Biotechnological applications of venom toxins

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Bothrops jararaca venom (Brazilin snake), which represented one of the first “block buster” drugs stemming from a venom toxin. Since then several generations ...

Research Journal of Biotechnology

Vol. 8 (9) September (2013) Res. J. Biotech

From the Editor’s Desk

Biotechnological applications of venom toxins Dhananjaya B.L. Our guest editor from Toxinology Lab, School of Chemical and Biotechnology (SCBT), SASTRA University, Thirumalaisamudram, Thanjavur-613401, INDIA [email protected]

Biotechnology is the application of science and technology to living organisms, as well as parts, products and models thereof, to develop useful products to improve human lives and its environment. By application of modern advanced technologies, manipulating and thus intervening the biological organisms or biological process, has thus far brought revolution in production of useful products used profitably in health care (medicine, diagnosis etc.) agriculture, animal husbandry and environmental implications, thus having a dramatic effect on the world economy and society. In these lines in the recent years the use of animal venoms and its toxins – a natural product, as a source of material for biotechnological application has received much attention from pharmaceutical industry and experts in the field of applied research.

from a venom toxin. Since then several generations of these drugs have been brought to market by Squibb and other pharmaceutical companies. Later on many different drugs have been developed, based on purified toxins with the help of advanced biotechnological tools and those have been evaluated for its biotechnological applications, particularly in the areas of health care (medicines and clinical diagnosis), agriculture (pest control) and for its environmental implications. A number of venomous animals (snakes, scorpion, spider, snail, lizard, frog, fish and insects) have been investigated for their biological activities and possible biotechnological applications and the biologically active toxins participating and/or intervening in the cardiovascular system, central nervous system, hemostatic system and muscular systems have thus far led to discovery of several products that have lead to develop therapeutic utility molecules that are used in the treatment of various diseases.

Venoms are naturally selected and are highly evolved cocktail of biologically active proteins/peptides and other molecules. Venom is secreted and delivered through specialized “Venom glands” that is primarily used by the organism to immobilize, capture their prey and to defend against its predators. To bring about these effects the venom components interact with specific molecular targets and this ‘Cruise missile’ type of precision and optimization of structure-function enumerates its potential as molecules for drug discovery, in terms of both new lead discovery and/or new target identification. Over the years understanding the molecular pathways of the action of these site specific toxins have brought new insights in the field of biotechnology. Further, the recent advances in several biotechnological areas indicate its possibilities for contributions to newer biomedical research and other areas.

It is promising to note that there are numerous venom toxins and toxin-based drugs that are currently in use and/or some are still under various stages of clinical trial in different countries, for their therapeutical applications. Presently there are 18 toxin-based drugs that are approved for use (in US and other countries) and nearly 5 are approved for clinical trials and are at various stages of clinical trials for their application in various diseases. The toxin-based drugs that are approved (By U.S. Food and Drug Administration) for use include: i) Captropril® or Enalpril® for treatment of hypertension by inhibiting the Angiotension Converting Enzyme, which was developed based on Bradykini-potentiating peptides from Bothrops jararaca venom- Brazilian arrowhead viper,

The use of venoms for medicinal purposes dates back to ancient times and has been mentioned in ayurvedic, unani, chinese and homeopathic system of medicine. In ayurveda, cobra venom was used to treat joint pain, inflammation and arthritis. The Visachikitsha, the division of ayurveda deals with the use of venoms to cure diseases through ayurvedic technique known as suchikavoron (venom at the tip of a needle) and shodhono (detoxification of venom) was able to treat several chronic diseases. From the early 20th century, the idea of utilizing purified toxins as a source of therapeutics started and the first successful example of developing a drug from an isolated toxin was in 1975, a hypotensive agent – Captopril® – which was designed and developed based on the structure of bradykininpotentiating peptide (BPP) – Terperotide, isolated from Bothrops jararaca venom (Brazilin snake), which represented one of the first “block buster” drugs stemming

ii) Aggrastat® (Triofiban) used for heart diseases/ coagulopathies- for treatment of angina, whereby it reversibly antagonizes the platelet glycoprotein (GP) IIb/IIIa receptor and thus inhibits platelet aggregation, this was developed based on non-peptide structure based on RGD sequence from snake venom disintegrins from Echis carinatus (African saw-scaled viper), iii) Integrilin® (Eptifibatide) used for heart diseases/coagulopathies – particulary in use for coronary angioplasty, where by it inhibits platelet aggregation by acting as antagonist of the platelet receptor glycoprotein (GP) IIb/IIIa, but unlike Aggrastat®, this is developed (1)

Research Journal of Biotechnology

Vol. 8 (9) September (2013) Res. J. Biotech ii) ViperinexTM which can be used for treatment of heart diseases/coagulopathies and also for treatment of acute, ischemic stroke. It is a serine proteinase- obtained from Agkistrodon rhodostoma (Malayan pit viper),

based on the KGD sequence of disintegrin from Sistrurus miliarus barbouri (South-eastern pigmy rattlesnake), iv) Prialt® (Ziconotide) that is used for treating severe chronic pain, by blocking N-type Ca2+ channels which is developed based on the -conotoxin MVIIA from the cone snail Conus magus and

iii) Desmoteplase which is being developed for treatment of acute ischemic stroke, it is a plasminogen activator from the saliva of the vampire bat Desmodus rotundus.

v) ByettaTM (Exenatide) which is used for diabetes, to improve the blood sugar control in adults with type 2 Diabetes mellitus, which is achieved by binding and activating GLP-1 receptor to reduce plasma glucose and lower the HbA1c. This is being developed based on the structure of exendin-4 isolated from the saliva of the lizard Heloderma suspectus.

iv) Cilengitide (EMD 121974) which is being developed to contain growth and spread of tumor cells, v) Chlorotoxin (131I-TM-601) which is being developed to target malignant glioma, based on its capacity to act as chloride channel blocker. It is obtained from scorpion Leiurus quinqestriatus. Both these toxins/toxin-derived drugs are at phase II clinical trials. In addition to these there are numerous toxin-based drugs that are at preclinical stage of development.

