Abstract
Venoms are a rich source of potential lead compounds for drug discovery, and descriptive studies of venom form the first phase of the biodiscovery process. In this study, we investigated the pharmacological potential of crude Pseudocerastes and Eristicophis snake venoms in haematological disorders and cancer treatment. We assessed their antithrombotic potential using fibrinogen thromboelastography, fibrinogen gels with and without protease inhibitors, and colourimetric fibrinolysis assays. These assays indicated that the anticoagulant properties of the venoms are likely induced by the hydrolysis of phospholipids and by selective fibrinogenolysis. Furthermore, while most fibrinogenolysis occurred by the direct activity of snake venom metalloproteases and serine proteases, modest evidence indicated that fibrinogenolytic activity may also be mediated by selective venom phospholipases and an inhibitory venom-derived serine protease. We also found that the Pseudocerastes venoms significantly reduced the viability of human melanoma (MM96L) cells by more than 80%, while it had almost no effect on the healthy neonatal foreskin fibroblasts (NFF) as determined by viability assays. The bioactive properties of these venoms suggest that they contain a number of toxins suitable for downstream pharmacological development as candidates for antithrombotic or anticancer agents.
Highlights
Snake venoms are bioactive secretions that consist mainly of proteinaceous and peptidic toxins, which evolved for use in antagonistic interactions, such as predation and defence [1]
Each of the Pseudocerastes venoms significantly reduced the viability of the cancerous MM96L cells while having a limited effect on healthy neonatal foreskin fibroblasts (NFF) cells, showing specificity of these venoms towards tumorous cells
Future studies should be aimed at identifying the toxins and molecular mechanisms underpinning the selective cytotoxicity of the crude Pseudocerastes venoms in addition to tests on a wider range of melanoma cell lines of different mutations
Summary
Snake venoms are bioactive secretions that consist mainly of proteinaceous and peptidic toxins, which evolved for use in antagonistic interactions, such as predation and defence [1]. As a reflection of this ancestry, many venom toxins possess high potency and specificity for their molecular targets [3,4] This targeted activity constitutes essential criteria in drug design. One study to date has described the venom of P. urarachnoides, which is a potent procoagulant by activating both factor X and prothrombin [11]. The activities of these venoms largely adhere to the coagulopathic pathophysiology that is characteristic of viper envenoming. P. persicus and P. fieldi venoms have been found to possess extremely low levels of human factor X and prothrombin activation [11], though their action on human plasma manifests as anticoagulant and the underlying mechanisms are unexplored. The venoms showed promise as anticancer or antithrombotic agent candidates, and this study provides the foundation to explore their potential further
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