In the venom-only analyses, anticoagulation activity was observed as two sharp negative peaks in the bioactivity chromatograms (16

In the venom-only analyses, anticoagulation activity was observed as two sharp negative peaks in the bioactivity chromatograms (16.2C16.7 min and 16.7C17.1 min); however, no procoagulation activity was detected, which is usually consistent with previous findings using this venom [59]. 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]. One of the most common but serious pathological effects of systemic viper envenoming is usually coagulopathy, which renders snakebite victims vulnerable to suffering lethal internal hemorrhages [8]. Venom induced coagulopathy following bites by viperid snakes is usually predominately the result of the synergistic action of venom enzymes, such as phospholipases A2 (PLA2s), snake venom serine proteinases (SVSPs) and snake venom metalloproteinases (SVMPs) [9,10,11]. PLA2s can prevent blood clotting via anticoagulant effects. Enzymatic PLA2s function by hydrolyzing glycerophospholipids at the sn-2 position of the glycerol backbone releasing lysophospholipids and fatty acids [12]. SVSPs can proteolytically degrade fibrinogen and release bradykinins from plasma kininogens [13,14]. SVMPs act on various clotting factors to stimulate consumption coagulopathy and can also degrade capillary basement membranes, thereby increasing vascular permeability and causing leakage [10,15,16]. These toxins can therefore work synergistically to cause systemic hemorrhage and coagulopathy. The only specific therapies currently available for treating snake envenoming are animal-derived antivenoms. Consisting of immunoglobulins purified from hyperimmunized ovine or equine plasma/serum, these products save thousands of lives each year, but are associated with a number of therapeutic challenges, including limited cross-snake species efficacies, poor safety profiles and, for many snakebite victims residing in remote rural areas in developing countries, unacceptable issues with affordability and accessibility [17]. Small molecule toxin inhibitors are regarded as promising candidates for the development of affordable broad-spectrum snakebite treatments, as these can block the enzymatic activities of venoms [18,19,20]. Varespladib, an indole-based nonspecific pan-secretory PLA2 inhibitor has been studied extensively for repurposing for snakebite. Defactinib Having originally been investigated in Phase II and III clinical trials for treating septic shock, coronary heart disease and sickle cell disease-induced acute chest syndrome [21,22], varespladib has since been shown to be highly potent in suppressing venom-induced PLA2 activity, both in vitro and in vivo in murine models Defactinib [23]. Varespladib shows great promise against neurotoxic elapid snake venoms and has been shown to prevent lethality in murine in vivo models of envenoming [24], Bmp7 but is usually seemingly also capable of inhibiting certain myotoxic and coagulotoxic symptoms induced by snake venoms [25,26]. Moreover, varespladib has been demonstrated to inhibit the anticoagulant activity of snake venom, which was not neutralized by its currently used antivenom [27]. A number of other small molecules have shown promise for repurposing to inhibit SVMP venom toxins. Marimastat is usually a broad-spectrum matrix metalloprotease inhibitor that functions by binding to the active site of matrix metalloproteinases where it coordinates the metal ion in the binding pocket [28,29]. As a water-soluble orally bioavailable matrix metalloproteinase inhibitor [30,31], marimastat reached phase II and III clinical trials for multiple solid tumor types [32,33,34], including pancreatic, lung, breast, colorectal, brain and prostate cancer [35,36,37]. SVMPs are toxins that are structurally and functionally homologous to matrix metalloproteinses [38,39,40]. Like other compounds in this class of drugs (e.g., batimastat [41]), marimastat is usually a promising drug candidate for treating snakebite due to its inhibitory capabilities against SVMP toxins [42,43]. Marimastat was found to effectively inhibit the hemorrhagic, coagulant and defibrinogenating effects and proteinase activities induced by venom [42]. Dimercaprol, a historical drug approved by the World Health Organization (WHO) for treatment of heavy metal poisoning [44], contains two metal-chelating thiol groups and has long been used against arsenic, mercury, gold, lead and antimony intoxication [45,46,47]. It also represents a treatment option for Wilsons disease in which the body retains copper. Moreover, it has been studied as a candidate for acrolein detoxification as it can effectively reduce the acrolein concentration in vivo in murine because of its ability to bind to both the carbon double bond and aldehyde group of acrolein. The water-soluble, tissue-permeable and licensed metal chelator, 2,3-dimercaptopropane-1-sulfonic acid (DMPS), is also suitable for treating acute and chronic heavy metal intoxication including lead, mercury, cadmium and copper [48,49]. It was recently shown that both dimercaprol and DMPS displayed potential for repurposing as small Defactinib molecule chelators to treat snake envenoming [20], most Defactinib probably by chelating and removing Zn2+ from the active.