If not treated with antivenom, these early signs will eventually be followed by increasing difficulty talking, swallowing and, ultimately, breathing. The Australian paralysis tick also has neurotoxins but, unlike snakes, these toxins take many days to cause paralysis. It usually starts by causing weakness in the legs.
Many paralysing venoms contain a cocktail of molecules that act together but in different ways to interfere with the transmission of nerve impulses. The most dangerous paralysing toxins destroy the nerves themselves. Some Australian snake venoms, such as the mainland tiger snake, contain both receptor blocking and nerve destructive types of neurotoxins. Once this latter type of damage occurs, it may take weeks for the nerves to repair and during this time you may not be able to breathe without external support.
Another potentially lethal effect of snakebite, rarely seen with other types of venoms, is altered blood clotting. The eastern brown snake, for example, can cause a very severe clotting disturbance.
This type of venom can cause the sudden death of some people bitten by these snakes. Arguably the most dangerous venom in the world is that of the box jellyfish, Chironex fleckeri , because of its ability to kill a healthy adult human in minutes. This remarkable lethality is attributed to powerful toxins that are injected into the skin through millions of tiny venom-filled harpoon-like weapons on the jellyfish tentacles. Once in the circulation, these toxins seem to home in on, and punch holes in, the outer membrane of heart muscle cells.
These holes disturb the smoothly co-ordinated contraction of the heart muscles. A more insidious effect, particularly of snake venoms, is muscle destruction known as myotoxicity. The World Health Organization has added 'snakebite' to its list of neglected tropical diseases , but what is the real scale of the problem it faces against such a vicious venom?
Snake venom is made up of several hundred proteins which all have a slightly different toxic effect on the human body. One snake's poison may not be like another's, even if they are from the same species. But, on the whole, there are two main ways snakes make us suffer - by attacking the circulatory system ie.
Haemotoxic venom goes for the bloodstream. It can trigger lots of tiny blood clots and then when the venom punches holes in blood vessels causing them to leak, there is nothing left to stem the flow and the patient bleeds to death. Other venoms can increase blood pressure, decrease blood pressure, prevent bleeding or create it.
They are all bad news. Neurotoxic venom tends to act more quickly, attacking the nervous system and stopping nerve signals getting through to the muscles. This means paralysis, starting at the head, moving down the body until, if untreated, the diaphragm is paralysed and the patient can't breathe.
A classic sign of this is ptosis, when people can't keep their eyes open. Around the area of the bite, necrosis can set in. That happens when the venom destroys nearby muscles, tissues and cells. Long-term, this can lead to amputations, the loss of the use of a limb or the need for multiple skin grafts.
Snakes get closer to humans and cause more damage and more deaths than any other venomous animal, including spiders, scorpions and jellyfish. That's because venomous snakes are found across large swathes of the planet, typically in rural, tropical areas, like sub-Saharan Africa and south-east Asia.
But they also live in Australia and North America. Since snakes lurk on the ground, often camouflaged and unseen, farmers, rural workers and many young children can easily disturb them and get bitten. Each year, up to five million people worldwide are estimated to be bitten by snakes. Out of those, around , die and , are left disabled or disfigured by their injuries.
But the numbers could be even larger - because many of the worst-affected countries don't keep data on snakebites and research into this problem is scarce. These life-saving antidotes to snake bites are made by extracting venom from snakes then injecting it diluted into sheep or horses, which build up antibodies against it.
These antibodies are then separated from the animal's blood and used to make anti-venom - but there's a problem. Anti-venoms are expensive and only produced in limited quantities. First, SVMPs cleave the basement membrane and adhesion proteins of endothelial cells-matrix complex to weaken the capillary vessels. During the second stage, the endothelial cells detach from the basement membrane and become extremely thin, resulting in disruption of the capillary walls and effusion of blood from the fragile capillary walls.
In addition to the proteinase activity, SVMPs impact on homeostasis by altering coagulation, which contributes to their toxic hemorrhagic effects Markland, ; Takeda et al. This occurs through modulation of factors such as fibrinogenase and fibrolase that mediate the coagulation cascade, depletion of pro-coagulation factors through consumption processes e. Some SVMPs also induce inflammation, including edema, and pain by triggering hyperalgesia Dale et al.
