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From venom to toxin to drug?

  • Alan L. Harvey (a1)

Synopsis:

Venoms are complex mixtures of many different components, whereas a toxin is a single pure compound whose activity can be specified. Toxins often have novel, highly specific activities. Studies on toxins open the way to design therapeutically useful molecules based on the structural information obtained from the toxins.

An example of successful drug development from a component of a snake venom is that of the inhibitors of angiotensin-converting enzyme (ACE). The first ACE inhibitors were developed from work on peptides isolated from the Brazilian arrowhead viper Bothrops jaracusa that prolonged the action of bradykinin. The venom components blocked the enzyme that inactivated bradykinin; the same enzyme activated the precursor of the vasoconstrictor hormone angiotensin. Hence, a valuable new type of therapy was established by developing the leads provided by the natural toxin.

Dendrotoxins are small proteins from mamba venoms that block rapidly activating K+ channels in neurones. There are possibilities that dendrotoxin could be the basis for drug design. A small analogue that mimicked the activity of dendrotoxin in the central nervous system might boost the activity of certain neuronal pathways. Potentially, such a compound might be able to restore some of the function of systems damaged by progressive neurodegenerative diseases. Although dendrotoxin-like compounds would not be a cure for these diseases, they may provide temporary relief from symptoms.

Conversely, compounds with the specificity of dendrotoxin but with ability to activate K+ channels, rather than block them, may be a novel way of reducing abnormal electrical activity in the brain. Hence, they may form the basis of a new type of anticonvulsant drug for epilepsies.

Recent work at Strathclyde has concentrated on defining the structure-activity relationships of the naturally occurring dendrotoxins and on synthesising small analogues of the postulated ‘active site’. Preliminary results are encouraging, and it is hoped to go from green mamba venom to dendrotoxin to therapeutically useful drugs.

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From venom to toxin to drug?

  • Alan L. Harvey (a1)

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