Abstract
A global strategy, under the coordination of the World Health Organization, is being unfolded to reduce the impact of snakebite envenoming. One of the pillars of this strategy is to ensure safe and effective treatments. The mainstay in the therapy of snakebite envenoming is the administration of animal-derived antivenoms. In addition, new therapeutic options are being explored, including recombinant antibodies and natural and synthetic toxin inhibitors. In this review, snake venom toxins are classified in terms of their abundance and toxicity, and priority actions are being proposed in the search for snake venom metalloproteinase (SVMP), phospholipase A2 (PLA2), three-finger toxin (3FTx), and serine proteinase (SVSP) inhibitors. Natural inhibitors include compounds isolated from plants, animal sera, and mast cells, whereas synthetic inhibitors comprise a wide range of molecules of a variable chemical nature. Some of the most promising inhibitors, especially SVMP and PLA2 inhibitors, have been developed for other diseases and are being repurposed for snakebite envenoming. In addition, the search for drugs aimed at controlling endogenous processes generated in the course of envenoming is being pursued. The present review summarizes some of the most promising developments in this field and discusses issues that need to be considered for the effective translation of this knowledge to improve therapies for tackling snakebite envenoming.
Highlights
Key Contribution: The search for natural and synthetic inhibitors of snake venom key toxins is reviewed
In 2018, the World Health Assembly approved a resolution that urged member states to take action for the prevention and control of snakebites [12], and a global strategy aimed at reducing the number of deaths and disabilities caused by envenomings by 50% by the year 2030 was launched by the World Health Organization (WHO) in 2019 [13]
The main limitations of antivenom therapy are: (1) Antivenoms need to be administered by trained medical and nursing staff in healthcare facilities under conditions that enable the management of potentially serious adverse reactions that may occur following their administration and whose incidence varies depending on the product [17,18]
Summary
Snake venoms are complex secretions which are thought to have evolved in advanced snakes to facilitate prey capture [31,39,40,41], though snakes will deploy these chemical weapons defensively, as exemplified by human snakebites. The search for venom PLA2 inhibitors should aim to address both the inhibition of enzymatic activity (i.e., binding to the active site and the abrogation of the catalytic process), and blockage of the molecular sites that enable these toxins to bind to key targets Another group of 3FTxs, which play an important role in envenomings by some terrestrial elapids of the genus Naja, includes the ‘cytotoxins’ or ‘cardiotoxins’. Serine proteinases are widely present in snake venoms and display a variety of activities, some of which exert a role in envenomings, their contribution is generally less relevant than that of SVMPs, PLA2s and 3FTxs. In addition to several activities described in vitro, i.e., kallikrein-like activity, activation of coagulation factor V, protein C and plasminogen, and induction of platelet aggregation [79,80], the most significant actions of SVMPs from a pathophysiological standpoint are the formation of fibrin from fibrinogen (‘thrombin-like’ activity, known as ‘pseudo-procoagulant activity’) [81,82,83] and prothrombin activation [84,85]. Serine proteinases are involved in cardiovascular alterations associated with increments in vascular permeability through the release of endogenous mediators from plasma proteins [79]
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