THERAPEUTIC POTENTIAL OF VENOMOUS PEPTIDE IN VARIOUS DISEASES

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 (7^th 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

ROLE OF VENOM PEPTIDES IN VARIOUS DISEASES :
Hypertension
Hypertension, simply stated is when the blood pressure measurement exceeds 140/90 mmHg. Many physiological conditions can lead to high blood pressure and the long term effect of hypertension include heart failure, aneurysms, kidney failure, heart attacks, strokes and ruptures in the small blood vessels of the eyes contributing to blindness. Given that one of three Americans suffers from hypertension this is a potentially devastating disease. A number of treatments are available, simply beginning with healthier living habits to a plethora of drugs most of which function to relax vessel walls and thus decrease the blood pressure. Snake venoms, particularly Viperidae venoms have long been known to be rich sources of peptides as well as proteins. In nature these peptide are thought to play a role in inhibiting the metalloproteinase activity in the venoms and crystal structures of snake venom metalloproteinases have been observed having peptides coordinated to the zinc in the active site of these proteinases (Robeva A et al., 1991) ⁽¹⁴⁾. However, it was also clear that they may be important in the pathological effects of the venom as well. One of the typical symptoms of Viperidae envenoming is hypotension and shock (Marsh N et al., 1978) ⁽¹⁵⁾. In 1965 there appeared in the literature a report of a Bradykinin-potentiating factor (BPF) present in the venom of the South American snake Bothrops jararaca (Ferreira SH, 1965)⁽¹⁶⁾.Bradykinin, a strong hypotensive agent that functions as a vasodilator, is derived by proteolytic processing of the plasma protein kininogen and the BPF from the venom appeared to function to potentiate the vasodilatory effects of bradykinin. It was later shown that these venom extracts could inhibit a zinc metalloproteinase termed angiotensin converting enzyme (ACE) which is responsible for the conversion of angiotensin I to the vasoconstrictor peptide angiotensin II in vivo (Ng KKF et al., 1970) ⁽¹⁷⁾. The venom factors responsible for the BPF activity/ACE inhibition were isolated by Ferreira and colleagues (Ferreira SH et al., 1970) ⁽¹⁸⁾ and the sequence pGlu- Lys-Trp-Ala-Pro was determined for one of the peptides and was synthesized and shown to have biological activity (Stewart JM et al., 1971)⁽¹⁹⁾_. Independently Ondetti and colleagues also isolated several BPF peptides from B. jararaca which were demonstrated to inhibit ACE (Ondetti MA et al., 1971) ⁽²⁰⁾. Ondetti, who was working at Squibb, New Brunswick, began collaborations with D. W. Cushman, who also was at Squibb working on ACE and the renin-angiotensin system. One of the nonapeptides isolated by this group, termed Teprotide, was used as a starting point for the development of a drug. Subsequently using these peptide structure/activity studies as a foundation an orally active ACE inhibitor termed Captopril was synthesized in 1975 (Smith CG et al., 2003) ⁽²¹⁾. Several generations of these drugs have been brought to market by Squibb and other pharmaceutical companies. Although these drugs are still in use there are a large number the alternative therapeutic choices available for treatment of hypotension. Nevertheless, the development of Captopril, clearly based on the research associated with the structure/function analysis of biologically active peptides in Viperidae venoms, represents one of the first “block buster” drugs stemming from a venom toxin.

