Venomics

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[1] Venomics is the study of proteins associated with venom , a toxic substance secreted by animals, which is typically injected either offensively or defensively into prey or aggressors, respectively.

Contents

Background

Venom is produced in a specialised gland (or glands) and is delivered through hollow fangs or a stinger in a process called envenomation. The main function of venom is to disrupt the physiological processes of the wounded animal through neurotoxic cytotoxic, myotoxic, or haemotoxic mechanisms. This can then help in certain processes such as procuring prey or in defense predators. Venom has evolved many times in multiple phyla, each having developed their own unique types of venom and methods of delivery independently. [2] However, due to the excessive amounts of venomous animals in the world, they are the major cause of animal-related deaths (~ 57,000 in 2013) than non-venomous animals (~22,000). [3] For example, globally, someone is bitten by a snake every 10 seconds, according to estimates. Snakes are responsible for more than 5.4 million biting-injuries, resulting to 1.8 - 2.7 million envenomings and around 81,410 to 137,880 deaths annually. [4] Bites by venomous snakes can cause acute medical emergencies involving severe paralysis that may prevent breathing, cause bleeding disorders that can lead to fatal haemorrhage, cause irreversible kidney failure and severe local tissue destruction that can cause permanent disability and limb amputation. Children may suffer more severe effects and can experience the effects more quickly than adults due to their smaller body mass. [5] With venomic methods, venom can be co-opted into beneficial substances such as new medicines and effective insecticides. [6] [7] For instance, Captopril® (Enalapril), Integrilin® (Eptifibatide) and Aggrastat® (Tirofiban) are drugs based on snake venoms, which have been approved by the FDA. In addition to these approved drugs, many other snake venom components are now involved in preclinical or clinical trials for a variety of therapeutic applications [8] .

The Creation and History of Venomics Techniques

Venom is made up of multiple proteinous components, with each component differing in its structural complexity. Venom can be a mixture of simplistic peptides, secondary (α-helices and β-sheets) structured proteins and tertiary structured proteins (crystalline structures). [9] Furthermore, depending on the organism, there can be fundamental differences in the strategies they incorporate in their venom contents, the biggest difference being between invertebrates and vertebrates. For example, the majority of funnel-web spider’s venom was made up of peptides between 3-5 KDa (75%), with the remaining peptides being between 6.5-8.5 KDa in mass. [10] Conversely, snake venom is made up of more complex protein such as modified saliva proteins (CRISPs & kallikrein) and protein families that have had their genes recruited from other tissue groups (Acetylcholinesterase, crotasin, defensin & cystatin). [11] Due to this extraordinary amount of variation in the components that make up venom, a new field was needed to identify and categorise the millions of bioactive molecules that are found within the venom. [2] Therefore, by combining the methods of multiple fields such as genomics, transcriptomics, proteomics and bioinformatics, an aptly named new field emerged named venomics.

Venomics was first established in the latter half of the 20th century as different ‘-omic’ technologies began to rise in popularity. However, the progression of venomics since its inception has always been reliant on and limited by the advancement of technology. Juan Calvete draws attention to this with explicitly when detailing the history of venomics. [12] He declares that ''the last revolutions made in venomics research in the last decade (1989-1999) are the direct result of advancements made in proteomic-centered methods and the indirect result of more widely available and cost-effective forms of transcriptomics and bio-informatics analysis''. One of the first popular research topics of venomics was the pharmacological properties of the polypeptide toxins found in snake venom (Specifically, Elapidae and Hydrophidae ) due to the neurotoxic properties and their ability to cause respiratory failure in animals. [13] However, due to the lack of competent technology, less complex techniques (such dialysis to separate the venom), followed by simplistic chromatography and electrophoresis analysis, research was limited.

(Left) The amino acid structure, (Middle) diagram and (Right) Stereodiagram of k-Bungarotoxin. Venom amino acid structure.png
(Left) The amino acid structure, (Middle) diagram and (Right) Stereodiagram of k-Bungarotoxin.

