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Article ; Online: Acetylcholine-Binding Protein Affinity Profiling of Neurotoxins in Snake Venoms with Parallel Toxin Identification

Giulia Palermo / Wietse M. Schouten / Luis Lago Alonso / Chris Ulens / Jeroen Kool / Julien Slagboom

International Journal of Molecular Sciences, Vol 24, Iss 23, p

2023 Volume 16769

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 ... ...

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.
Keywords	snake venom ; neurotoxicity ; AChBP bioassay ; three-finger toxins ; nanofractionation ; elapid venom profiling ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	540
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

Steven R. Hall / Sean A. Rasmussen / Edouard Crittenden / Charlotte A. Dawson / Keirah E. Bartlett / Adam P. Westhorpe / Laura-Oana Albulescu / Jeroen Kool / José María Gutiérrez / Nicholas R. Casewell

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 15

Abstract: Abstract Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. Repurposed small ... ...

Abstract	Abstract Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. Repurposed small molecule drugs that inhibit specific snake venom toxins show considerable promise for tackling this neglected tropical disease. Using human skin cell assays as an initial model for snakebite-induced dermonecrosis, we show that the drugs 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combination, inhibit the cytotoxicity of a broad range of medically important snake venoms. Thereafter, using preclinical mouse models of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib significantly inhibit the dermonecrotic activity of geographically distinct and medically important snake venoms, even when the drug combinations are delivered one hour after envenoming. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite.
Keywords	Science ; Q
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Monitoring Snake Venom-Induced Extracellular Matrix Degradation and Identifying Proteolytically Active Venom Toxins Using Fluorescently Labeled Substrates

Mátyás A. Bittenbinder / Nick D. Bergkamp / Julien Slagboom / Jan Paul M. Bebelman / Nicholas R. Casewell / Marco H. Siderius / Martine J. Smit / Jeroen Kool / Freek J. Vonk

Biology, Vol 12, Iss 765, p

2023 Volume 765

Abstract: Snakebite envenoming is an important public health issue with devastating consequences and annual mortality rates that range between 81,000 and 138,000. Snake venoms may cause a range of pathophysiological effects affecting the nervous system and the ... ...

Abstract	Snakebite envenoming is an important public health issue with devastating consequences and annual mortality rates that range between 81,000 and 138,000. Snake venoms may cause a range of pathophysiological effects affecting the nervous system and the cardiovascular system. Moreover, snake venom may have tissue-damaging activities that result in lifelong morbidities such as amputations, muscle degeneration, and organ malfunctioning. The tissue-damaging components in snake venoms comprise multiple toxin classes with various molecular targets including cellular membranes and the extracellular matrix (ECM). In this study, we present multiple assay formats that enable investigation of snake venom-induced ECM degradation using a variety of (dye-quenched) fluorescently labeled ECM components. Using a combinatorial approach, we were able to characterise different proteolytic profiles for different medically relevant snake venoms, followed by identification of the responsible components within the snake venoms. This workflow could provide valuable insights into the key mechanisms by which proteolytic venom components exert their effects and could therefore prove useful for the development of effective snakebite treatments against this severe pathology.
Keywords	snakebite ; tissue-damaging activities ; extracellular matrix ; protease ; SVMP ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Combined Bioassay and Nanofractionation Approach to Investigate the Anticoagulant Toxins of Mamba and Cobra Venoms and Their Inhibition by Varespladib

Arif Arrahman / Taline D. Kazandjian / Kristina B. M. Still / Julien Slagboom / Govert W. Somsen / Freek J. Vonk / Nicholas R. Casewell / Jeroen Kool

Toxins, Vol 14, Iss 736, p

2022 Volume 736

Abstract: Envenomation by elapid snakes primarily results in neurotoxic symptoms and, consequently, are the primary focus of therapeutic research concerning such venoms. However, mounting evidence suggests these venoms can additionally cause coagulopathic symptoms, ...