Heart Disease
Two drugs based on snake venom toxin structures are in use as reversible antagonists of the platelet glycoprotein GPIIb/IIIa receptor which essentially functions to inhibit platelet aggregation and thereby play a therapeutic role in the treatment of angina and in coronary angioplasty as anti-platelet factors. Disintegrins are snake venom peptides ranging from 40-100 amino acid residues that possess 4 to 8 disulfide bonds. They were first described by Huang and colleagues (Huang TF et al., 1987) ⁽²²⁾ and were distinguished by the Arg-Gly-Asp motif which was demonstrated to be involved in binding to the GPIIb/IIIa integrin receptor on platelets to block aggregation. More recently, numerous other disintegrins have been isolated and characterized and many of these have been shown to bind to non-Arg-Gly-Asp receptors(Calvette JJ et al., 2005) ⁽²³⁾. Tirofiban (Aggrastat® [N- (butylsulfonyl)-O-[4-(4- piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate]) is a non-peptide drug based on the Arg-Gly-Asp sequence found in snake venom disintegrin proteins (Egbertson MS et al., 1994) ⁽²⁴⁾. The other drug, Eptifibatide (Integrilin®)[N6 -(aminoiminomethyl)-N2 -(3-mercapto-1- oxopropyl-L- lysylglycyl-L-a-aspartyl- L-tryptophyl-L -prolyl-Lcysteinamide, cyclic (1Ø6)-disulfide] is modeled on the biologically active Lys-Gly-Asp motif in the disintegrin barbourin from Sistrurus barbouri (Scarborough RM et al., 1993) ⁽²⁵⁾. In the venom the disintegrins play a variety of roles in the symptomatology and pathology of envenomation by blocking platelet aggregation and thereby synergizing the effects of other toxins, such as the snake venom hemorrhagic metalloproteinases in the venom to produce bleeding and shock (Phillips DR et al., 1997) ⁽²⁶⁾. They likely possess other important functions that play into the pathology by virtue of various disintegrin’s abilities to bind to many different cell surface integrin receptors and modulate their signal transduction properties(Marcinkiewcz C, 2005) ⁽²⁷⁾. Given the specificity of these non-RGD containing disintegrins for non-RGD dependent integrins and the important roles these integrins play in a variety of biological processes one can imagine that these disintegrins are also under investigation and consideration for providing novel drug leads as did the RGDcontaining disintegrins for anti-platelet agents.

Cancer
Cancer, despite the all out effort from developed countries still causes one in five deaths. Surgey, chemotherapy, and radiotherapy provide inadequate protection and instead , affect normal cells alongwith the cancer cells. The search for cancer cure from natural products (plants and animals ) has been practiced for over a century and the use of purified chemicals to treat cancer still continues. Use of venom in the treatment of cancer in laboratory animals was first reported by Calmette (Calmette A et al., 1993) ⁽²⁸⁾. Venoms from the snake family Elapidae, Crotalidae and Viperidae but not Hydrophidae cause lysis of Yoshida sarcoma cells (Braganca BM et al., 1967) ⁽²⁹⁾. Venoms from two viperidae species (Bothrops jararaca and Crotalus durissus ) acted directly on tumour cells. Their antitumour activity may be due to the indirect phenomenon of inflammatory response mediated by IL-2, IL-8 and TNF α (Da Silva RJ et al., 1996) ⁽³⁰⁾.

Scorpion and its venom have been used as traditional and folk therapy in various pathophysiological conditions that has been mentioned in folk and traditional medicines of India, China, Africa and Cuba. An antitumour –analgesic peptide from Bothus martense venom shows strong inhibitory effect on both visceral and somatic pain and also antitumour activity on E. ascites tumour and S-180 fibrosarcoma cells (Liu YF et al., 2003) ⁽³¹⁾.

Medical and pharmaceutical significance of purified compounds from toads and frogs skin and oocyte had been established (Gomes A et al., 2007 ) ⁽³²⁾. The anticancer activity of crude toad skin extract was tried with Chan Su, a traditional Chinese medicine prepared from the dried white secretion of the auricular and skin glands of toad (Bufo bufo gargarizans ) Chan Su induced apoptosis in T24, human carcinoma bladder cell line. Chan Su treatment was coupled with a down- regulation of anti-apoptotic  bcl-2 and bcl-X (S/L) and an up-regulation of pro-apoptotic bax expression. It induced the proteolytic expression of caspase-3 and caspase-9 (Ko WS et al., 2005) ⁽³³⁾.

Epilepsy
According to the Epilepsy Foundation of America, an estimated 1% of the total population suffers from epilepsy and seizures, affl icting more than 2.3 million Americans, with combined direct and indirect costs to the American economy of USD 12.5 billion. Total market volume of anti-epileptic drugs reaches USD 1.9 billion a year worldwide, with a 5% annual growth rate. NMDA Receptor Antagonist NMDA receptors have been shown to participate in a number of CNS malfunctions.

