THERAPEUTIC POTENTIAL OF VENOMOUS PEPTIDE IN VARIOUS DISEASES

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ABOUT AUTHORS:
1*Anjali Choba, 2Shikha Attri
1M.Pharma in pharmacology from shoolini university solan, himachal pradesh
2M.Pharm in pharmaceutical chemistry from lachoo memorial college of science and technology, jodhpur
*anji5057@yahoo.in

ABSTRACT
Venomous creatures have a sophisticated mechanism for prey capture which includes a vast array of biologically-active compounds, such as enzymes, proteins, peptides and small molecular weight compounds. The venom peptides are directed against a wide variety of pharmacological targets, making them an invaluable source of ligands for studying the properties of these targets in different experimental paradigms. Much knowledge has been gained in terms of how poisons and venoms and their composite toxins give rise to the syndromes associated with envenoming and poisoning and in some isolated cases there have been a few such agents promoted for therapeutic use. A number of these peptides have been used for the treatment of pain, diabetes, multiple sclerosis and cardiovascular diseases.


REFERENCE ID: PHARMATUTOR-ART-1833

INTRODUCTION
A large number of organisms produce and secrete venoms to defend themselves and to capture prey. Venom is a rich source of biochemically active enzymes, proteins, peptides and low molecular weight substances. Toxins isolated from the venom either inhibit or activate a vast number of targets such as ion channels, acetylcholine receptors, acetylcholinesterase, membranes, coagulant/anticoagulant pathways, and metalloproteases, with high selectivity and affinity. They can be roughly divided into non-peptide and peptide toxins. Non-peptide toxins have been isolated from algae, plants, dinoflagellate, fish and from higher organisms which accumulate alkaloids through their diet as exemplified in toxic frogs. Peptide toxins are generally synthesized in the venomous ducts of poisonous creatures (Lewis RJ et al., 2003) (1,2).

Medicinal importance of venoms and toxins has been mentioned in Ayurvedic, Chinese, Unani and Homeopathic system of medicines. For example,the ancient Indian physician Sushruta (7th century B.C.) used snake venom to prolong life. Charaka had the opinion that in case of “Udra Roga” (disease of gastrointestinal tract), which was uncontrollable by other medicinal measures, snake venom was very useful.In “Charak Samhita” and “Vagbata” cobra venom had been said to be useful in “Dushydara” and “Jalodara” (ascites). Venom of spider, bee and snakes are routinely used in Homeopathic medicine. (Pal SK et al., 2002) (3). The biodiversity and specificity of venoms and toxins make them a unique source of leads and structural templates from which new therapeutic agents.


ANIMAL VENOMS AND POISONS
Snake Venoms
The most well recognized venomous land animals are the venomous snakes which have highly developed glands for producing venom with variable apparatuses for delivering the venom into the prey. The composition and biological activities of snake venoms vary based on the family and often genus and species of snakes as well as their environments, diets and sex  (Menezes MC et al., 2006) (4). However, in general they contain some combination of peptides, enzymes and neurotoxins. In the peptide group are found activities such as proteinase inhibitors, integrin antagonists and cholinesterase inhibitors. The enzyme group includes phospholipases A2, amino acid oxidases and serine and metalloproteinases. Members of each group have been demonstrated to have toxic activities. In the case of neurotoxins a variety of functional classes has been identified. The presynaptic toxins include neurotoxic phospholipases A2 that block acetylcholine release from the synapse and toxins which block ion 2928 channels such as dendrotoxins from mamba venoms and cause anincrease in neurotransmitter from the endplate. L-amino acid oxidasefrom certain snake venoms has been demonstrated to causecellular apoptosis (Torii S et al., 2000) (5). The serine and metalloproteinases in snakevenoms are generally attributed for the coagulopathies associatewith snake envenoming (White J, 2005) (6). In general a variety of symptomsis associated with snake envenoming and they are dependent on thetype of snake and to a certain extent the prey. As mentioned therecan be neurotoxic symptoms most typically found in envenomingby Elapidae snakes due to the presence of neurotoxic blockage ofneuromuscular synapases to give rise to a paralysis often leading torespiratory failure. Coagulopathies associated with envenoming byvipers is common and is a result of a number of proteolytic andnon-proteolytic toxins in these venoms which generally lead toincoagulability of the blood  This, coupled with hemorrhageand edema also caused by proteinases present in viper and pit-vipervenoms, often leads to cardiovascular shock. Many snake venomsalso have phospholipases A2 which directly affect and destroymuscle tissue releasing myoglobulin which may lead to renal failure (Danse JM et al., 1997) (7).

