Snake Venom and Therapeutic Potential

Abstract

Many active secretions produced by animals have been employed in the development of new drugs to treat diseases such as hypertension and cancer. Snake venom toxins contributed significantly to the treatment of many medical conditions. Snake venoms are the secretion of venomous snakes, which are synthesized and stored in specific venom glands. Many toxins from snake venom are investigated and formulated into drugs for the treatment of conditions such as cancer, hypertension, and thrombosis. Most of the venoms are complex mixture of a number of proteins, peptides, enzymes, toxins and non-protein inclusions. Cytotoxic effects of snake venom have potential to degrade and destroy tumor cells. Different species have different types of venom, which depends upon its species, geographical location, its habitat, climate and age. The purpose of this chapter is to review focusing on the therapeutic potential of snake venoms and to establish a scientific basis for diseases treatment particular antitumor.

1. Introduction

Snake venoms are the secretion of venomous snakes, which are synthesized and stored in special glands. The venom were synthesized and stored into the base of channeled or tubular fangs through which it is ejected. Most of the venoms are complex mixture of a number of proteins, peptides, enzymes, toxins and non-protein inclusions [1]. Some of snake venom possess biological effects on various functions, such as blood coagulation and pressure, regulation, and transmission of nerve impulses. These venoms have been studied and developed by researchers for use as pharmacological or diagnostic tools, and even drugs. Snake venom is a therapeutic agent for various diseases due to its physiologically active components [2]. More specifically, cobra venom has been used historically in Ayurveda in the treatment of arthritis and other chronic diseases [3].

Chinese physicians are implementing the use of snake venom products to treat stroke patients, and research has been conducted surrounding its analgesic, anti- cancerous and anti-inflammatory effects [2]. Cytotoxic effects of snake venom have potential to degrade and destroy tumor cells [4]. There are basically three types of snake venom according to its effects [5, 6]. (a) Hemotoxic venoms, which affects cardiovascular system and blood functions, (b) cytotoxic venoms targets specific cellular sites or muscles and (c) neurotoxic venoms harms nervous system of human body. The families, Elapidae and Viperidae, are large majority of the research done surrounding the medical application of snake venom involves species within these groups. Both elapids and vipers are front fanged snakes that belong to the superfamily Colubroidea. Notable species of the elapid family are cobras of the genus Naja, and a well-researched species in the viper family is Crotalus durissus terrificus.

Snake venom components caused retardation of growth of cancerous cells due to its therapeutic activity, potency for many diseases and disorders [7]. Many excellent publications characterized use of venoms for the treatment of various therapeutic conditions such as human diseases, cancer and inflammation [8, 9].

2. Components of snake venom

Snake venoms are complex mixtures; mainly it has proteins, which have enzymatic activities, inorganic cations, calcium, potassium, magnesium, zinc, nickel, cobalt, iron, and manganese. Zinc is necessary for anti-cholinesterase activity; calcium is required for activation of enzyme like phospholipase. Some snake venoms also contain carbohydrate, lipid, biogenic amines, and free amino acids [10].

3. Snake enzymes

Proteins found in snake venom include toxins, neurotoxins, nontoxic proteins, and many enzymes, especially hydrolytic ones. Enzymes are protein in nature including digestive hydrolases, L-amino-acid oxidase, phospholipases, thrombin-like pro-coagulant, and kallikrein-like serine proteases and metalloproteinases (hemorrhagins), which damage vascular endothelium.

Phosphodiesterases enzyme interfere with the prey’s cardiac system, mainly to lower the blood pressure. Phospholipase A2 causes hemolysis by lysing the phospholipid cell membranes of red blood cells [2]. Amino acid oxidases and proteases are used for digestion. Also amino acid oxidase triggers some other enzymes and is responsible for the yellow color of the venom. Hyaluronidase enzymes increases tissue permeability to accelerate the absorption of other enzymes into tissues Table 1.