CGX-1007 (conantokin-G synthetic derivative) is currently in Phase II clinical trials as an anticonvulsant and for intractable epilepsy (when delivered directly into the central nervous system). The Phase I, randomized, double blind, placebo-controlled trial involved intravenous delivery of single, escalating doses of CGX-1007 in healthy, normal subjects to determine safety of the compound when administered to the systemic circulation. The results of the Phase I trial demonstrated that CGX-1007 was safe, with no clinically remarkable drug-related adverse experiences observed. Recently it was shown that although considered NR2B-specifi c, CGX- 1007 is less specifi c or acts differently, than the investigational CI-1041 compound, in corneal kindled rats and in an NMDA receptor mediated excitatory postsynaptic currents model (N- EPSC) (Barton ME et al., 2004) ⁽³⁴⁾.

Diabetes
Glucagon-Like Peptide-1 is an insulinotopic hormone secreted from endocrine cells of the small and large intestine in a nutrient-dependent manner. GLP-1 stimulates insulin secretion and modulates gastric emptying to slow the entry of ingested sugars into the bloodstream. The GLP- 1 related peptide is a peptide initially derived from the salivary secretions of the Gila monster (Heloderma suspectum), a large venomous lizard. Amylin Pharmaceuticals is developing a synthetic version of Exenatide (synthetic exendin-4), a 39 amino acid peptide, currently in Pre-Phase III for use in treating type-2 diabetes and related metabolic disorders. Diabetic animal models have demonstrated that Exenatide is biologically active when administered via oral, sublingual, pulmonary, tracheal and nasal routes. Furthermore, GLP-1 like peptides share structural homology to α-Latrotoxin, isolated from the venom of the black widow spider and might have potential in the treatment of Alzheimer’s disease (Holz GG et al., 1998) ⁽³⁵⁾.

Autoimmune disorder
The existence and participation of the voltage-dependent K+ channel KV1.3 and the Ca2+-activated intermediate K+ channel IKCa1 (KCa3.1) in T-lymphocyte activation is well established.1,9 Furthermore, a marked elevation of KV1.3 is reported in encephalitogenic T-cells, which mediate demyelination of axons in the brain and spinal cord, the hallmark of multiple sclerosis. The use of specifi c blockers for KV channels might have therapeutic potential for treatment of autoimmune disease, and as immunosuppressents for transplantations. In in vitro studies, the use of peptidyl toxins has indicated that blockage of KV1.3 inhibits T-cell activation, suggesting that KV1.3 may be a target for immunosuppression.9 This concept was verifi ed by in vivo experiments on peripheral T- cells of mini-swine using Margatoxin as specifi c KV1.3 toxin (Koo G 1997) ⁽³⁶⁾.Side effects of Margatoxin administration have been observed, mainly in the enteric nervous system which is expected for all non-specifi c KV1.3 toxins (Vianna-Jorge R et al., 2004) ⁽³⁷⁾. Furthermore,high serum concentrations of Margatoxin caused transient hyperactivity in pigs, indicating possible effects on KV1.1 and KV1.2 channels in the brain. Stichodactyla toxin (ShK), a toxin isolated form the venom of sea anemone Stichdactyla helianthus, has relatively similar affinities towards KV1.3 and KV1.1 ( Middleton RE, 2003) ⁽³⁸⁾

Pain
Ziconotide (Prialt®) is the name given to a 25-residue peptidetoxin called ϖ-conotoxin MVIIA isolated from the cone snail Conusmagus (Olivera BM et al., 1991) ⁽³⁹⁾. Ziconotide is a selective, reversible blocker ofneuronal N-type voltage-sensitive calcium channels that producespotent antinociceptive effects by blocking neurotransmission fromprimary nociceptive afferents  (Bowersox SS et al., 1998) ⁽⁴⁰⁾.This drug and second generationnon-peptide drugs are considered to be some of the best new drugsto treat chronic pain (Garber K , 2005) ⁽⁴¹⁾.

