evolution of cytotoxic venom thus appears to facilitate the evolution of defensive spitting behaviour. In contrast, a secondary loss of cytotoxicity and reduction of the hood occurred in the water cobra Naja annulata, which possesses streamlined neurotoxic venom similar to that of other aquatic elapid snakes (e.g., hydrophiine sea snakes). The results of this study make an important contribution to our growing understanding of the selection pressures shaping the evolution of snake venom and its constituent toxins. The data also aid in elucidating the relationship between these selection pressures and the medical impact of human snakebite in the developing world, as cytotoxic cobras cause considerable morbidity including loss-of-function injuries that result in economic and social burdens in the tropics of Asia and sub-Saharan Africa.

ACS Style

Nadya Panagides; Timothy N.W. Jackson; Maria P. Ikonomopoulou; Kevin Arbuckle; Rudolf Pretzler; Daryl C. Yang; Syed A. Ali; Ivan Koludarov; James Dobson; Brittany Sanker; Angelique Asselin; Renan C. Santana; Iwan Hendrikx; Harold Van Der Ploeg; Jeremie Tai-A-Pin; Romilly Van Den Bergh; Harald M.I. Kerkkamp; Freek J. Vonk; Arno Naude; Morné A. Strydom; Louis Jacobsz; Nathan Dunstan; Marc Jaeger; Wayne C. Hodgson; John Miles; Bryan G. Fry. How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting. Toxins 2017, 9, 103 .

AMA Style

Nadya Panagides, Timothy N.W. Jackson, Maria P. Ikonomopoulou, Kevin Arbuckle, Rudolf Pretzler, Daryl C. Yang, Syed A. Ali, Ivan Koludarov, James Dobson, Brittany Sanker, Angelique Asselin, Renan C. Santana, Iwan Hendrikx, Harold Van Der Ploeg, Jeremie Tai-A-Pin, Romilly Van Den Bergh, Harald M.I. Kerkkamp, Freek J. Vonk, Arno Naude, Morné A. Strydom, Louis Jacobsz, Nathan Dunstan, Marc Jaeger, Wayne C. Hodgson, John Miles, Bryan G. Fry. How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting. Toxins. 2017; 9 (3):103.

Chicago/Turabian Style

Nadya Panagides; Timothy N.W. Jackson; Maria P. Ikonomopoulou; Kevin Arbuckle; Rudolf Pretzler; Daryl C. Yang; Syed A. Ali; Ivan Koludarov; James Dobson; Brittany Sanker; Angelique Asselin; Renan C. Santana; Iwan Hendrikx; Harold Van Der Ploeg; Jeremie Tai-A-Pin; Romilly Van Den Bergh; Harald M.I. Kerkkamp; Freek J. Vonk; Arno Naude; Morné A. Strydom; Louis Jacobsz; Nathan Dunstan; Marc Jaeger; Wayne C. Hodgson; John Miles; Bryan G. Fry. 2017. "How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting." Toxins 9, no. 3: 103.

Review
Published: 01 December 2016 in Toxins
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Snake genome sequencing is in its infancy—very much behind the progress made in sequencing the genomes of humans, model organisms and pathogens relevant to biomedical research, and agricultural species. We provide here an overview of some of the snake genome projects in progress, and discuss the biological findings, with special emphasis on toxinology, from the small number of draft snake genomes already published. We discuss the future of snake genomics, pointing out that new sequencing technologies will help overcome the problem of repetitive sequences in assembling snake genomes. Genome sequences are also likely to be valuable in examining the clustering of toxin genes on the chromosomes, in designing recombinant antivenoms and in studying the epigenetic regulation of toxin gene expression.

ACS Style

Harald M. I. Kerkkamp; R. Manjunatha Kini; Alexey S. Pospelov; Freek J. Vonk; Christiaan V. Henkel; Michael K. Richardson. Snake Genome Sequencing: Results and Future Prospects. Toxins 2016, 8, 360 .

AMA Style

Harald M. I. Kerkkamp, R. Manjunatha Kini, Alexey S. Pospelov, Freek J. Vonk, Christiaan V. Henkel, Michael K. Richardson. Snake Genome Sequencing: Results and Future Prospects. Toxins. 2016; 8 (12):360.

Chicago/Turabian Style

Harald M. I. Kerkkamp; R. Manjunatha Kini; Alexey S. Pospelov; Freek J. Vonk; Christiaan V. Henkel; Michael K. Richardson. 2016. "Snake Genome Sequencing: Results and Future Prospects." Toxins 8, no. 12: 360.

Book chapter
Published: 11 August 2015 in Toxins and Drug Discovery
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There are over 3,000 species of snakes known to man. These limbless predators have been divided into two groups, the basal snakes (Henophidia) and the advanced snakes (Caenophidia). Venom evolved prior to the advanced snake radiation and, consequently, many use venom to subdue their prey. To do so, venom is injected via the use of a venom delivery system. The venom delivery system includes a postorbital venom gland on each side of the upper jaw that is associated with specialized venom-conducting fangs or teeth. Both the venom gland and fangs are considered to have originated from a common ancestor and are thought to be developmentally linked to one another. Even though the venom gland has a common ancestral origin, it can exhibit considerable morphological variation among the main snake families. Similarly, the fangs can occupy various positions on the upper jaw but are always found on the maxilla. Caenophidians are often referred to by the position of their fangs as either rear- or front-fanged snakes. The vast majority of snakes that are medically important to humans are front-fanged, and this character has evolved independently on at least three occasions. In addition, some front-fanged snakes have evolved a secondary gland associated with the venom system, known as the accessory gland. The venom glands, accessory glands, and fangs of different caenophidian snake families exhibit substantial morphological differences reflecting their evolutionary history. However, further studies are required to fully elucidate the ecological significance of differences in fang position, the function of the accessory gland, and the driving forces underpinning the convergent evolution observed in the snake venom delivery system.