Type	Name	Origin species
Oxidoreductases	Dehydrogenase Lactate	Elapidae
	L-amino-acid oxidase	All species
	Catalase	All species
Transferases	Alanine amino transferase
Hydrolases	Phospholipase A2	All species
	Lysophospholipase	Elapidae, Viperidae
	Acetylcholinesterase	Elapidae
	Alkaline phosphatase	Bothrops atrox
	Acid phosphatase	Deinagkistrodon acutus
	5′-nucleotidase	All species
	Phosphodiesterase	All species
	Deoxyribonuclease	All species
	Ribonuclease 1	All species
	Adenosine triphosphatase	All species
	Amylase	All species
	Hyaluronidase	All species
	NAD-nucleotidase	All species
	Kininogenase	Viperidae
	Factor X activator	Viperidae, Crotalinae
	Heparinase	Crotalinae
	α-Fibrinogenase	Viperidae, Crotalinae
	β-Fibrinogenase	Viperidae, Crotalinae
	α-β-Fibrinogenase	Bitis gabonica
	Fibrinolytic enzyme	Crotalinae
	Prothrombin activator	Crotalinae
	Collagenase	Viperidae
	Elastase	Viperidae
Lyases	Glucosaminate ammonia-lyase

Table 1.

Main enzymes of snake venom [1].

4. Polypeptide toxins

Pllypeptides include cytotoxins, cardiotoxins, and postsynaptic neurotoxins (such as α-bungarotoxin and α-Cobratoxin), which bind to acetylcholine receptors at neuromuscular junctions. Also polypeptides contains metals, peptides, lipids, nucleosides, carbohydrates, amines, and oligopeptides. Chemical composition variations of snake venom due to geographical and Ontogenic of the different species [3].

4.1 Proteolytic enzymes

These enzymes catalyze the breakdown of tissue proteins and peptides. They are also known as peptide hydrolases, protease, endopeptidases and proteinases. Some metal ions of the proteolytic enzymes help in catalysis involved in the activity of certain venom proteases and phospholipases [10].

4.2 Arginine ester hydrolase

Non-cholinesterase enzymes, it causes hydrolysis of the ester or peptide linkage, to which an arginine residue contributes the carboxyl group. This activity was found in snake, crotalid, viperid and some sea snake venoms [10]. Several arginine ester hydrolases have been isolated from the venoms of different snake species. These enzymes eventually showed fibrinogenolytic, caseinolytic, bradykinin releasing or edema-inducing activities. Most of them are serine proteases [11].

4.3 Thrombin-like enzymes

Snake venom thrombin-like enzymes (SVTLEs) constitute the major portion (10–24%) of snake venom and these are the second most abundant enzymes present in the crude venom. These enzymes are glycoprotein in nature, and act as defibrinating anticoagulants in vivo, whereas in vitro they clot plasma, heparinised plasma and purified fibrinogen. It used as therapeutic agent for the treatment of various diseases such as congestive heart failure, ischemic stroke, thrombotic disorders. Thrombin like enzymes such as crotalase, agkistrodon, ancrod and batroxobin can be purified from different snake venoms [12].

4.4 Collagenase

Collagenase enzymes are proteinase in nature that digests collagen and mesenteric collagen fibers [13]. Collagenase are also compounds of snake venoms, may induce disruption of retinal veins that, in turn, result in retinal hemorrhage. Collagenase could as drug leading to the development of new treatments due to its proteolytic properties in their pathophysiology.

4.5 Hyaluronidase

hyaluronidase beyond its role as a spreading factor venom it deserves to be explored as a therapeutic target for inhibiting the systemic distribution of venom bite. It acts upon connective tissues and decreases their viscosity, catalyzes the cleavage of internal glycoside bonds. Hyaluronidase enzyme has been found to be ubiquitously distributed in snake venoms. Hyaluronidase enzyme by itself is non-toxic and has long been known as ‘spreading factor’. The breakdown in the hyaluronic barrier allows some other fractions of venom to penetrate the organ tissues [2].