Neurogenic inflammation was also implicated in the local hemorrhage induced by Bothrops jararaca which was shown to be dependent on serotonin and other neuronal factors Goncalves and Mariano, The mechanisms on how neurogenic inflammation is triggered by the snake venom components and how it participates in the hemorrhagic process are still not understood. Pain induced by SVMPs is characterized by hyperalgesia and inflammatory pain, which is dependent on the production of cytokines, nitric oxide, prostaglandins, histamine, leukotrienes, and migration of leukocytes, mast cell degranulation and NFkB activation Fernandes et al.
However, the mechanisms underlying SVMP-induced pain are still poorly understood, with neurogenic inflammation and neuronal excitatory properties still underexplored. The multifunctional properties of SMVPs are also well-described. These observations suggest that these domains are involved in the inflammatory hyperalgesia induced by SVMPs. Furthermore, the pronounced hemorrhagic and necrotic activities are strongly dependent on biological effects driven by the disintegrin-like and cysteine-rich domains, as observed for BJ-PI2 da Silva et al.
The hemorrhagic activity of Bothrops jararaca venom was also shown dependent on neurogenic inflammation Goncalves and Mariano, These venom toxins have evolved from kallikrein-like serine proteases and, following their recruitment for use in the venom gland, have undergone gene duplication events giving rise to multiple isoforms Fry et al.
SVSPs catalyze the cleavage of polypeptide chains on the C-terminal side of positively charged or hydrophobic amino acid residues Page and Di Cera, ; Serrano, Whilst the SVMPs are well-known for their ability to rupture capillary vessels, SVSPs execute their primary toxicity by altering the hemostatic system of their victims, and by inducing edema and hyperalgesia through mechanisms still poorly understood Table 1.
Hemotoxic effects caused by SVSPs include perturbations of blood coagulation pro-coagulant or anti-coagulant , fibrinolysis, platelet aggregation and blood pressure, with potential deadly consequences for snakebite victims Murakami and Arni, ; Kang et al.
Figure 3. Structure of Serine proteinases from snake venoms. For example, the activation of prothrombin produces thrombin which in turn produces fibrin polymers that are cross-linked. Thrombin also activates aggregation of platelets which, together with the formation of fibrin clots, results in coagulation Murakami and Arni, In addition, platelet-aggregating SVSPs will activate the platelet-receptors to promote binding to fibrinogen and clot formation Yip et al.
These procoagulant and platelet-aggregating activities will lead to the rapid consumption of key factors in the coagulation cascade and clot formation. Furthermore, fibrinolytic SVSPs play an important role in the elimination of blood clots by acting as thrombin-like enzymes or plasminogen activators, which eliminates the fibrin in the clots and contributes significantly to the establishment of the coagulopathy Kang et al.
Little is known about inflammatory responses and hyperalgesia induced by SVSPs. SVSPs in the venoms of Bothrops jararaca and Bothrops pirajai induce inflammation through edema formation, leucocyte migration mainly neutrophils and mild mechanical hyperalgesia, however, the mediators involved in these effects are still unknown Zychar et al. Three-fingers toxins 3FTXs are non-enzymatic neurotoxins ranging from 58 to 81 residues that contain a three-finger fold structure stabilized by disulfide bridges Osipov and Utki, ; Kessler et al.
They are present mostly in the venoms of elapid and colubrid snakes, and exert their neurotoxic effects by binding postsynaptically at the neuromuscular junctions to induce flaccid paralysis in snakebite victims Barber et al. Furthermore, they can exist as monomers and as covalent or non-covalent homo or heterodimers.
The diversity of 3FTX isoforms described above are a direct result of a diverse evolutionary history, whereby ancestral 3FTXs have diversified by frequent gene duplication and accelerated rates of molecular evolution. These processes, which are broadly similar to those underpinning the evolution of the other toxin families described above, are particularly associated with the evolution of a high-pressure hollow-fanged venom delivery system observed in elapid snakes Sunagar et al.
For example, gene duplication events have resulted in the expansion of 3FTX loci from one in non-venomous snakes like pythons, to 19 in the elapid Ophiophagus hannah king cobra Vonk et al. The consequences of this evolutionary history are the differential production of numerous 3FTX isoforms that often exhibit considerable structural differences and distinct biological functions Figures 4B—E.
Although many elapid snakes exhibit broad diversity of these functionally varied toxins in their venom e. Figure 4. Structure of three-finger toxins from snake venoms. K Neurotoxin II from N.
L Neurotoxin b NTb from O. Despite the shared three-finger fold, the 3FTXs have diverse targets and biological activities. Their toxic biological effects include flaccid or spastic paralysis due to the inhibition of AChE and ACh receptors Grant and Chiappinelli, ; Changeux, ; Marchot et al. In addition to their multitude of bio-activities, 3FTXs can remarkably display toxicities that target distinct classes of organisms as demonstrated in non-front fanged snake venoms that produce 3FTX isoforms which are non-toxic to mice but highly toxic to lizards, and vice-versa Modahl et al.
