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Article

Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib

1
Centre for Snakebite Research and Interventions, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
2
Department of Chemistry and Pharmaceutical Sciences, Division of Bioanalytical Chemistry, Faculty of Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081HV Amsterdam, The Netherlands
3
Centre for Analytical Sciences Amsterdam (CASA), 1012WX Amsterdam, The Netherlands
4
Faculty of Pharmacy, Kampus Baru UI, Universitas Indonesia, Depok 16424, Indonesia
5
Naturalis Biodiversity Center, Darwinweg 2, 2333CR Leiden, The Netherlands
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
Toxins 2021, 13(5), 302; https://doi.org/10.3390/toxins13050302
Received: 10 March 2021 / Revised: 7 April 2021 / Accepted: 18 April 2021 / Published: 23 April 2021
(This article belongs to the Section Animal Venoms)
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. View Full-Text
Keywords: snakebite; Naja nigricollis; coagulopathy; varespladib; marimastat; nanofractionation; mass spectrometry snakebite; Naja nigricollis; coagulopathy; varespladib; marimastat; nanofractionation; mass spectrometry
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MDPI and ACS Style

Kazandjian, T.D.; Arrahman, A.; Still, K.B.M.; Somsen, G.W.; Vonk, F.J.; Casewell, N.R.; Wilkinson, M.C.; Kool, J. Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib. Toxins 2021, 13, 302. https://doi.org/10.3390/toxins13050302

AMA Style

Kazandjian TD, Arrahman A, Still KBM, Somsen GW, Vonk FJ, Casewell NR, Wilkinson MC, Kool J. Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib. Toxins. 2021; 13(5):302. https://doi.org/10.3390/toxins13050302

Chicago/Turabian Style

Kazandjian, Taline D., Arif Arrahman, Kristina B.M. Still, Govert W. Somsen, Freek J. Vonk, Nicholas R. Casewell, Mark C. Wilkinson, and Jeroen Kool. 2021. "Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib" Toxins 13, no. 5: 302. https://doi.org/10.3390/toxins13050302

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