4.6 Phospholipase

Phospholipases are enzymes that hydrolyse glycerophospholipids. It catalyzes the calcium dependent hydrolysis of the 2-acyl ester bond thereby producing free fatty acids and lysophospho lipid. Neurotoxic phospholipases A₂ (PLA₂s) very large superfamily of enzymes composed of 16 groups within six major types. PLA₂s can bind to and hydrolyse membrane phospholipids of the motor nerve terminal to cause degeneration of the nerve terminal and skeletal muscle. PLA2 can also cause hydrolysis of membrane phospholipids, and liberation of some bioactive products [14]. The biotechnological effectively of PLA2 inhibitors may support the therapeutic potential with antiophidian activity.

4.7 Phosphodiestsrase

Snake poisonous venom phosphodiesterase is a zinc metalloenzyme that share a number of mechanistic features with the nucleotidyl transferases. Zinc of this enzyme is activated by magnesium, and catalyze α-β phosphoryl bond cleavage. Phosphodiesterase releases 5-mononucleotide chain act as an exonucleotidase, thereby affecting DNA and RNA functions [15].

4.8 Acetylcholinesterase

Snake acetylcholinesterase in general is found in cobra and sea snake but absent in viperid and crotalid venoms. It plays a role in cholinergic transmission which located at the neuro-muscular junction of vertebrates.

5. Pharmaceutical assessment of snake venom

Some of snake venom components which have spurred the development of novel pharmaceutical compounds. Snake venom are investigated for the treatment of many diseases as cancer, hypertension, and thrombosis. Venoms of rattlesnakes and other crotalids produce alterations in resistance of blood vessels, changes in blood cells and coagulation and changes in cardiac and pulmonary dynamics. Also it may cause alterations in nervous system and respiratory system [16, 17, 18, 19, 20]. The potency of venom and its effect on human depend on the type and amount of venom injected and the site where it is deposited. Different other parameters and therapeutic derived such as hypotension and nerve shock and fall in blood pressure and varying degree of shock followed by a decrease in heamatocrit values are associated with snake venom [21, 22, 23].

6. Snake venom in medicine

Snake venoms are a cocktail of potent compounds which specifically and avidly target numerous essential molecules with high efficacy. The individual effects of all venom toxins integrate into lethal dysfunctions of almost any organ system. Such toxin mimetic may help in influencing a specific body function pharmaceutically for the sake of man’s health. Such snake toxin-derived mimetic are in clinical use, trials, or consideration for further pharmaceutical exploitation, especially in the fields of hemostasis, thrombosis, coagulation, and metastasis. Snake venom has great potential use as a medicine, because of all the compounds it contains, and their specific actions. Two analgesics derive from cobra venom; Cobroxin is used like morphine to block nerve transmission, and Nyloxin reduces severe arthritis pain [24]. Arvin compound from Malayan pitviper is an effective anticoagulant. Venom components allow researchers to develop novel drugs for treatment many diseases such as, nerve epilepsy, multiple sclerosis, myasthenia gravis, Parkinson’s disease, and poliomyelitis, musculoskeletal disease [24].

7. Snake venom and diseases treatment

Given that snake venom contains many biologically active ingredients, some may be useful to treat disease [25].

Phospholipases type A2 (PLA2s) from the Tunisian vipers Cerastes cerastes and Macrovipera lebetina have been found to have antitumor activity [26, 27]. PLA2s hydrolyze phospholipids, thus could act on bacterial cell surfaces, providing novel antimicrobial activities [28]. The analgesic activity of many snake venom proteins has been long known [29, 30] and the main challenge is how to deliver protein to the nerve cells.

8. Serotherapy of snake venom

Serotherapy using antivenom is a common current treatment, both adaptive immunity and serotherapy are specific to the type of snake; venom with identical physiological action do not cross-neutralize [31, 32].

