How is snake venom produced

Snakes are very difficult to look after," Cammack said, who was not involved with the research. Clevers said his lab now plans to make venom gland organoids from the world's 50 most venomous animals and they will share this biobank with researchers worldwide. At the moment, Clevers said they are able to produce the organoids at a rate of one a week.

But producing antivenom is not an area that pharmaceutical companies have traditionally been keen to invest in, Clevers said.

Campaigners often describe snakebites as a hidden health crisis, with snakebites killing more people than prostrate cancer and cholera worldwide, Cammack said.

Don't underestimate how many people die. Sharks kill about 20 per year. Snakes kill , or ,," said Clevers. Venom is a complex cocktail. One challenge to making synthetic antivenom is the sheer complexity of how a snake disables its prey.

Its venom contains several different components that have different effects. Researchers in India have sequenced the genome of the Indian Cobra, in an attempt to decode the venom. How nature's deadliest venoms are saving lives. 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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Snake venoms vary a lot between species in their make-up and effects, which is a major problem for developing treatments. Snakes use these venoms for two main purposes. The first is foraging, where venom helps the snake to overpower its prey before eating it.

The second is self-defence against potential predators — this is how millions of people get bitten, and around , killed, every year. Many studies have shown that the need to capture and eat prey often drives the evolution of different snake venoms. For instance, many species have venoms that are especially lethal to their main prey species. On the other hand, scientists know surprisingly little about the role of natural selection for self-defence in the evolution of venoms.

If you have ever been stung by a bee, you will know that the sting hurts almost immediately, and the pain rapidly reaches its peak. And if you think a bee sting is no big deal, consider the consequences of being stung by a lionfish.

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