Haemotoxic snake venoms: their functional activity, impact on snakebite victims and pharmaceutical promise

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.

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

“…These abundance differences likely underpin the distinct pathologies observed following envenomings by snakes found in these families. SVMPs contribute extensively to the hemorrhagic and coagulopathic venom activities following bites by viperid snakes, and the diversity of SVMPs isoforms often present in their venom likely facilitate synergistic effects, such as simultaneous action on multiple steps of the blood clotting cascade (Kini and Koh, 2016;Slagboom et al, 2017). Certain "colubrid" snakes, whether medically important or not, also show evidence of having multiple SVMP toxins in their venom, even if they do not show the sub-class diversity observed in the vipers (Mackessy and Saviola, 2016;Pla et al, 2017;Modahl et al, 2018a;Perry et al, 2018).…”

“…In these animal venoms, the pharmacological effects are primarily caused by disulfide bridged peptides, whilst snake venoms consist of a more diverse array of larger proteins and peptides which results in a wider variety of pharmacological and toxicological effects (Zhang, 2015). These venoms comprise 50-200 components distributed in dominant and secondary families which can be presented in multiple proteins and peptides isoforms (Vonk et al, 2011;Slagboom et al, 2017;Tasoulis and Isbister, 2017). The dominant families are secreted phospholipases A 2 (PLA2s), snake venom metalloproteinases (SVMP), snake venom serine proteases (SVSP), and three-finger peptides (3FTX), while the secondary families comprise cysteine-rich secretory proteins, Lamino acid oxidases, kunitz peptides, C-type lectins, disintegrins, and natriuretic peptides (Slagboom et al, 2017;Tasoulis and Isbister, 2017;Munawar et al, 2018).…”

“…These venoms comprise 50-200 components distributed in dominant and secondary families which can be presented in multiple proteins and peptides isoforms (Vonk et al, 2011;Slagboom et al, 2017;Tasoulis and Isbister, 2017). The dominant families are secreted phospholipases A 2 (PLA2s), snake venom metalloproteinases (SVMP), snake venom serine proteases (SVSP), and three-finger peptides (3FTX), while the secondary families comprise cysteine-rich secretory proteins, Lamino acid oxidases, kunitz peptides, C-type lectins, disintegrins, and natriuretic peptides (Slagboom et al, 2017;Tasoulis and Isbister, 2017;Munawar et al, 2018). Interestingly, snake venom composition varies interspecifically (Fry et al, 2008;Tasoulis and Isbister, 2017), as well as intraspecifically, with many factors influencing this diversity including age (Dias et al, 2013), gender (Menezes et al, 2006;Zelanis et al, 2016), location (Durban et al, 2011;Goncalves-Machado et al, 2016), diet (Barlow et al, 2009), and season (Gubensek et al, 1974).…”

“…In addition, other PLA2s and 3FTXs, along with SVMPs, cause local tissue damage resulting in swelling, blistering, bruising, and necrosis, and systemic effects such as hypovolemic shock (Gutierrez and Rucavado, 2000;Gutierrez et al, 2005;Harris and Scott-Davey, 2013;Rivel et al, 2016). Furthermore, SVSPs and SVMPs induce hemostatic and cardiovascular effects as coagulopathy, hypotension and hemorrhage (Slagboom et al, 2017). Interestingly, some PLA2s, SVSPs, and SVMPs are also capable of triggering severe pain by modulating pain pathways through activation of ion channels, such as transient receptor potential vanilloid type 1 (TRPV1) and acid-sensing ion channel (ASIC) (Bohlen et al, 2011;Zhang et al, 2017); and/or by pain sensitization through inflammatory mediators (Zychar et al, 2010;Menaldo et al, 2013;Ferraz et al, 2015;Mamede et al, 2016;Zambelli et al, 2017b).…”

High throughput screening and identification of coagulopathic snake venom proteins and peptides using nanofractionation and proteomics approaches

“…farmers, herdsmen, etc) of the tropics and sub-tropics who suffer the greatest burden of snakebite, with incidences and case fatality rates highest in south and south-east Asia and sub-Saharan Africa (1). In part this is due to socioeconomic reasons, as victims in these parts of the world often do not have rapid access to specialized medical care due to limited health and logistical infrastructure (5), which severely restricts access to snakebite therapy. The only specific therapy available for treating snake envenoming is antivenom.…”