Abstract	Envenomation by elapid snakes primarily results in neurotoxic symptoms and, consequently, are the primary focus of therapeutic research concerning such venoms. However, mounting evidence suggests these venoms can additionally cause coagulopathic symptoms, as demonstrated by some Asian elapids and African spitting cobras. This study sought to investigate the coagulopathic potential of venoms from medically important elapids of the genera Naja (true cobras), Hemachatus (rinkhals), and Dendroaspis (mambas). Crude venoms were bioassayed for coagulant effects using a plasma coagulation assay before RPLC/MS was used to separate and identify venom toxins in parallel with a nanofractionation module. Subsequently, coagulation bioassays were performed on the nanofractionated toxins, along with in-solution tryptic digestion and proteomics analysis. These experiments were then repeated on both crude venoms and on the nanofractionated venom toxins with the addition of either the phospholipase A 2 (PLA 2 ) inhibitor varespladib or the snake venom metalloproteinase (SVMP) inhibitor marimastat. Our results demonstrate that various African elapid venoms have an anticoagulant effect, and that this activity is significantly reduced for cobra venoms by the addition of varespladib, though this inhibitor had no effect against anticoagulation caused by mamba venoms. Marimastat showed limited capacity to reduce anticoagulation in elapids, affecting only N. haje and H. haemachatus venom at higher doses. Proteomic analysis of nanofractionated toxins revealed that the anticoagulant toxins in cobra venoms were both acidic and basic PLA 2 s, while the causative toxins in mamba venoms remain uncertain. This implies that while PLA 2 inhibitors such as varespladib and metalloproteinase inhibitors such as marimastat are viable candidates for novel snakebite treatments, they are not likely to be effective against mamba envenomings.
Keywords	snakebite ; coagulopathy ; varespladib ; marimastat ; Dendroaspis ; Naja ; Medicine ; R
Subject code	616
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The molecular mechanism of snake short-chain α-neurotoxin binding to muscle-type nicotinic acetylcholine receptors

Mieke Nys / Eleftherios Zarkadas / Marijke Brams / Aujan Mehregan / Kumiko Kambara / Jeroen Kool / Nicholas R. Casewell / Daniel Bertrand / John E. Baenziger / Hugues Nury / Chris Ulens

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 12

Abstract: Bites by elapid snakes can result in life-threatening paralysis caused by α-neurotoxins blocking the neuromuscular nicotinic acetylcholine receptor. Here, the authors determine the cryo-EM structure of this receptor in complex with a short-chain α- ... ...

Abstract	Bites by elapid snakes can result in life-threatening paralysis caused by α-neurotoxins blocking the neuromuscular nicotinic acetylcholine receptor. Here, the authors determine the cryo-EM structure of this receptor in complex with a short-chain α-neurotoxin.
Keywords	Science ; Q
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins

Chunfang Xie / Laura-Oana Albulescu / Mátyás A. Bittenbinder / Govert W. Somsen / Freek J. Vonk / Nicholas R. Casewell / Jeroen Kool

Biomedicines, Vol 8, Iss 297, p

2020 Volume 297

Abstract: 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 ... ...

Abstract	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 A 2 (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 A 2 -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 ...
Keywords	snakebite treatments ; marimastat ; varespladib ; dimercaprol ; DMPS ; nanofractionation ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: High throughput screening and identification of coagulopathic snake venom proteins and peptides using nanofractionation and proteomics approaches.

Julien Slagboom / Marija Mladić / Chunfang Xie / Taline D Kazandjian / Freek Vonk / Govert W Somsen / Nicholas R Casewell / Jeroen Kool

PLoS Neglected Tropical Diseases, Vol 14, Iss 4, p e

2020 Volume 0007802

Abstract: Snakebite is a neglected tropical disease that results in a variety of systemic and local pathologies in envenomed victims and is responsible for around 138,000 deaths every year. Many snake venoms cause severe coagulopathy that makes victims vulnerable ... ...

Abstract	Snakebite is a neglected tropical disease that results in a variety of systemic and local pathologies in envenomed victims and is responsible for around 138,000 deaths every year. Many snake venoms cause severe coagulopathy that makes victims vulnerable to suffering life-threating haemorrhage. The mechanisms of action of coagulopathic snake venom toxins are diverse and can result in both anticoagulant and procoagulant effects. However, because snake venoms consist of a mixture of numerous protein and peptide components, high throughput characterizations of specific target bioactives is challenging. In this study, we applied a combination of analytical and pharmacological methods to identify snake venom toxins from a wide diversity of snake species that perturb coagulation. To do so, we used a high-throughput screening approach consisting of a miniaturised plasma coagulation assay in combination with a venom nanofractionation approach. Twenty snake venoms were first separated using reversed-phase liquid chromatography, and a post-column split allowed a small fraction to be analyzed with mass spectrometry, while the larger fraction was collected and dispensed onto 384-well plates. After fraction collection, any solvent present in the wells was removed by means of freeze-drying, after which it was possible to perform a plasma coagulation assay in order to detect coagulopathic activity. Our results demonstrate that many snake venoms simultaneously contain both procoagulant and anticoagulant bioactives that contribute to coagulopathy. In-depth identification analysis from seven medically-important venoms, via mass spectrometry and nanoLC-MS/MS, revealed that phospholipase A2 toxins are frequently identified in anticoagulant venom fractions, while serine protease and metalloproteinase toxins are often associated with procoagulant bioactivities. The nanofractionation and proteomics approach applied herein seems likely to be a valuable tool for the rational development of next-generation snakebite treatments by ...
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Subject code	616 ; 540
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Whole snake venoms: Cytotoxic, anti-metastatic and antiangiogenic properties