Scorpion Venoms
The venoms from scorpions are primarily composed of a complex mixture of peptide toxins. These peptides generally function as ion-channel toxins to give rise to a complex, synergistic neurotoxic effect due to numerous, specific ion-channel toxins present in the Venoms (Rodriguez de la RC et al., 2005) (8).

Amphibian Poisons
Poisonous secretions have been identified in the secretions of a number of frogs, toads, newts and salamanders and contain amines, steroids, alkaloids and peptides (Daly JW et al., 1987)(9). The poisonous effects of the secretions are highly variable but can include neurotoxic effects, hallucinogenic effects, analgesia, vasoconstriction and seizures. The newt Taricha torosa and some species of toads have been reported to have high concentrations of the neurotoxin tetrodotoxin. It is believed that most of the toxins found in amphibian secretions are derived from food sources for these amphibians.

Lizard Venoms
Both the Gila monster and the Mexican beaded lizard (Heloderma suspectum and Heloderma horridum, respectively) are venomousand their venoms are primarily comprised of protein toxins. On envenomation by these lizards, the venom secreted from theglands mix with saliva and then via capillary action flows along thesides of the teeth and enters the wounds produced by the bite. Hyaluronidases, kallikreins and arginine ester hydrolases are someof the enzymes reported in the venom (Russell FE et al., 1981) (10).

Mammalian Toxins
In the saliva of the new world vampire bats (Desmodontidae) are potent anticoagulatant plasminogen activator enzymes that prevent clot formation and thus promote blood flow from the bite of these animals (Schleuning, 2001) (11).

Cone Snail Venoms
Cone snail venoms are comprised of protein and peptide toxins and these venoms have provided researchers one of the richest sources of reagents for investigating ion-channels. There are four major classes of toxins found in cone snail venoms: α-conotoxins, ϖ-conotoxins; μ-conotoxins and δ-conotoxins (Terlau H et al., 2004) (12). Each class is  characterized by a particular biological function. For example, the δ-conotoxins act at neuromuscular synapses to block nerve transmission. The μ-conotoxins block sodium channels of skeletal muscle. The δ-conotoxins cause a hyperpolarization of sodium channels and the ϖ-conotoxins block calcium-channels.

Marine Animals Containing Tetrodotoxin
A variety of marine organisms have sequestered within their bodies the toxin tetrodotoxin(Daly JW et al., 1987) (13). Tetrodotoxin is a potent inhibitor of sodium channels that causes paralysis of predators which ingest the organisms such as is the case with the puffer fish, Fugu rubripes and other members of the family Tetraodontidae, or in the case of the blue-ringed octopuses, Hapalochlaena maculosa and H. lunulata, where the toxin is present in the saliva of these animals and enters the prey when bitten by these octopi.

Table 1 : Toxin-Based Drugs Approved for Use by the U.S. Food and Drug Administration

Drug

Origin

Indication

Mechanism of action

Captopril

Bothrops jararaca venom

Treatment of hypertension

Inhibition of Angiotensin

Converting Enzyme.

Aggrastat

(Tirofiban)

Snake venom

Treatment of angina

Reversible antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor; inhibits platelet aggregation

Integrilin

(Eptifibatide)

Sistrurus barbouri

Use in coronary angioplasty

Antagonist of the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets; inhibits platelet aggregation

Prialt

(Ziconotide)

Conus magus

Treatment of severe chronic pain.

Block N-type Ca2+ channels

Byetta

(Exenatide)

Heloderma suspectum

To improve blood sugar control in adults with type 2 Diabetes Mellitus

Binding and activation of GLP-1 receptor to reduce plasma glucose and lower HbA1c

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