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Varespladib Inhibits the Phospholipase A 2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes

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Xie, Chunfang, Albulescu, Laura-Oana, Still, Kristina B. M., Slagboom, Julien, Zhao, Yumei, Jiang, Zhengjin, Somsen, Govert W., Vonk, Freek J., Casewell, Nicholas ORCID: https://orcid.org/0000-0002-8035-4719 and Kool, Jeroen (2020) 'Varespladib Inhibits the Phospholipase A 2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes'. Biomedicines, Vol 8, Issue 6, e165.

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Abstract

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.

Item Type: Article
Subjects: QU Biochemistry > Enzymes > QU 136 Hydrolases
WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 140 Hematopoietic system and hematopoiesis. Developmental theories. Blood cells (General)
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.3390/biomedicines8060165
SWORD Depositor: JISC Pubrouter
Depositing User: JISC Pubrouter
Date Deposited: 19 Jun 2020 09:48
Last Modified: 19 Jun 2020 09:48
URI: https://archive.lstmed.ac.uk/id/eprint/14791

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