Evidence of early interest in snake venom was prevalent throughout the early 20th century with one of the first big breakthroughs being in the mid-1960s. For example, Halbert Raudonat was one of the first researchers to fractionate Cobra ( Naja nivea ) venom using a sophisticated dialysis and paper chromatography techniques. [15] Furthermore, Evert Karlsson and David Eaker were able to successfully purify the specific neurotoxins found in Cobra ( Naja nigricollis ) venom and found that those isolated polypeptides had a consistent molecular weight of around 7000. [16]

Future research in this field would eventually lead to indirect predictive models and then direct crystal structures of important many protein superfamilies. [17] [14] For example, Barbara Low was one of the first to release a 3D structure of the three-finger protein (TFP), Erabutoxin-b. [18] TFPs are an example of α-Neurotoxins, they are small in structure (~60-80 amino acid length) and are a predominant component found in many snake venoms (representing up to 70%-95% of all toxins). [19] [20]

The Current State and Methodology of Venomics

Retrospectively, venomics has made a lot of progress in sequencing and creating accurate models of toxic molecules through current advanced methods. Through these methods, global categorisation of venoms has also taken place, with previously studied venoms being documented and widely available. An example of this would be the ‘Animal toxin annotation project’ (Provided by the UniProtKB/Swiss-Prot), which is a database that aims to provide a high quality and freely available source of protein sequences, 3D structures and functional information on thousands of animal venom/poisons. So far, they have categorised over 6,500 toxins (Both venoms & poisons) at the protein-level, with the overall UniProt organisation having reviewed over 500,000 proteins and provided the proteomes of 100,000 organisms. However, even with today’s technology the deconstruction and cataloguing of the individual components of what makes up an animal’s venom takes a large amount of time and resources due to the overwhelming amount of molecules that are found in a single venom sample. This is complicated further when there are some animals (I.e. Cone snails) that can change the complexity and make-up of their venom depending on the circumstances (Offensive related or defensive related matters) of the envenoming. [21] Furthermore, inter-specific differences exist between male and female of a species with their venoms varying in quantities and toxicity. [22]

A typical workflow for the isolation and screening of compounds found in venom. Venomics workflow.png
A typical workflow for the isolation and screening of compounds found in venom.

Professor Juan J. Calvete is a prolific researcher in venomics at the biomedical institute in Valencia and has extensively explained the process involved in untangling and analysing venom (Once in 2007 and recently in 2017. [24] [23]

These involve the following steps:

(1) Venom collection, (2) Separation and quantification, (3) Identification and (4) Representation of components found.

(1) Venom collection methods

Venom milking is the most simplistic way of collecting a venom sample. It usually involves a vertebrate animal (Typically a snake) to deliver a venomous bite into a container. Similarly, electrical stimulation can be used for invertebrate animal (Insects and arachnids) subjects. [25] This practice has allowed for the discovery of the basic properties of venom and to understand the biological factors involved in venom production such as venom regeneration periods. Other methods involve post-mortem dissection of the venom glands to collect the required materials (Venom or tissue).

(2) Separation and quantification methods

Separation methods are the first step to decomplexify the venom sample, with a common method being reverse‐phase high performance liquid chromatography (RP-HPLC). This method can be applied broadly to nearly all venoms as a crude fractionation method and to detect the peptide bonds found. A less common techniques like 1D/2D gel electrophoresis can also be used in cases of venoms containing heavy, complex peptides (Preferable >10KDa). This means in additions to RP-HPLC, Gel electrophoresis can help identify large molecules (such as enzymes) and to help refine venom prior to further analytical methods. [2] Next, N-terminal sequencing is used to find the amino acid order of the fractionated proteins/peptides starting with the N-terminal end. [26] Furthermore, SDS‐PAGE (Sodium dodecyl sulfate-polyacrylamide gel electrophoresis) can be performed on the isolated proteins from the RP-HPLC to identify proteins of interest before moving on to the identification stage. [24]

(3) Identification methods

(Left) Representation of Bottom-up and Top-down proteomic analysis. (Right) Similarities and differences between the Proteomic and the Transcriptomics/Genomics analytical methods. Proteomic analysis.png
(Left) Representation of Bottom-up and Top-down proteomic analysis. (Right) Similarities and differences between the Proteomic and the Transcriptomics/Genomics analytical methods.