9. Snake venom therapy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents up to 90% of all liver malignancies. Recently, the World Health Organization (WHO) reported that HCC is the fifth most common tumor worldwide, and the second most common cause of cancer-associated deaths. For the majority of advanced HCC cases, curative treatments are not possible, and the prognosis is dismal because of underlying cirrhosis as well as poor tumor response to standard chemotherapy. For patients with advanced HCC, the only approved molecular targeted therapy is sorafenib (SOR), the first orally active multi-kinase inhibitor. It provides only temporary therapeutic efficacy by increasing the survival rate by approximately 3 months [33]. Besides, a great inter-individual variation in the pharmacokinetics of SOR, due to systemic overexposure, has contributed to its toxicity [34, 35]. Therapeutic approaches to identify and develop novel compounds such as snake venom components are urgent to have potential ability for cancer treatment [36]. Moreover, better finding alternative natural safe, and better ways to treat cancer with less toxicity and deteriorated effect on normal cells is highly desirable [37].

The combining snake venoms (SVs) could synergistically enhance the antiproliferative effects at low doses on liver cancer cells (HepG2). In such Research the gene expression for apoptotic, inflammatory, antioxidant and cell cycle regulator was determined [38].

Varies compounds from venomous animals such as spiders, scorpions, snakes, caterpillars, centipedes, wasp, bees, toads, ants, and frogs have largely shown biotechnological and pharmacological applications against many diseases including cancer [39, 40, 41, 42]. Venoms obtained from snakes were reported to exhibit a cytotoxic effect against tumor cells [26]. This potency is due to inhibiting cell proliferation, promoting cell death through activating the apoptotic mechanisms [43, 44]. Meanwhile snake venom increased cytochrome-c production, modulating the expression levels of proteins that controlling the cell cycle, and treat triggering damages in the cell membranes [45, 46, 47].

The complex mixtures of snake venom, L-amino acid oxidase (LAAO) are a effect as anticancer therapeutic activity and through the induction of oxidative stress in cancer cells [48]. L-amino acid oxidase (LAAO) has been reported to exhibit a potent anti-tumor activity to different cancer cell lines including [49]. LAAO can selectively bind to the cancer cell surface at specific phospholipid compositions to deliver the hydrogen peroxide [47, 48, 49, 50]. LAAO mediates its cytotoxicity to the cell surface and produces H₂O₂ [49, 51, 52]. Moreover studies are confirmed this safer effect on animal models [38]. In terms of cytotoxicity, combined administration of LAAO with SOR has reduced the cell death on normal liver cells THLE-2 as compared to a single administration [38]. On the other hand the administration of LAAO and SV alone or in combination with SOR has significantly induced cell death and apoptosis in HepG2 cells as compared to control untreated cells [53]. Additionally, [54] showed that the LAAO isolated from Ophiophagus hannah venom selectively kills cancer cells via the apoptotic pathway by regulating the caspase 3, 7 activity but is non-toxic to normal cells. One of the consequences of the excessive damage caused by the reactive oxygen species (ROS) is changes in mitochondrial membrane permeability causing Ca⁺² overload that result in cytochrome c release and apoptotic death [55].

10. Therapeutic effects of snake venom on rheumatoid

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease in which the immune system primarily attacks healthy tissue of synovial joints (NIH). The disease affects between 0.5–1.0% of the developed world population, and is a significant cause of disability [56]. The primary characteristic of RA is the progressive destruction and inflammation of synovial joints, most commonly in metacarpophalangeal, proximal interphalangeal, metatarsophalangeal, wrist, and knee joints. Articular manifestations include symmetric joint swelling, tenderness, stiffness, and motion impairment, and general symptoms such as fevers, fatigue, weight loss, and discomfort are also common [57].