Kerkkamp, Harald / Babette van Soolingen / Christoph Bagowski / Daniëlle Vlecken / Freek J. Vonk / Jeroen Kool

Toxicon. 2018 Aug., v. 150

2018

Abstract: 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 ... ...

Abstract	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.
Keywords	angiogenesis ; antineoplastic activity ; cell death ; cytotoxicity ; Danio rerio ; Echis carinatus ; in vitro studies ; Naja annulifera ; Naja kaouthia ; neoplasm cells ; Ophiophagus hannah ; organic matter ; pancreatic neoplasms ; peptides ; snake venoms ; snakes ; therapeutics ; yolk sac
Language	English
Dates of publication	2018-08
Size	p. 39-49.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	204479-1
ISSN	1879-3150 ; 0041-0101
ISSN (online)	1879-3150
ISSN	0041-0101
DOI	10.1016/j.toxicon.2018.05.004
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Author Correction

Laura-Oana Albulescu / Chunfang Xie / Stuart Ainsworth / Jaffer Alsolaiss / Edouard Crittenden / Charlotte A. Dawson / Rowan Softley / Keirah E. Bartlett / Robert A. Harrison / Jeroen Kool / Nicholas R. Casewell

Nature Communications, Vol 12, Iss 1, Pp 1-

A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite

2021 Volume 1

Keywords	Science ; Q
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Terrestrial venomous animals, the envenomings they cause, and treatment perspectives in the Middle East and North Africa.

Timothy P Jenkins / Shirin Ahmadi / Matyas A Bittenbinder / Trenton K Stewart / Dilber E Akgun / Melissa Hale / Nafiseh N Nasrabadi / Darian S Wolff / Freek J Vonk / Jeroen Kool / Andreas H Laustsen

PLoS Neglected Tropical Diseases, Vol 15, Iss 12, p e

2021 Volume 0009880

Abstract: The Middle East and Northern Africa, collectively known as the MENA region, are inhabited by a plethora of venomous animals that cause up to 420,000 bites and stings each year. To understand the resultant health burden and the key variables affecting it, ...

Abstract	The Middle East and Northern Africa, collectively known as the MENA region, are inhabited by a plethora of venomous animals that cause up to 420,000 bites and stings each year. To understand the resultant health burden and the key variables affecting it, this review describes the epidemiology of snake, scorpion, and spider envenomings primarily based on heterogenous hospital data in the MENA region and the pathologies associated with their venoms. In addition, we discuss the venom composition and the key medically relevant toxins of these venomous animals, and, finally, the antivenoms that are currently in use to counteract them. Unlike Asia and sub-Saharan Africa, scorpion stings are significantly more common (approximately 350,000 cases/year) than snakebites (approximately 70,000 cases/year) and present the most significant contributor to the overall health burden of envenomings, with spider bites being negligible. However, this review also indicates that there is a substantial lack of high-quality envenoming data available for the MENA region, rendering many of these estimates speculative. Our understanding of the venoms and the toxins they contain is also incomplete, but already presents clear trends. For instance, the majority of snake venoms contain snake venom metalloproteinases, while sodium channel-binding toxins and potassium channel-binding toxins are the scorpion toxins that cause most health-related challenges. There also currently exist a plethora of antivenoms, yet only few are clinically validated, and their high cost and limited availability present a substantial health challenge. Yet, some of the insights presented in this review might help direct future research and policy efforts toward the appropriate prioritization of efforts and aid the development of future therapeutic solutions, such as next-generation antivenoms.
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Subject code	910
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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