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Coaxing Cures from Venomous Snakes
by Dr Liew Soo Chin

s a Chinese saying goes, "Once bitten by a snake, ten years scared of ropes," revealing the strong aversion triggered by the slithery creature, especially if known to be poisonous. The average layperson equates snake venom with suffering or even painful death.

However, this unpleasant mental association has little basis in fact, says Associate Professor R Manjunatha Kini at the Department of Biological Sciences, National University of Singapore. This expert has been examining poisonous snakes since his postgraduate days in India, a fascination arising from a childhood spent in an area that had its fair share of the reptiles and snakebites.

Initially working on how active components from Indian herbal concoctions neutralised deadly snakebite, he became intrigued by the toxicological components of the venom and the way each affected the functions of the human body. One venom contains 100 to 200 toxins that attack multiple tissues or organs, breaking down various physiological systems simultaneously.

Kini switched his focus from simply looking at antidotes to questioning why venom proteins act as toxins even though they are structurally similar to human proteins, as well as attempting to determine where responsibility for the toxic effects lies. The theoretical approach used in his studies sparked a mini revolution in the understanding of the structure-function relationships of toxins and other proteins. Currently, he is pursuing studies in the structure, function, and mechanism of toxins.

This accumulation of increasingly precise knowledge about snake venom has the exciting potential of leading to the development of more effective drugs and vaccines. In addition, the toxins provide a wide array of highly specific molecular scalpels that help explain the fundamental details in normal physiological processes. For instance, venom exists that interferes with blood clotting by acting as an anticoagulant. If extracted, the active components from the toxins responsible for the effect could be used to prevent cardiac arrest or stroke. Such work will also help further understanding of the process of human blood coagulation.

Some of the bodily effects of venom include neurotoxicity (poisoning of nerve tissue), muscular toxicity, anticoagulant effects, hypertension, toxicity on the heart, internal haemorrhage, convulsion, and tissue damage. Because some toxins can produce a number of different physiological responses simultaneously, researchers must isolate the active parts that induce each of these actions. For instance, a toxin could show both detrimental and beneficial effects because a distinctly different part of the toxin could be responsible for a specific outcome. Using protein chemistry techniques, Kini has been able to identify beneficial sites and develop them as prototypes of therapeutic agents.

Toxins exhibiting different physiological effects from various snakes' venom have been identified. So far, scientists have been working on either the most toxic component of the venom (such as neurotoxins and cardiotoxins) or the most abundant protein. With the advances in technology, Kini can now study proteins found in small amounts, and these novel proteins have exciting new biological properties. He has worked extensively on two groups of snake venom according to their structures: phospholipase, an enzyme ubiquitous in the venom; and three-finger toxins, so-called because of their uncanny structural resemblance to human digits. "The exciting feature of venom toxins," he says, "is that there are some toxins with common structures but demonstrate diverse functions, while others possess diverse structures but exhibit similar functions."

In addition, he has isolated two new families of snake toxin in terms of their function. One is involved in reducing thermal stress, the way the body responds to high temperature. He has discovered a protein that maintains a constant body temperature in extreme heat, thus preventing heat stroke. Other members of these families are still under investigation.

Kini works with some of the most lethal reptiles on earth which produce highly toxic venom, including the Indian cobra, the Malayan krait, the viper, the spitting cobra, some African snakes, and some Australian snakes. Each has its own unique toxin that attacks different parts and systems of the body by means of specific mechanisms.

One of the latest venom proteins isolated in Kini's laboratory, from the rough-scale snake from Australia, has similarities to blood coagulation factors with binding sites like the human protein. Currently, he is working to develop anticoagulant peptides based on this protein. He has also extracted a reversible neurotoxin that can be "turned on or off" as required. This protein, now undergoing animal testing for efficacy, can be used as a muscle relaxant during surgery.

Kini, an affiliate Associate Professor with the Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, Virginia Commonwealth University, has worked in the US to uncover 140 peptides with various biological activities. His projects have led to the filing of more than 15 patent applications, 8 of which have already been granted.

His research in various laboratories related to a number of these patents has been co-licensed to drug companies. These patents include the design and development of potent bioactive peptides and prototypes of peptides with various therapeutic applications, as anticoagulant, antiplatelet, hypotensive, analgesic, and antitumour agents.

This prolific scientist also works with different groups to study the neurotoxic and analgesic (pain relieving) effects of venom. His NUS collaborators, which include the Departments of Pharmacology and Anatomy, work to test the clinical actions of the poisons, while the Singapore Defence Medical Research Institute investigates the effect of thermal stress. Other joint research underway involves teams from the University of Sydney in Australia, Tata Institute of Fundamental Research in India, and Stanford University in the US.

With the multitude of potential cures that could be derived from snake venom, we may now want to look at these feared reptiles in a new, more positive light.

For more information check out: www.dbs.nus.edu.sg/Staff/kini.htm, or contact Assoc Prof R Manjunatha Kini at: dbskinim@nus.edu.sg

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