Some of the other toxin-derived drugs that are being approved for use in other countries include: i) Defibrase® for use in heart diseases/coagulopathies, by converting fibrinogen to fibrin through the release of fibrinopeptide A from fibrinogen. This was developed based on the serine proteinase isolated from Bothrops atox moojeni (Brazilian lancehead).

Apart from the applications of toxins or toxin-derived drugs in various diseases and conditions, the toxins have also found their usefulness as diagnostic tools and these include: i) Reptilase®- Reagent (Serine protenase from Bothrops jaraca), which is used in diagnosis of blood coagulation disorder,

ii) Haemocoagulase® for treatment of coagulopathies/ hemorrhage, with thrombin like activity from Bothrops atrox venom (lance head viper).

ii) Protac® (Serine proteinase from Agkistrodon contortix venom), which is used to determine protein C and protein S level/clinical diagnosis of haemostatic disorder,

iii) Exanta® (Ximelagatran) as oral anticoagulant, by inhibiting thrombin, which was developed based on the peptide isolated from venom of cobra.

iii) Botrocetin® (Platelet-aggregating protein from Bothrops jararaca and other Bothrops species), which is used to assay vWF in plasma,

iv) ABT-594 as an analgesic by acting as agonist of nicotinic acetylcholine receptor. This was developed based on the structure of epibatidine found in secretions of frog Epipedobates tricolor,

iv) RVV-V (Serine proteinase from Vipera russelli), which is used to destabilize and selectively inactivate factor V in plasma and thus prepare a routine reagent for factor V determination,

v) Contulakin-G as an analgesic by acting as an agonist for neurotensionn receptor, which is a glycopeptide from cone snail – Conus geograph,

v) RVV-X (a P-IV metalloproteinase from Vipera russelli), used in diagnostic procedures to quantitatively convert the zymogen factor X into factor Xa,

vi) TectinTM/TetrodinTM/TocudinTM as analgesic which blocks action potentials in nerves by binding to the pores of the voltage-gated sodium channels in nerve cell membranes.

vi) Ecarin (Proteinase from Echis carinatus), as prothrombin activator, Exanta (from cobra) used as anticoagulant/blood thinner and as thrombin inhibitor.

Further, it is interesting to note that there are few toxinbased drugs that are presently being approved for phase III clinical trials and are at various stages of development with promising aspect of application in the USA. These include:

The other area of application of venom toxins includes their use as biological pest control agent. It is well known that anti-insect toxins have been largely used as means for biological insect control and in recent years venoms of scorpions, spiders, sea anemones, mites and parasitoids have been explored for insect-specific neurotoxins that act within the insect hemocoel (body cavity) and modulate the voltage-gated Na+ channels and thus acting as a bioagents of pest control. Recently, it has been shown that scorpion

i) Alfimeprase which can be used to treat arterial occlusive diseases, as it rapidly dissolves the blood clots and thus help prevent the need for surgery on leg arteries. This is a recombinant analog of fibrase, a P-I snake venom metalloproteinase from Agkistrodon contotrix (Copper head snake). (2)

Research Journal of Biotechnology

Vol. 8 (9) September (2013) Res. J. Biotech

α-toxins have differential preference for insect and mammalian sodium channels.

chitosan, nano-gold, nano-silver, magnetic and supermagnetic nano-particles, dendrimers etc. are being studied extensively in the role of drug delivery vehicles by conjugating them with several therapeutically potent venoms and toxins, particularly peptides, proteins and antigen. It seems that in future the conjugation of venomtoxins with suitable nano-particles would not only provide insights to newer drugs but also better drug delivery systems which would have better biocompatibility with increased therapeutic potential.

As long as modern agriculture depends heavily on the use of insecticides, evidently there will be a great need for such molecules capable of differentiating between different sodium channel subtypes, thereby emphasizing the importance of rational design of more sensitive and safer insecticides. In these lines, attempts are being made to engineer plants for expressing selective anti-insect toxins or use of natural vectors that express toxins near their target site (e.g. baculoviruses), designing anti-insect selective peptidomimetics are also being explored to find selective and safe insect-toxin. Therefore it seems in future the discovery and development of venom-toxins from different organisms for their use as bio-agents will have a great potential to become alternatives to chemicals used as pesticide which will be eco-friendly and thereby help in for a sustainable environment.

Although, the use of venoms for medical and other purposes dates back to ancient times, the past few decades have seen advent in practical applications as evidenced by toxin and toxin structure based drugs that are in clinical use and myriad others that are in development pipeline. Hope with the occurrence of advancement of understanding venoms/toxins at different levels, with advanced biotechnological tools available, we could perhaps hope for more accelerated approach towards biotechnological applications of venom and/or its toxins. Recent advances in several biotechnological areas indicate new avenues for biotechnological application for venom toxins and hope in the near future, the biotechnological use of venoms-/toxins will provide potential tools that can be applicable in wide range of fields. *****

The recent advent of nano-medicine has given raise for more robostic application of venom-toxin derived drugs and the drugs are being developed and/or venom-toxins are nano-particle conjugated to increase its efficacy against disease. In these lines hydrophylic nano-particles such as

(3)

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