There are two predominantly used proteomic methods when identifying the structure of a peptide/protein, Top-down proteomics (TDP) and Bottom-up proteomics (BUP). TDP involves taking fractionated venom samples and analysing those peptides/proteins with Liquid chromatography tandem-mass spectrometry (LC-MS/MS). This results in the identification and characterisation of all peptides/proteins present in the initial sample. While, BUP consists of fractionating and breaking down the peptides/proteins before analysis (LC-MS/MS) using chemical reduction, alkylating and enzymatic digestion (Typically with trypsin). BUP is more commonly used than TDP as breaking down the samples allows the components to meet the ideal mass range for LC-MS/MS analysis. [27] [2] However, there are disadvantages and limitations with both identification methods. BUP results are prone to protein inference problems as large toxins can be broken down into smaller toxins which are shown in the output, but do not exist naturally within the venom sample. While, TDP is the newer method and is able to fill-in the gaps BUP leaves, TDP needs instruments with high amounts of resolving power (Typically 50,000 or above). Most studies will actually use both methods in parallel to obtain the most accurate results. Furthermore, transcriptomic/genomic methods can be used to create cDNA libraries from the extracted mRNA molecules expressed in the venom glands of a venomous animal. These methods optimise the protein identification process by producing the DNA sequences of all proteins expressed in the venom glands. A large problem in using transcriptomic/genomic analysis in venomic studies is the lack of full genome sequences of many venomous animals. However, this is a fleeting problem due to the amount of full genome projects involved in sequencing venomous animals such as the ‘venomous system genome project’ (Launched in 2003). [28] Through these projects, various fields of study such as ecological/evolutionary studies and venomic studies can provide supporting information and systematic analysis of toxins.

(4) Accurate representation of components

The finding of (Left) proteomic practices and (Right) transcriptomic practices when analysing the venomone of the Bothropoides pauloensis . Analysing the venomone.png
The finding of (Left) proteomic practices and (Right) transcriptomic practices when analysing the venomone of the Bothropoides pauloensis.

Renata Rodrigues produced an informative study detailing both the proteome and the transcriptome of the Neuwied’s Lancehead ( Bothropoides pauloensis ), with all the methods described above. [29] The proteome showed the presence of nine protein families with the majority of components belonging to snake venom metalloproteinases (38%), phospholipase A2 (31%) and Bradykinin-potentiating peptides/C-type natriuretic peptides (12%). The transcriptome gave a cDNA of over 1100 expressed sequence tags (ESTs), with only 688 sequences being related to the venom gland. Similarly, the transcriptome showed matching results with 36% of SVMP’s being the majority of the ESTs followed by PLA2 (26%) and BPP/C-NP (17%) sequences. Furthermore, this study shows that through both the use of proteomic and transcriptomics, we can fully comprehend the components within venom. This can then lead to both the molecular structure and functions of many bioactive components, which can intern lead to bioprospecting venom components into new medicines and can help to develop better methods of creating anti-venoms.

The Future Possibilities of Venomics

The field of venomics has been vastly revamped since its origin in the 20th century and continues to be improved with contemporary methods such as next generation sequencing and nuclear magnetic resonance spectroscopy. From this trend, it would seem that venomics will be progressively enhanced in its capabilities through the persistent technological advancements of the 21st century. As previously mentioned, a potential route that can be expanded upon further by venomics could be venom-specific molecules being co-opted into specialised medicines. The first example of this was in the early 1970s, when Captopril was found to be an inhibitor of angiotensin converting enzymes (ACE) and had the means of treating hypertension in people. [30] Glenn King discusses the current state of venom-derived drugs, with six drugs derived from venom being FDA-approved and ten more currently being under clinical trials. [31] Michael Pennington gives a detailed update on the current landscape of venom-derived drugs and the potential future of the field (Table 1). [6]