Snake venom has been used for treatment of rheumatoid arthritis and pain management. Venom from the families Elapidae and Viperidae have been shown to have anti-inflammatory and analgesic effects. Snake venom has anti-inflammatory effects by reducing levels of pro- inflammatory cytokines and increasing levels of anti-inflammatory cytokines [58]. Additionally, snake venom can reduce structural damage from prolonged inflammation by acting as a (tumor necrosis factor alpha), TNF-alpha blocker, and by inhibiting the proliferation of fibroblast-like synoviocytes. The mechanisms of snake venom pain modulation seen in murine pain models follow the cholinergic and opioidergic systems. Analgesic findings involving the cholinergic system concluded not only that the effects of snake venom have similar effects to morphine, but also that no withdrawal symptoms were observed after administration of venom stopped. These results show incredible promise for a non-addictive analgesic that could be used for pain management in rheumatoid arthritis patients [58].

A study found that while the general health status of RA patients in Norway improved between the years of 1994 and 2001, alleviation of pain remained the highest priority in both cohorts [59]. In another study, 88% of participants selected pain as their top priority for improvement during a year of treatment [60]. Pain scores are also disproportionately greater in women, minorities, and those with lesser levels of education, and pain is a top contributor to emotional health in RA patients [61, 62].

One of the main treatments for pain in RA patients is the administration of disease modifying antirheumatic drugs (DMARDs), which act peripherally to reduce the inflammatory response and the pain associated with it. Additionally, non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen are often suggested to patients to manage their pain. These medications can be coupled with over the counter medications such as acetaminophen to further alleviate pain. When the combination of NSAID and acetaminophen administration has failed to provide relief, weak opioids are considered [63]. Therapies for RA have generally shifted focus from symptom management to the treatment of underlying inflammation that causes the symptoms [64]. Biologic disease modifying drugs are act to reduce immune responses in the body such as TNF inhibitors are used to block tumor necrosis factor (a proinflammatory cytokine) activity. Similarly, Abatacept prevents the overactivity of T cells, and Tocilluzumab inhibits the activity of another proinflammatory protein, IL-6 [65, 66].

Mechanical and thermal hyperalgesia have been found to be suppressed in several murine models with the administration of snake venom. Inflammation can also affect central pain processing, so a decrease in inflammation with snake venom could positively affect central pain and sensitization as well. The effects of snake venom from elapids and vipers on cholinergic and opioidergic mechanisms of pain are arguably the most promising relevant to treating rheumatoid arthritis. In one study, snake venom acting on cholinergic receptors to produce analgesia was found to be just as effective as morphine, with a longer lasting effect [67]. A handful of studies have utilized venom from elapids, particularly the species Naja kaouthia and Naja naja, in murine arthritis models to study the anti-inflammatory and anti-arthritic properties of the venom or its specific components [68]. Observed the effects of NN-32, a cytotoxic protein from N. naja venom, on arthritic rats. It was found that while arthritic rats showed significantly increased levels of inflammatory cytokines TNF-α, IL-17, and cytokine-induced neutrophil chemoattractant 1 (CINC-1, a rat cytokine (homolog of IL-8) with hyperalgesic properties) compared to non-arthritic control rats, NN-32 treatment significantly decreased levels of these cytokines. Another study by the same researchers found that IL-10 levels were decreased in adjuvant induced arthritic rats, but the levels were significantly restored when treated by N. kaouthia venom [69].

Produced similar results using cobratoxin, a neurotoxin from a Naja cobra, on complete Freund’s adjuvant (CFA) induced arthritis rats [70]. The arthritic rats showed increased serum levels of (tumor necrosis factor) TNF-α, IL-1, and IL-2, and decreased levels of IL-10. With the cobratoxin treatment, the rats exhibited lower proinflammatory cytokine levels, and a reversal of the CFA induced IL-10 decrease [69]. Found similar results with neurotoxin-NNA, another peptide from N. naja atra: Treatment with the peptide exhibited a dose dependent decrease in TNF-α and IL-1β levels in rat models of inflammation. These studies add to the evidence that cobra venom could modulate the production of inflammatory cytokines in RA and subsequently reduce inflammatory pain.

