Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib
| Autor: | Freek J. Vonk, Arif Arrahman, Nicholas R. Casewell, Jeroen Kool, Mark C. Wilkinson, Kristina B.M. Still, Govert W. Somsen, Taline D. Kazandjian |
|---|---|
| Přispěvatelé: | BioAnalytical Chemistry, AIMMS, Chemistry and Pharmaceutical Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Health
Toxicology and Mutagenesis qu_136 Venom Naja nigricollis Pharmacology varespladib Toxicology medicine.disease_cause marimastat snakebite complex mixtures coagulopathy 03 medical and health sciences chemistry.chemical_compound Phospholipase A2 medicine 030304 developmental biology mass spectrometry qw_630 nanofractionation 0303 health sciences biology Toxin 030302 biochemistry & molecular biology biology.organism_classification chemistry Snake venom biology.protein Varespladib Medicine Spitting cobra Marimastat medicine.drug wd_410 |
| Zdroj: | Toxins, 13(5):302, 1-20. Multidisciplinary Digital Publishing Institute (MDPI) Toxins, Vol 13, Iss 302, p 302 (2021) Toxins Volume 13 Issue 5 Kazandjian, T D, Arrahman, A, Still, K B M, Somsen, G W, Vonk, F J, Casewell, N R, Wilkinson, M C & Kool, J 2021, ' Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib ', Toxins, vol. 13, no. 5, 302, pp. 1-20 . https://doi.org/10.3390/toxins13050302 |
| ISSN: | 2072-6651 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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