CONCLUSION
A number of venomous animals and their  toxins have been investigated to explore their biological activities and therapeutic potential. Among the animals, toxins of snake, scorpion, spider, frog, lizard and snail have been proved to have therapeutic value.However, for therapeutic applications, a number of issues associated with safety, pharmacokinetics and delivery need to be addressed. Optimization of peptide delivery to peripheral and central targets will help to determine whether or not these peptides can be considered candidates for drug development. Peptides that block channels by altering the gating mechanism might have potential to become selective potassium-channel inhibitors, whereas poreblocking toxins could be designed to be selective inhibitors of subtypes of sodium channels. There is occurring an incredible advance in understanding venoms at the genomic, transcriptomic and proteomic levels and therefore we will soon have a rather complete biomolecular assessment of many types of venom. In these cases, knowledge of these structures and the identification of new structures may provide relevant “leads” for use against appropriate drug targets.

REFERENCES
1. Lewis RJ and Garcia ML. Nat. Rev. Drug. Discov. 2003;2:790.
2. Livett BG et al. Curr. Med. Chem. 2004;11:1715.
3. Pal SK, Gomes A, and Dashgupta SC. Snake venom as therapeutic agents : From toxin to drug development. Indian J Exp Biol 2002;40:1353.  
4. Menezes MC, Furtado MF, Travaglia-Cardoso SR, Camargo AC, and Serrano SMT. Sex-based individual variation of snake venom proteome among eighteen Bothrops jararaca siblings. Toxicon 2006; 47(3): 304-12.
5. Torii S, Yamane K, Mashima T, Haga N, Yamamoto K, Fox JW, et al. Molecular cloning and functional analysis of apoxin I, a snake venom-derived apoptosis-inducing factor with L-amino acid oxidase activity. Biochemistry 2000; 39: 3197-205.
6.  White J. Snake venoms and coagulopathy. Toxicon 2005; 45: 951-67.
7. Danse JM, Gasparini S, and Menez A. In: Kini RM, Ed, Venom phospholipase A2 enzyme: structure, function and mechanism. United Kingdom, Wiley 1997; 29-71.
8. Rodriguez de la Vega RC and  Possani LD. Overview of scorpion toxins specfic for Na+ channels and related peptides: biodiversity, structure-function relationships and evolution. Toxicon 2005; 46:831-44.
9. Daly JW, Myers CW and  Whittaker N. Further classification of skin alkaloids from neotropical poison frogs (Dendrobatidae), with a general survey of toxic/noxious substances in the amphibia. Toxicon 1987;25:1023-95.
10. Russell FE and  Bogert CM. Gila monster: its biology, venom and bite-a review. Toxicon 1981;19:341-59.
11. Schleuning WD. Vampire bat plasminogen activator DSPA-alpha-1 (desmoteplase): a thrombolytic drug optimized by natural selection. Haemostasis 2001;31(3-6):118-22.
12. Terlau H, Olivera BM. Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol Rev 2004; 84: 41-68.
13. Daly JW, Myers CW and Whittaker N. Further classification of skin alkaloids from neotropical poison frogs (Dendrobatidae), with a general survey of toxic/noxious substances in the amphibia. Toxicon 1987; 25(10):1023-95.
14. Robeva A, Politi V, Shannon JD, Bjarnason JB and  Fox JW. Synthetic and endogenous inhibitors of snake venom metalloproteinases. Biomed Biophys Acta 1991; 50: 769-73.
15. Marsh N and Whaler B. The effects of snake venoms on the cardiovascular and haemostatic mechanisms. Int. J. Biochem 1978; 9: 217-20.
16. Ferreira SH. A bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca. Br J Pharmacol 1965; 34: 163-69.