Compared the effects of cobratoxin from N. naja atra to dexamethasone, a corticosteroid that relieves inflammation. This revealed the dexamethasone administered to arthritic rats showed greater effects on acute inflammation than the cobrotoxin, but inhibition of the long-term inflammatory process (observed by a decrease of cytokines IL-6, TNF-α, and IL- 1β) was strong in both. The maintenance of the levels suggests that orally administered CTX has anti-inflammatory properties by decreasing pro-inflammatory cytokine levels and maintaining pro-inflammatory cytokine levels. Rats treated with CTX showed slightly greater anti-inflammatory and analgesic effects, suggesting the potential for components of venom to function as NSAIDs [69].

11. Snake venom therapy of joint destruction

The use of tumor necrosis factor (TNF) blockers, a more recent therapeutic option for RA, provides a correlation between the cytokine TNF-α and bone erosion. Several studies have found that the five TNF blockers that are currently in use have all been correlated with continued inhibition of bone erosion [71]. The positive effect of TNF inhibitors provides evidence that a decrease in the cytokine TNF-α could have beneficial effects on reducing not only initial inflammatory pain but also pain induced by bone erosion and other structural changes. Additionally, the anti arthritic and anti inflammatory activity of NN-32, a cytotoxic protein from Indian spectacle cobra snake (Naja naja) venom showed significant decrease in physical and urinary parameters, serum enzymes, serum cytokines levels as compared to arthritic control group of rats. NN-32 treatment recovered carrageenan induced inflammation [72]; Cobratoxin (CTX), the long-chain α-neurotoxin from Thailand cobra venom, has been demonstrated to have analgesic action in rodent pain models [73]. Structural changes of bone and cartilage are a hallmark of inflammatory joint diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) [74, 75] found that cobrotoxin from N. naja atra venom inhibited the activation of nuclear factor kappa B (NF-κB). NF-κB is a transcriptional factor that plays a role in inflammation by expressing pro-inflammatory cytokines, including TNF-α, and inhibition of NF-κB has been shown to delay progression of joint destruction in animal arthritis models. Another study also found that cobrotoxin has an inhibitory effect on NF-κB activation, which led to decreased levels of TNF-α [76]. These studies indicate that cobra venom can decrease proinflammatory cytokine levels, affecting as anti-inflammatory properties pain associated with physical destruction of the joint. These properties could reduce both peripheral and central inflammation, and potentially prevent further joint damage and sensitization of nerves [77].

12. Therapeutic potential of snake venom on cancer

The anti-cancer potential of snake venom depend on its protein peptides and enzymes which bind to cancer cell membranes, affecting the migration and proliferation of these cells [78].

Cancer is characterized by uncontrolled cell division, cell transformation, and escape of apoptosis, invasion, angiogenesis and metastasis. Induction of apoptosis is the most important mechanism of many anticancer agents. Snake integrins are important in cell adhesion, cell migration, tissue organization, cell growth, hemostasis and inflammatory responses, so they are in the study for the development of drugs for the treatment of cancer [53]. The induction of the apoptosis manifests the control on the tumor size and number of tumor cells hence establishing the application of apoptosis inducers as vital components in the treatment of cancer [55].

Isolation and purification of L-amino acid oxidases (LAAOs) from Bothrops leucurus (Bl-LAAO) and cobra was effected on platelet function and cytotoxicity [79, 80]. The mechanism of this enzyme action may be related to the inhibition of thymidine incorporation and an interaction with DNA [81]. Also different tumor cell lines were found to susceptible from lytic action and from synthetic peptide. Also NN-32 showed cytotoxicity on EAC cells, increased survival time of inoculated EAC mice, reduced solid tumor volume and weight. NN-32 increased proapoptotic protein [82]. Pharmacokinetics effect of cytotoxin from Chinese cobra (N. naja atra) venom was studied on rabbits [49]. Plasma levels of the cytotoxin were analyzed by a biotinavidin enzyme-linked immunosorbent assay.