Furthermore, 3FTXs are relatively small compared to the other snake toxins discussed herein, and do not exhibit multiple domains to produce their multiple toxic functions. Nevertheless, the number of receptors, ion channels, and enzymes targeted by snake 3FTXs highlights the unique capacity of this fold to modulate diverse biological functions and the arsenal of toxic effects that are induced by 3FTXs. The unique multifunctionality of the 3FTX scafold occurs because of their resistance to degradation and tolerance to mutations and large deletions Kini and Doley, Therefore, the structure-activity relationship of the 3FTXs is complex and yet to be fully understood.
Their functional sites are located on various segments of the molecule surface. Conserved regions determine structural integrity and correct folding of 3FTXs to form the three loops, including eight conserved cysteine residues found in the core region. Additional disulfide bonds can be observed either in the loop I or loop II which can potentially change the activity of the 3FTX in some cases. Specific amino acid residues in critical segments of the 3FTXs have been identified to be important for binding to their targets.
For example, the interactions between fasciculin and AChE enzyme has been studied. The first loop or finger of fasciculin reaches down the outer surface of the enzyme, while the second loop inserts into the active site and exhibit hydrogen bonds and hydrophobic interaction Harel et al. Several basic residues in fasciculin make key contacts with AChE. From docking studies, hydrogen bonds, and hydrophobic interactions where shown to establish receptor-toxin assembly. Hydrophobic interactions are also observed between eight amino acid residues Lys32, Cys59, Val34, Leu48, Ser26, Gly36, Thr15, Asn20 from fasciculin and the enzyme active site Waqar and Batool, These interactions involve charged residues but lacks intermolecular salt linkages.
Muscarinic toxins from mamba venoms, such as MT1 and MT7 Figures 4G,H , act as highly potent and selective antagonists of M1 receptor subtype through allosteric interactions with the M1 receptor. Fruchart-Gaillard et al. In this study, substitution within loop 1 and loop 3 weaken the toxin interactions with the M1 receptor, resulting in a 2-fold decrease in affinity Figures 4I,J.
Furthermore, modifications in loop 2 of the MT1 and MT7 significantly reduce the affinity for the M1 receptor. These two residues were not located at the tip of the toxin loop, however, they played a critical role in the interactions with their molecular targets Bourne et al.
The insertion of the loop II into the binding pocket of a nAChR induces the neurotoxin activity and significantly determines the toxin-receptor interactions, while loop I and III contact the receptor residues by their tips only and determine the immunogenicity of the short neurotoxins.
The structure of neurotoxin b NTb , a long neurotoxin from Ophiophagus hannah , has been elucidated Peng et al. Conserved residues in loop II also play an important role in the toxicity of the long neurotoxins by making ionic interactions between toxin and receptor.
Positively charged residues Trp27, Lys24 and Asp28 are highly conserved residues in the long neurotoxins. Furthermore, a modification of the Trp27 in the long neurotoxin analog of NTb from king cobra venom led to a significant loss in neurotoxicity. The additional disulphide bridge in loop II of long neurotoxins does not affect the toxin activity. Nevertheless, cleavage of the additional disulphide bridge in loop II can disrupt the positively charged cluster at the tip of loop II.
Changes in loop II conformation will affect the binding of the long neurotoxin to the target receptor resulting the loss of neurotoxicity Peng et al. Long and short neurotoxins show sequence homology and similar structure. Previous studies show that many residues located at the tip of loop II are conserved in both short and long neurotoxins. However, significant differences between long-chain neurotoxin and short chain neurotoxin are indicated by the immunological reactivity. Many of the residues involved in the antibody-long neurotoxins binding are located in loop II, loop III, and in the C-terminal, while in short neurotoxins the antibody's epitope makes interactions with the loop I and loop II Engmark et al.
Animal-derived antivenoms are considered the only specific therapy available for treating snakebite envenoming Maduwage and Isbister, ; Slagboom et al. These consist of polyclonal immunoglobulins, such as intact IgGs or F ab' 2 , or Fab fragments Ouyang et al. Antivenoms can be classified as monovalent or polyvalent depending on the immunogen used during production. Monovalent antivenoms are produced by immunizing animals with venom from a single snake species, whereas polyvalent antivenoms contain antibodies produced from a cocktail of venoms of several medically relevant snakes from a particular geographical region.