Anti-venoms is another branch of medicine, which needs to be improved due to the problems many developing countries face with venomous animals. Places like south/southeast Asia and sub-Saharan Africa are where many cases of both morbidity (limb amputation) and mortality take place. [32] Snakes (especially Elapidae and Viperidae ) are the leading cause of envenomings and antivenoms are in constant short supply in high risk areas due to the strenuous productive methods (Immunised animals) and the strict storage preferences (Constant below 0OC storage). This problem continues, when the medicine itself has limited effects on localised tissue and inevitably causes either acute (anaphylactic or pyrogenic) and delayed (serum sickness type) reactions in most patients. [33] However, by using different ‘omic’ technologies, the use of ‘Antivenomics’ can potentially make safer, more cost effective and less time-consuming ways of producing antivenoms for a range of toxic organisms. New antivenom methods are even being investigated today with the use of monoclonal antibodies (mAbs) and the expansion of venomous databases, allowing for more effective approaches when screening of cross-reactivity of antivenoms. [34] [35] Lastly, agriculture can be improved upon by enhanced-venomic techniques through the invention of insect-specific biopesticides created from venom. Insects are both an agricultural/horticultural pest and act as vector/carriers of many parasites and disease. [36] Ergo, effective insecticides are always needed to control the destructive effects of many insect species. However, many insecticides used in the past, do not meet current regulations and have been banned due to harmful effects such as affecting non-target species (DDT) and having a high toxicity level towards mammals (Neonicotinoids). [37] Monique Windley propose arachnid venom is a potential solution to this problem due to the abundance of neurotoxic compounds present in their venom (Predicted 10million bioactive peptides) and due to their venom being specific towards insect. [7]

Table 1. Venom-derived medicines discussed by Pennington, Czerwinski et al., (2017). [6]

Treatment forMode of action/ Target siteAnimal of originDevelopment stage
Captopril Hypertension/ Congestive heart failureACE inhibitorPit viper

( Bothrops jararaca )

Approved
Eptifibatide Antiplatelet drugCirculatory systemPygmy rattlesnake

( Sistrurus miliarius barbouri )

Approved
Tirofiban Antiplatelet drugCirculatory systemRussell's viper

( Daboia russelii )

Approved
Lepirudin AnticoagulantThrombin inhibitorSaw-scaled viper

( Echis carinatus )

Approved
Bivalirudin AnticoagulantThrombin inhibitorMedicinal leech

( Hirudo medicinalis )

Approved
Ziconotide Chronic painVoltage-gated calcium channelsCone snail

( C. geographus )

Approved
Exenatide Type 2 diabetesGLP-1 receptorGila monster

( Heloderma suspectum )

Approved
Chlorotoxin Tumour imagingCl− channels/

Glioma cells

Deathstalker scorpion

( Leiurus quinquestriatus )

Clinical

development

Stichodactyla (ShK) Autoimmune disease(s)Voltage-gated potassium channelsCaribbean sea anemone

( Stoichactis helianthus )

Clinical

development

SOR-C13CancerTRPV6N. short-tailed shrew

( Blarina brevicauda )

Clinical

development

HsTX1 [R14A] Autoimmune disease(s)Voltage-gated potassium channelsGiant Forest scorpion

( Heterometrus spinnife )

Preclinical

development

NaV1.7 blockersPainNaV1.7Several tarantula species ( Thrixopelma pruriens, Selenocosmia huwena, Pamphobeteus nigricolor )Preclinical

development

α-conotoxin RgIAPainnACh receptorsCone snail

( Conus regius )

Preclinical

development

α-Conotoxin Vc1.1PainnAChRsCone snail

( Conus victoriae )

Discontinued
χ-Conotoxin MrIAPainNorepinephrine transporter inhibitorCone snail

( Conus marmoreus )

Discontinued
Contulakin-GPainNeurotensin receptorsCone snail

( Conus geographus )

Discontinued
Conantokin-GPain/EpilepsyNMDA receptorsCone snail

(Conus geographus)

Discontinued
Cenderitide Cardiovascular disease(s)ANP receptor BModified Green mamba venom

( Dendroaspis angusticeps )

Discontinued

Related Research Articles

<span class="mw-page-title-main">Venom</span> Toxin secreted by an animal

Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved venom apparatus, such as fangs or a stinger, in a process called envenomation. Venom is often distinguished from poison, which is a toxin that is passively delivered by being ingested, inhaled, or absorbed through the skin, and toxungen, which is actively transferred to the external surface of another animal via a physical delivery mechanism.