The extraction of specific protein Okinawa Habu apoxin protein-1 (OHAP-1) from Okinawa Habu venom studied for its toxic effects [83]. In this study, OHAP-1 could induce apoptosis in some glioma cell. Also the apoptotic effect of OHAP-1 on malignant glioma cells could be through the generation of intracellular ROS and p53 protein expression. Antitumor activity using snake venom (Lapemis curtus) caused decreasing of Hep2 tumor volume and considered as an important indicator of reduction of tumor burden [84]. Cardiotoxin III (CTX III), was isolated from N. naja atra venom, and reported its anticancer activity [85]. The anti-tumor potential as well as its cytotoxicity and hemolysis activity was occurred as a galactoside-binding lectin which isolated from B. leucurus venom [86]. Purification of BjcuL, a lectin from Bothrops jararacussu venom was observed its cytotoxic effects to gastric carcinoma cells. This confirmed cytotoxicity of BJcuL on tumor cells mainly by altering cell adhesion and through induction of apoptosis [87].

13. Anti-microbial potency of snake venom

Snakes venoms were assayed in order to investigate their antimicrobial activities giving promising results [88]. Since 1930s, cobra venom has been used to treat various diseases like asthma, polio, multiple sclerosis, rheumatism, severe pain and trigeminal neuralgia. Among antimicrobial components that have been isolated from snake venom are (i) L-amino acid oxidase (LAAO), and (ii) phospholipase A2 (PLA2) [89]. The LAAO antibacterial action appears to result from hydrogen peroxide generated by the oxidative action of the enzymes, as the effect is abolished in the presence of hydrogen peroxide scavengers such as catalase [10, 90, 91, 92, 93]. Also antimicrobial peptides including cathelicidins, nerve growth factor and omwaprin have been isolated from various venomous snake species [94, 95, 96]. The antibacterial effects of cobra venom LAAO were affected against strains including S. aureus, S. epidermidis, P. aeruginosa, Klebsiella pneumoniae, E. coli, gram-positive and negative bacteria [92, 97]. Purified L-amino acid oxidase from Bothrops pauloensis snake venom had bactericidal activities [98, 99].

Electron microscopic assessments of both Gram-positive and Gram-negative bacterial strains suggested that the H₂O₂ produced by LAO induced bacterial membrane rupture and consequently loss of cytoplasmatic content [100, 101]. Akbu-LAAO an L-amino acid oxidase isolated from the venom of Agkistrodon blomhoffii ussurensis snake exhibited a strong bacteriostasis effect on S. aureus [102].

The most mode of action involved in the bactericidal activity of LAAOs is that H₂O₂ causes oxidative stress in the target cell, triggering disorganization of the plasma membrane and cytoplasm and consequent cell death Table 2 [103, 104].

Snake species	Antibacterial component	Effective against
Bothrops mattogrosensis	BmLAAO	Gram positive and negative bacteria
Ophiophagus Hannah	King cobra L-amino acid oxidase (Oh-LAAO)	Gram positive and negative bacteria
B. alternatus	Balt-LAAO-I	E. coli and S. aureus
Daboia russellii siamensis	DRS-LAAO	S. aureus (ATCC 25923),; P. aeruginosa (ATCC 27853) and E. coli (ATCC 25922).
King cobra venom	LAAO	S. aureus, S. epidermidis,; P. aeruginosa, K. pneumoniae, and E. coli
B. pauloensis	Bp-LAAO	Not specific
Bothriechis schlegelii	BsLAAO	S. aureus and Acinetobacter baumannii
Naja naja oxiana	LAAO	B. subtilis and E. coli
Crotalus durissus cascavella	Casca LAAO	(Xanthomonas axonopodis pv passiflorae) and S. mutans
Crotalus durissus cumanensis	CdcLAAO	S. aureus and A. baumannii
Vipera lebetina	LAAO	Gram-negative and Gram-positive bacteria
Agkistrodon blomhoffiiussurensis	Akbu-LAAO	S. aureus
Trimeresurus mucrosquamatus	TM-LAO	E. coli, S. aurues and; B. dysenteriae
Trimeresurus jerdonii	TJ-LAO	E. coli, S. aureus, P. aeruginosa, and Bacillus megaterium.
Bothrops marajoensis	BmarLAAO	S. aureus, and P. aeruginosa
Bothrops jararaca	LAAO	S. aureus
Agkistrodon haly Pallas	LAAO	E coli K12D31
B. leucurus	BleuLAAO	S. aureus

