Abstract
Animal-derived antivenoms are the only specific therapies currently available for the treatment of snake envenoming, but these products have a number of limitations associated with their efficacy, safety and affordability for use in tropical snakebite victims. Small molecule drugs and drug candidates are regarded as promising alternatives for filling the critical therapeutic gap between snake envenoming and effective treatment. In this study, by using an advanced analytical technique that combines chromatography, mass spectrometry and bioassaying, we investigated the effect of several small molecule inhibitors that target phospholipase A2 (varespladib) and snake venom metalloproteinase (marimastat, dimercaprol and DMPS) toxin families on inhibiting the activities of coagulopathic toxins found in Viperinae snake venoms. The venoms of Echis carinatus, Echis ocellatus, Daboia russelii and Bitis arietans, which are known for their potent haemotoxicities, were fractionated in high resolution onto 384-well plates using liquid chromatography followed by coagulopathic bioassaying of the obtained fractions. Bioassay activities were correlated to parallel recorded mass spectrometric and proteomics data to assign the venom toxins responsible for coagulopathic activity and assess which of these toxins could be neutralized by the inhibitors under investigation. Our results showed that the phospholipase A2-inhibitor varespladib neutralized the vast majority of anticoagulation activities found across all of the tested snake venoms. Of the snake venom metalloproteinase inhibitors, marimastat demonstrated impressive neutralization of the procoagulation activities detected in all of the tested venoms, whereas dimercaprol and DMPS could only partially neutralize these activities at the doses tested. Our results provide additional support for the concept that combinations of small molecules, particularly the combination of varespladib with marimastat, serve as a drug-repurposing opportunity to develop new broad-spectrum inhibitor-based therapies for snakebite envenoming.
Highlights
Bites by venomous snakes cause 81,000–138,000 deaths per annum, with the majority occurring in the rural resource-poor regions of the tropics and sub-tropics [1]
A nanofractionation approach was used to evaluate the inhibitory effects of varespladib, marimastat, dimercaprol and dimercaptopropane-1-sulfonic acid (DMPS) on the coagulopathic properties of venom toxins fractionated from a variety of Viperinae snake species
The inhibitory effects of varespladib, marimastat, dimercaprol and DMPS against the coagulopathic activities observed for LC fractions of both venoms were investigated in a concentration-dependent fashion (Figures 1 and 2)
Summary
Bites by venomous snakes cause 81,000–138,000 deaths per annum, with the majority occurring in the rural resource-poor regions of the tropics and sub-tropics [1]. Viper venoms typically contain numerous proteins that disrupt the functioning of the coagulation cascade, the hemostatic system and tissue integrity [4,5]. Envenomings caused by these snakes can cause prominent local effects including necrosis, hemorrhage, edema and pain, and often result in permanent disabilities in survivors [6,7]. SVMPs act on various clotting factors to stimulate consumption coagulopathy and can degrade capillary basement membranes, thereby increasing vascular permeability and causing leakage [10,15,16]
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