<span class="mw-page-title-main">King cobra</span> Group of venomous snakes from Asia

The king cobra is a species complex of snakes endemic to Asia. With an average of 3.18 to 4 m and a record length of 5.85 m (19.2 ft), it is the world's longest venomous snake and among the heaviest. Under the genus Ophiophagus, it is not phylogenetically a true cobra despite its common name and some resemblance. Spanning from the Indian Subcontinent through Southeastern Asia to Southern China, the king cobra is widely distributed albeit not commonly seen.

<span class="mw-page-title-main">Antivenom</span> Medical treatment for venomous bites and stings

Antivenom, also known as antivenin, venom antiserum, and antivenom immunoglobulin, is a specific treatment for envenomation. It is composed of antibodies and used to treat certain venomous bites and stings. Antivenoms are recommended only if there is significant toxicity or a high risk of toxicity. The specific antivenom needed depends on the species involved. It is given by injection.

<span class="mw-page-title-main">Mamba</span> Genus of venomous snakes

Mambas are fast-moving, highly venomous snakes of the genus Dendroaspis in the family Elapidae. Four extant species are recognised currently; three of those four species are essentially arboreal and green in colour, whereas the black mamba, Dendroaspis polylepis, is largely terrestrial and generally brown or grey in colour. All are native to various regions in sub-Saharan Africa and all are feared throughout their ranges, especially the black mamba. In Africa there are many legends and stories about mambas.

<span class="mw-page-title-main">Snakebite</span> Injury caused by bite from snakes

A snakebite is an injury caused by the bite of a snake, especially a venomous snake. A common sign of a bite from a venomous snake is the presence of two puncture wounds from the animal's fangs. Sometimes venom injection from the bite may occur. This may result in redness, swelling, and severe pain at the area, which may take up to an hour to appear. Vomiting, blurred vision, tingling of the limbs, and sweating may result. Most bites are on the hands, arms, or legs. Fear following a bite is common with symptoms of a racing heart and feeling faint. The venom may cause bleeding, kidney failure, a severe allergic reaction, tissue death around the bite, or breathing problems. Bites may result in the loss of a limb or other chronic problems or even death.

<span class="mw-page-title-main">Snake venom</span> Highly modified saliva containing zootoxins

Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is usually injected by unique fangs during a bite, though some species are also able to spit venom.

<span class="mw-page-title-main">Boomslang</span> Species of snake

The boomslang is a highly venomous snake in the family Colubridae. The species is native to Sub-Saharan Africa.

<i>Crotalus scutulatus</i> Species of snake

Crotalus scutulatus is known commonly as the Mohave Rattlesnake. Other common English names include Mojave Rattlesnake and, referring specifically to the nominate (northern) subspecies: Northern Mohave Rattlesnake and Mojave Green Rattlesnake, the latter name commonly shortened to the more colloquial “Mojave green”. Campbell and Lamar (2004) supported the English name “Mohave (Mojave) rattlesnake” with some reluctance because so little of the snake’s range lies within the Mojave Desert.

<span class="mw-page-title-main">Toxicofera</span> Proposed clade of scaled reptiles

Toxicofera is a proposed clade of scaled reptiles (squamates) that includes the Serpentes (snakes), Anguimorpha and Iguania. Toxicofera contains about 4,600 species of extant Squamata. It encompasses all venomous reptile species, as well as numerous related non-venomous species. There is little morphological evidence to support this grouping; however, it has been recovered by all molecular analyses as of 2012.