Table 2.

Anti-bacterial profile of various snake venom LAAOs [88].

13.1 Anti-microbial activity of phospholipase A2 (PLA2)

Phospholipase has antimicrobial activity against E. coli and S. aureus as well as the Gram-positive bactericidal activity of sPLA(2)-I [105]. Also Phospholipases A2 (PLA2S) isolated from C. durissus terrificus venom showed antimicrobial activity against Xanthomonas axonopodis pv. Passiflorae Table 3 [106].

Snake species	Antibacterial component	Effective against
Bungarus fasciatus	BFPA	E. coli and S. aureus
Agkistrodon spp	AgkTx-II	S. aureus, P. vulgaris and Burkholderia pseudomallei
Echis carinatus	EcTx-I	Enterobacter aerogenes, E. coli, P. vulgaris, P. mirabilis, P. aeruginosa and S. aureus
Vipera berus berus	VBBPLA2	B. subtilis
Bothrops asper	PLA2 myotoxins	S. typhimurium and S. aureus
Porthidium nasutum	PnPLA2	S. aureus

Table 3.

Antibacterial profile of various snake venom Phospholipae A2s [88].

13.2 Antimicrobial activity of peptides

Peptides are have a critical defense against all kinds of microorganisms, bacteria, fungi, and viruses. Peptides play an important role in the bactericidal effect. Antimicrobial peptides can be divided into four structural groups known as α-helical, β-sheet, α-hairpin, and extended peptides [107].

13.3 Cathelicidin

Cathelicidin-BF found in the venom of the snake Bungarus fasciatus in treating Salmonella typhimurium infection. Cathelicidins are a family of antimicrobial peptides acting as multifunctional effectors molecule in innate immunity. Cathelicidin-BF had been purified from the snake venoms of B. fasciatus (BF) and it was the first identified cathelicidin antimicrobial peptide in reptiles [88]. S. epidermidis, was also effectively killed by Cathelicidin-BF [108, 109].

Cathelicidin-BF is active against Salmonella infected-mice and it showed strong antibacterial activity against various bacteria [110]. Cathelicidin from the venom of B. fasciatus has antibacterial activity against drug-resistant E. coli, P. aeruginosa, and S. aureus. Also cathelicidin BF-30 had stronger antimicrobial activities against a broad spectrum of microorganisms [111].

14. Conclusions

Snake venoms are the complex mixtures of several biologically active proteins, peptides, enzymes, and organic and inorganic compounds.

Snake venoms are very important agents for many types of diseases as well as antimicrobial, anti-inflammation, anti-rheumatoid and cancer therapy. Snake venoms acts by inhibiting cell proliferation and promoting cell death by different means: induction of apoptosis in cancer cell, increasing Ca²⁺ influx; inducing cytochrome C release; decreasing or increasing the expression of proteins that control cell cycle; leading to damage of cell membranes. Snake venoms contain many components that act on the peripheral nervous system for killing or immobilizing prey. All the above mentioned attracted our attention to develop of a new drugs from snake venoms will be useful as therapeutic agents of many diseases.