THERAPEUTIC POTENTIAL OF VENOMOUS PEPTIDE IN VARIOUS DISEASES

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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 $12.5 billion. Total market volume of anti-epileptic drugs reaches $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.

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