No abstract

SummarySnake venoms are mixtures of numerous proteinacious components that exert diverse functional activities on a variety of physiological targets. Because the toxic constituents found in venom vary from species to species, snakebite victims can present with a variety of life‐threatening pathologies related to the neurotoxic, cytotoxic and haemotoxic effects of venom. Of the 1·8 million people envenomed by snakes every year, up to 125 000 die, while hundreds of thousands survive only to suffer with life‐changing long‐term morbidity. Consequently, snakebite is one of the world's most severe neglected tropical diseases. Many snake venoms exhibit strong haemotoxic properties by interfering with blood pressure, clotting factors and platelets, and by directly causing haemorrhage. In this review we provide an overview of the functional activities of haemotoxic venom proteins, the pathologies they cause in snakebite victims and how their exquisite selectivity and potency make them amenable for use as therapeutic and diagnostic tools relevant for human medicine.

Snake envenoming causes several potentially lethal pathologies. The specific pathology is dictated by the toxin composition of venom, which varies by species, geography and ontogeny. This variation severely restricts the paraspecific efficacy of antivenoms used to treat snakebite victims. With a view to devising pathology-specific snakebite treatments, we assessed the procoagulant activity of 57 snake venoms and investigated the efficacy of various antivenoms. We find that procoagulant venoms act differentially on key steps of the coagulation cascade, and that certain monospecific antivenoms work in a previously unrecognised paraspecific manner to neutralise this activity, despite conventional assumptions of congener-restricted efficacy. Moreover, we demonstrate that the metal chelator EDTA is also capable of neutralising venom-induced lethality in vivo. This study illustrates the exciting potential of developing new, broad-spectrum, toxin-targeting antivenoms capable of treating key snakebite pathologies, and advocates a thorough re-examination of enzyme inhibiting compounds as alternative therapies for treating snakebite victims.

Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and financial snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibiting different enzymatic toxin families. Furthermore, using murine in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents murine lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings support the translation of combinations of repurposed small molecule-based toxin inhibitors as broad-spectrum therapeutics for snakebite.

Animal venoms have evolved over millions of years for prey capture and defense from predators and rivals. Snake venoms, in particular, have evolved a wide diversity of peptides and proteins that induce harmful inflammatory and neurotoxic effects including severe pain and paralysis, hemotoxic effects, such as hemorrhage and coagulopathy, and cytotoxic/myotoxic effects, such as inflammation and necrosis. If untreated, many envenomings result in death or severe morbidity in humans and, despite advances in management, snakebite remains a major public health problem, particularly in developing countries. Consequently, the World Health Organization recently recognized snakebite as a neglected tropical disease that affects ∼2.7 million p.a. The major protein classes found in snake venoms are phospholipases, metalloproteases, serine proteases, and three-finger peptides. The mechanisms of action and pharmacological properties of many snake venom toxins have been elucidated, revealing a complex multifunctional cocktail that can act synergistically to rapidly immobilize prey and deter predators. However, despite these advances many snake toxins remain to be structurally and pharmacologically characterized. In this review, the multifunctional features of the peptides and proteins found in snake venoms, as well as their evolutionary histories, are discussed with the view to identifying novel modes of action and improving snakebite treatments.