ACS Style

Harald M. I. Kerkkamp; Nicholas R. Casewell; Freek J. Vonk. Evolution of the Snake Venom Delivery System. Toxins and Drug Discovery 2015, 1 -11.

AMA Style

Harald M. I. Kerkkamp, Nicholas R. Casewell, Freek J. Vonk. Evolution of the Snake Venom Delivery System. Toxins and Drug Discovery. 2015; ():1-11.

Chicago/Turabian Style

Harald M. I. Kerkkamp; Nicholas R. Casewell; Freek J. Vonk. 2015. "Evolution of the Snake Venom Delivery System." Toxins and Drug Discovery , no. : 1-11.

Review
Published: 01 April 2013 in Trends in Ecology & Evolution
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Venoms have evolved on numerous occasions throughout the animal kingdom. These 'biochemical weapon systems' typically function to facilitate, or protect the producing animal from, predation. Most venomous animals remain unstudied despite venoms providing model systems for investigating predator-prey interactions, molecular evolution, functional convergence, and novel targets for pharmaceutical discovery. Through advances in 'omic' technologies, venom composition data have recently become available for several venomous lineages, revealing considerable complexity in the processes responsible for generating the genetic and functional diversity observed in many venoms. Here, we review these recent advances and highlight the ecological and evolutionary novelty of venom systems.

ACS Style

Nicholas R. Casewell; Wolfgang Wüster; Freek J. Vonk; Robert A. Harrison; Bryan G. Fry. Complex cocktails: the evolutionary novelty of venoms. Trends in Ecology & Evolution 2013, 28, 219 -229.

AMA Style

Nicholas R. Casewell, Wolfgang Wüster, Freek J. Vonk, Robert A. Harrison, Bryan G. Fry. Complex cocktails: the evolutionary novelty of venoms. Trends in Ecology & Evolution. 2013; 28 (4):219-229.

Chicago/Turabian Style

Nicholas R. Casewell; Wolfgang Wüster; Freek J. Vonk; Robert A. Harrison; Bryan G. Fry. 2013. "Complex cocktails: the evolutionary novelty of venoms." Trends in Ecology & Evolution 28, no. 4: 219-229.

Journal article
Published: 01 August 2012 in Toxicon
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Nicholas R. Casewell; Wolfgang Wüster; Simon C. Wagstaff; Camila Renjifo; Michael K. Richardson; Freek J. Vonk; Robert A. Harrison. 49. The Origin and Evolution of Metalloproteinases in the Venom of Snakes. Toxicon 2012, 60, 119 .

AMA Style

Nicholas R. Casewell, Wolfgang Wüster, Simon C. Wagstaff, Camila Renjifo, Michael K. Richardson, Freek J. Vonk, Robert A. Harrison. 49. The Origin and Evolution of Metalloproteinases in the Venom of Snakes. Toxicon. 2012; 60 (2):119.

Chicago/Turabian Style

Nicholas R. Casewell; Wolfgang Wüster; Simon C. Wagstaff; Camila Renjifo; Michael K. Richardson; Freek J. Vonk; Robert A. Harrison. 2012. "49. The Origin and Evolution of Metalloproteinases in the Venom of Snakes." Toxicon 60, no. 2: 119.

Journal article
Published: 01 August 2012 in Toxicon
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ACS Style

Freek J. Vonk; Christiaan V. Henkel; R. Manjunatha Kini; Harald M.I. Kerkkamp; Herman P. Spaink; Hans J. Jansen; S. Asad Hyder; Pim Arntzen; Guido E.E.J.M. Van Den Thillart; Marten Boetzer; Walter Pirovano; Ron P.H. Dirks; Michael K. Richardson. 53. Evolutionary Expansion of Venom Genes in the King Cobra Genome. Toxicon 2012, 60, 121 .

AMA Style

Freek J. Vonk, Christiaan V. Henkel, R. Manjunatha Kini, Harald M.I. Kerkkamp, Herman P. Spaink, Hans J. Jansen, S. Asad Hyder, Pim Arntzen, Guido E.E.J.M. Van Den Thillart, Marten Boetzer, Walter Pirovano, Ron P.H. Dirks, Michael K. Richardson. 53. Evolutionary Expansion of Venom Genes in the King Cobra Genome. Toxicon. 2012; 60 (2):121.

Chicago/Turabian Style

Freek J. Vonk; Christiaan V. Henkel; R. Manjunatha Kini; Harald M.I. Kerkkamp; Herman P. Spaink; Hans J. Jansen; S. Asad Hyder; Pim Arntzen; Guido E.E.J.M. Van Den Thillart; Marten Boetzer; Walter Pirovano; Ron P.H. Dirks; Michael K. Richardson. 2012. "53. Evolutionary Expansion of Venom Genes in the King Cobra Genome." Toxicon 60, no. 2: 121.