<span class="mw-page-title-main">Chinese red-headed centipede</span> Subspecies of centipede

The Chinese red-headed centipede, also known as the Chinese red head, is a centipede from East Asia. It averages 20 cm (8 in) in length and lives in damp environments.

<span class="mw-page-title-main">Indian cobra</span> Species of snake

The Indian cobra, also known commonly as the spectacled cobra, Asian cobra, or binocellate cobra, is a species of cobra, a venomous snake in the family Elapidae. The species is native to the Indian subcontinent, and is a member of the "big four" species that are responsible for the most snakebite cases in India.

<span class="mw-page-title-main">Caspian cobra</span> Species of snake

The Caspian cobra, also called the Central Asian cobra or Russian cobra, is a species of highly venomous snake in the family Elapidae. The species is endemic to Central Asia. First described by Karl Eichwald, a German physician, in 1831, it was for many years considered to be a subspecies of the Naja naja until genetic analysis revealed it to be a distinct species.

<i>Naja</i> Genus of snakes

Naja is a genus of venomous elapid snakes commonly known as cobras. Members of the genus Naja are the most widespread and the most widely recognized as "true" cobras. Various species occur in regions throughout Africa, Southwest Asia, South Asia, and Southeast Asia. Several other elapid species are also called "cobras", such as the king cobra and the rinkhals, but neither is a true cobra, in that they do not belong to the genus Naja, but instead each belong to monotypic genera Hemachatus and Ophiophagus.

α-Bungarotoxin Chemical compound

α-Bungarotoxin is one of the bungarotoxins, components of the venom of the elapid Taiwanese banded krait snake. It is a type of α-neurotoxin, a neurotoxic protein that is known to bind competitively and in a relatively irreversible manner to the nicotinic acetylcholine receptor found at the neuromuscular junction, causing paralysis, respiratory failure, and death in the victim. It has also been shown to play an antagonistic role in the binding of the α7 nicotinic acetylcholine receptor in the brain, and as such has numerous applications in neuroscience research.

<span class="mw-page-title-main">Venomous fish</span> Fish that have the ability to produce toxins

Venomous fish are species of fish which produce strong mixtures of toxins harmful to humans which they deliberately deliver by means of a bite, sting, or stab, resulting in an envenomation. As a contrast, poisonous fish also produce a strong toxin, but they do not bite, sting, or stab to deliver the toxin, instead being poisonous to eat because the human digestive system does not destroy the toxin they contain in their bodies. Venomous fish do not necessarily cause poisoning if they are eaten, as the digestive system often destroys the venom.

<span class="mw-page-title-main">Evolution of snake venom</span> Origin and diversification of snake venom through geologic time

Venom in snakes and some lizards is a form of saliva that has been modified into venom over its evolutionary history. In snakes, venom has evolved to kill or subdue prey, as well as to perform other diet-related functions. While snakes occasionally use their venom in self defense, this is not believed to have had a strong effect on venom evolution. The evolution of venom is thought to be responsible for the enormous expansion of snakes across the globe.

Mipartoxin-I is a neurotoxin produced by Micrurus mipartitus, a venomous coral snake distributed in Central and South America. This toxin causes a neuromuscular blockade by blocking the nicotinic acetylcholine receptor. It is the most abundant component in the venom.

The whole blood clotting test is a blood test used to check the coagulation mechanism in the blood following a snake bite. If the test is positive after a bite in South East Asia it indicates the snake was a viper rather than an elapid. It can also be used to assess the effectiveness of antivenin therapy.

<i>Crotalus durissus cumanensis</i> Subspecies of Colombian and Venezuelan snake

Crotalus durissus cumanensis is a subspecies of venomous pit viper from Colombia and Venezuela. They account for 1-3% of all snake bites in Colombia.

References

  1. ↑ Mohamed Abd El-Aziz, Tarek; Soares, Antonio Garcia; Stockand, James D. (2019-09-25). "Snake Venoms in Drug Discovery: Valuable Therapeutic Tools for Life Saving". Toxins. 11 (10): 564. doi: 10.3390/toxins11100564 . ISSN   2072-6651. PMC   6832721 . PMID   31557973.
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