Polyvalent antivenoms are therefore designed to address the limited paraspecific cross-reactivity of monovalent antivenoms by stimulating the production of antibodies against diverse venom toxins found in different snake species, and to avoid issues relating to the wrong antivenom being given due to a lack of existing snakebite diagnostic tools O'leary and Isbister, ; Abubakar et al.
However, polyvalent therapies come with disadvantages—larger therapeutic dose are required to effect cure, potentially resulting in an increased risk of adverse reactions, and in turn increasing cost to impoverished snakebite victims Hoogenboom, ; O'leary and Isbister, ; Deshpande et al.
Variation in venom constituents therefore causes a great challenge for the development of broadly effective snakebite therapeutics. The diversity of toxins found in the venom of any one species represents considerable complexity, which is further enhanced when trying to neutralize the venom of multiple species, particularly given variations in the immunogenicity of the multi-functional toxins described in this review.
Antivenom efficacy is therefore, typically limited to those species whose venoms were used as immunogens and, in a number of cases, closely-related snake species that share sufficient toxin overlap for the generated antibodies to recognize and neutralize the key toxic components Casewell et al.
Because variation in venom composition is ubiquitous at every level of snake taxonomy e. Such studies have revealed surprising cross-reactivity of antivenoms against distinct, non-targeted, snake species, such as: i the potential utility of Asian antivenoms developed against terrestrial elapid snakes at neutralizing the venom toxicity of potent sea snake venoms Tan et al.
The later of these studies demonstrated cross-neutralization between distinct snake lineages e. Thus, detailed knowledge of venom composition can greatly inform studies assessing the geographical utility of antivenoms.
Such studies have stimulated much research into the development of novel therapeutic approaches to tackle snakebite. These include the use of monoclonal antibody technologies to target key pathogenic toxins found in certain snake species Laustsen et al.
It is anticipated that in the future these new therapeutics may offer superior specificities, neutralizing capabilities, affordability and safety over conventional antivenoms. However, the translation of their early research promise into the mainstay of future snakebite treatments will ultimately rely on further research on the toxins that they are designed to neutralize.
Specifically, the selection, testing and optimization of new tools to combat snake envenoming is reliant upon the characterization of key pathogenic, and often multifunctional, toxins found in the venom of a diverse array of medically important snake species. The first drug derived from animal venoms approved by the FDA is captopril, a potent inhibitor of the angiotensin converting enzyme sACE used to treat hypertension and congestive heart failure Cushman et al.
Captopril was derived from proline-rich oligopeptides from the venom of the Brazilian snake Bothrops jararaca Ferreira et al.
This milestone in translational science in the late 70's revealed the exceptional potential of snake venoms, and possibly other animal venoms such as from spider and cone snails, as an exquisite source of bioactive molecules with applications in drug development.
More recently, an anti-platelet drug derived from the venom of the southeastern pygmy rattlesnake Sistrurus miliarius barbouri was commercialized as Integrillin by Millenium Pharmaceuticals, and is used to prevent acute cardiac ischemia Lauer et al.
The resulting product is now commercialized as Syn-AKE. Snake toxins have been applied with great success in diagnostics.
Snake toxins also have the potential to become novel painkillers. These findings, alongside current research into venom toxins, suggest an exciting future for the use of snake venoms in the field of drug discovery. Snake venoms are amongst the most fascinating animal venoms regarding their complexity, evolution, and therapeutic applicability.
They also offer one of the most challenging drugs targets due to the variable toxin compositions injected following snakebite. The multifunctional approach adopted by the major components of their venoms, by using multidomain proteins and peptides with promiscuous folds e. Gaining a better understanding of the evolution, structure-activity relationships and pathological mechanisms of these toxins is essential to develop better snakebite therapies and novel drugs.
Recent developments in genomics, proteomics and bioactivity assays, as well as in the understanding of human physiology in health and disease, are enhancing the quality and speed of research into snake venoms.
We hope to improve the therapies used to neutralize the toxic effects of PLA2s, SVMPs, SVSPs and 3FTXs, and to develop drugs as new antidotes for a broad-spectrum of snake venoms that could also be effective in preventing the described inflammatory reactions and pain induced by snakebite. Finally, a diversity of biological functions in snake venoms is yet to be explored, including their inflammatory properties and their intriguing interactions with sensory neurons and other compartments of the nervous system, which will certainly lead to the elucidation of new biological functions and the development of useful research tools, diagnostics and therapeutics.
FC provided theme, scope, and guidance. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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