17. Ng KKF and Vane JR. Some properties of angiotensin converting enzyme in the lung in vivo. Nature 1970; 225: 1142-4.
18. Ferreira SH, Bartelt DC and  Green LJ. Isolation of bradykininpotentiating peptides from Bothrops jararaca venom. Biochemistry 1970; 9: 2583-93.
19. Stewart JM, Ferreira SH and Greene LJ. Bradykinin potentiating peptide PCA-Lys-Trp-Ala-Pro. An inhibitor of the pulmonary inactivation of bradykinin and conversion of angiotensin I to II. Biochem Pharmacol 1971; 20: 1557-67.
20. Ondetti MA, Williams NM, Sabo EF, Pluscec J, Weaver ER, and Kocy O. Angiotensin-coverting enzyme inhibitors from the venom of Bothrops jararaca: Isolation, elucidation of structure and synthesis. Biochemistry 1971; 10: 4033-39.
21. Smith CG and Vane JR. The discovery of captopril. FASEB J 2003; 17: 788-9.
22. Huang TF, Holt JC, Lukasiewicz H, Niewiarowski S and Trigramin. A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors expressed on glycoprotein IIB-IIIa complex. J. Biol. Chem 1987; 262: 16157-63.
23. Calvete JJ, Marcinkiewicz C, Monleon D, Esteve V, Celda B, Juarez P, et al. Snake venom disintegrins: evolution of structure and function. Toxicon 2005; 45: 1063-74.
24. Egbertson MS, Chang CT, Duggan ME, Gould RJ, Halczenko W, Hartman GD, et al. Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem 1994; 37: 2537-51.
25. Scarborough RM, Naughton MA, Teng W, Rose JW, Phillips DR, Nannizzi L, et al. Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for glycoprotein IIb- IIIa. J Biol Chem 1993; 268: 1066-73.
26. Phillips DR and  Scarborough RM. Clinical pharmacology of eptifibatide. Am J Cardiol 1997; 80: 11B-20B.
27. Marcinkiewcz C. Functional characteristic of snake venom disintegrins: potential therapeutic implication. Curr Pharm Des 2005; 11(7): 815-27.
28. Calmetta A, Saenz A, and Costil L. Effects du venimde cobra sur les greffes cancereuses et sur le cancer spontane (adenocarcinoma) de la souris. CR Acad Sci 1993;197:205.
29. Braganca BM, Patel NTand Badrinath PG. Isolation and properties of a cobra venom factor selectively cytotoxic to Yoshida sarcoma cells. Biochim Biophys Acta 1969;136:508.
30. Da Silva RJ, Fecchio D and Barraviera B. Antitumour effect of snake venom . J Venom Anim Toxins 1996;2.
31. Liu Y F,Ma RL, Wang SL, Duan ZY, Zhang JH, Wu LJ & Wu CF. Expression of an  antitumour analgesic peptide from the venom of Chinese scorpion Buthus martensii Karsch in Escherichia coli. Protein Expr. Purif., 2003;27: 253.
32. Gomes A, Giri B, Saha A, Mishra R, Dasgupta SC, Debnath A and Gomes A. Bioactive molecules from amphibian skin : Their biological activities with reference to therapeutic potential for possible drug development. Indian J Exp Biol 2007;45:579.
33. Ko WS, Park TY, Park C, Kim YH, Yoon HJ, Lee SY, Hong SH, Choi BT, Lee YT and Choi YH. Introduction of apoptosis by Chan Su, a traditional Chinese medicine, in human bladder carcinoma T24 cells. Oncal Rep 2005;14:475.
34. Barton ME and While HS. Epilepsy Res 2004; 59:1.
35. Holz, GG and Habener, JF  Comp. Biochem. Physiol.B 1998; 121:177.
36. Koo G.  J Immunol 1997;158:5120.
37. Vianna-Jorge R. and Suarez-Kurtz G. Biodrugs 2004;18: 329.
38. Middleton RE Biochemistry 2003;42:13698.
39. Olivera BM, Rivier J, Scott JK, Hillyard DR, Cruz LJ. Conotoxins. J Biol Chem 1991; 266: 22067-70.
40. Bowersox SS, Luther R. Pharmacotherapeutic potential of omegaconcotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus. Toxicon 1998; 36:1651-58.
41. Garber K. Peptide leads new class of chronic pain drugs. Nat Biotech 2005; 23: 399.

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

FIND OUT MORE ARTICLES AT OUR DATABASE