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Neutralising effects of small molecule toxin inhibitors on nanofractionated coagulopathic Crotalinae snake venoms

Xie, C, Slagboom, J, Albulescu, Laura-Oana, Somsen, GW, Vonk, FJ, Casewell, Nicholas ORCID: https://orcid.org/0000-0002-8035-4719 and Kool, J (2020) 'Neutralising effects of small molecule toxin inhibitors on nanofractionated coagulopathic Crotalinae snake venoms'. Acta Pharmaceutica Sinica B, Vol 10, Issue 10, pp. 1835-1845.

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Abstract

Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming. In this study, we investigated the inhibiting effects of the small molecules varespladib (nonspecific phospholipase A2 inhibitor), marimastat (broad spectrum matrix metalloprotease inhibitor) and dimercaprol (metal ion chelator) against coagulopathic toxins found in Crotalinae (pit vipers) snake venoms. Venoms from Bothrops asper, Bothrops jararaca, Calloselasma rhodostoma and Deinagkistrodon acutus were separated by liquid chromatography, followed by nanofractionation and mass spectrometry identification undertaken in parallel. Nanofractions of the venom toxins were then subjected to a high-throughput coagulation assay in the presence of different concentrations of the small molecules under study. Anticoagulant venom toxins were mostly identified as phospholipases A2, while procoagulant venom activities were mainly associated with snake venom metalloproteinases and snake venom serine proteases. Varespladib was found to effectively inhibit most anticoagulant venom effects, and also showed some inhibition against procoagulant toxins. Contrastingly, marimastat and dimercaprol were both effective inhibitors of procoagulant venom activities but showed little inhibitory capability against anticoagulant toxins. The information obtained from this study aids our understanding of the mechanisms of action of toxin inhibitor drug candidates, and highlights their potential as future snakebite treatments.

Item Type: Article
Subjects: QU Biochemistry > Enzymes > QU 136 Hydrolases
QV Pharmacology > Hematologic Agents > QV 195 Hemostatics. Coagulants
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 310 Mechanism of blood coagulation. Hemostatis
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1016/j.apsb.2020.09.005
Depositing User: Mary Creegan
Date Deposited: 16 Oct 2020 12:28
Last Modified: 14 Dec 2020 14:19
URI: https://archive.lstmed.ac.uk/id/eprint/15840

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