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From venom to toxin to drug?

Published online by Cambridge University Press:  05 December 2011

Alan L. Harvey
Alan L. Harvey
Affiliation:
Department of Physiology and Pharmacology, and Strathclyde Institute for Drug Research, University of Strathclyde, Glasgow G1 1XW, U.K.
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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.

Type
Research Article
Information
Proceedings of the Royal Society of Edinburgh, Section B: Biological Sciences , Volume 99 , Issue 1-2: The Advancement of Drug Discovery , 1992 , pp. 55 - 65
Copyright
Copyright © Royal Society of Edinburgh 1992

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References

Alder, M., Lazarus, R. A., Dennis, M. S. & Wagner, G. 1991. Solution structure of kistrin, a potent platelet aggregation inhibitor and GPIIb-IIIa antagonists. Science 253, 445–8.Google Scholar
Anderson, A. J. & Harvey, A. L. 1988. Effects of the potassium channel blocking dendrotoxins on acetylcholine release and motor nerve terminal activity. British Journal of Pharmacology 93, 215–21.Google Scholar
Barrett, J. C. & Harvey, A. L. 1979. Effects of the green mamba, Dendroaspis angusticeps on skeletal muscle and neuromuscular transmission. British Journal of Pharmacology 67, 199–205.Google Scholar
Benoit, E. & Dubois, J.-M. 1986. Toxin I from the snake Dendroaspis polylepis polylepis: A highly specific blocker of one type of potassium channel in myelinated nerve fibre. Brain Research 377, 373–7.CrossRefGoogle Scholar
Black, A. R., Donegan, C. M., Denny, B. J. & Dolly, J. O. 1988. Solubilization and physical characterisation of acceptors for dendrotoxin and β-bungarotoxin from synaptic membranes of rat brain. Biochemistry 27, 6814–20.CrossRefGoogle ScholarPubMed
Bowman, W. C. & Sutherland, G. A. 1986. Vecuronium (ORG-NC-45). In New neuromuscular blocking agents. Handbook of experimental pharmacology, vol. 79, pp. 419–43, ed. Kharkevich, D. A. Berlin: Springer-Verlag.CrossRefGoogle Scholar
Cook, N. S. (ed.) 1990. Potassium channels: structure, classification, function and therapeutic potential. Chichester: Ellis Horwood Ltd.Google Scholar
Creighton, T. E. 1978. Experimental studies of protein folding and unfolding. Progress in Biophysics and Molecular Biology 33, 231–97.CrossRefGoogle ScholarPubMed
Cushman, D. W., Ondetti, M. A., Cheung, H. S., Sabo, E. F., Antonaccio, M. J. & Rubin, B. 1980. Angiotensin-converting enzyme inhibitors. In Enzyme inhibitors and drugs, pp. 231–47, ed. Sandier, M. London: Macmillan.Google Scholar
Dennis, M. S., Henzel, W. J., Pitti, R. M., Lipari, M. T., Napier, M. A., Deisher, T. A., Bunting, S. & Lazarus, R. A. 1989. Platelet glycoprotein IIb-IIIa protein antagonists from snake venoms: evidence for a family of platelet-aggregation inhibitors. Proceedings of the National Academy of Sciences USA 87, 2471–5.CrossRefGoogle Scholar
Dolly, J. O., Halliwell, J. V., Black, J. D., Williams, R. S., Pelchen-Matthews, A., Breeze, A. L., Mehraban, F., Othman, I. B., & Black, A. R. 1984. Botulinum toxin and dendrotoxin as probes for studies on transmitter release. Journal de Physiologie (Paris) 79, 280–303.Google Scholar
Ducancel, F., Rowan, E. G., Cassar, E., Harvey, A. L., Ménez, A., & Boulain, J.-C. 1991. Amino acid sequence of a muscarinic toxin deduced from the cDNA nucleotide sequence. Toxicon 29, 516–20.Google Scholar
Dufton, M. J. 1985. Proteinase inhibitors and dendrotoxins. Sequence classification, structural prediction and structure/activity. European Journal of Biochemistry 153, 647–54.Google Scholar
Dufton, M. J. 1992. Protein evolution and its analytical potential. Proceedings of the Royal Society of Edinburgh 99B, 111–119.Google Scholar
Gould, R. J., Polokoff, M. A., Friedman, P. A., Huang, T.-F., Holt, J. C., Cook, J. J. & Niewiardwski, S. 1990. Disintegrins: a family of integrin inhibitory proteins from viper venoms. Proceedings of the Society for Experimental Biology and Medicine 195, 168–71.CrossRefGoogle ScholarPubMed
Halliwell, J. V., Othman, I. B., Pelchen-Mathews, A. & Dolly, J. O. 1986. Central action of dendrotoxin. Selective reduction of a transient K conductance in hippocampus and binding to localized acceptors. Proceedings of the National Academy of Sciences USA 83, 493–7.CrossRefGoogle ScholarPubMed
Harvey, A. L. & Anderson, A. J. 1985. Dendrotoxins: snake toxins that block potassium channels and facilitate neurotransmitter release. Pharmacology and Therapeutics 31, 33–55.CrossRefGoogle ScholarPubMed
Harvey, A. L. & Anderson, A. J. 1991. Dendrotoxins: snake toxins that block potassium channels and facilitate neurotransmitter release. In Snake toxins, pp. 131–64, ed. Harvey, A. L. New York: Pergamon Press.Google Scholar
Harvey, A. L. & Karlsson, E. 1980. Dendrotoxin from the venom of the green mamba, Dendroaspis angusticeps. A neurotoxin that enhances acetylcholine release at neuromuscular junctions. Naunyn-Schmiedeberg's Archives of Pharmacology 312, 1–6.CrossRefGoogle Scholar
Harvey, A. L., Anderson, A. J. & Karlsson, E. 1984. Facilitation of transmitter release by neurotoxins from snake venoms. Journal de Physiologie (Paris) 79, 222–7.Google ScholarPubMed
Harvey, A. L., Marshall, D. L., De-Allie, F. A. & Strong, P. N. 1989. Interactions between dendrotoxin, a blocker of voltage-dependent potassium channels, and charybdotoxin, a blocker of calcium-activated potassium channels at binding sites on neuronal membranes. Biochemical and Biophysical Research Communications 163, 394–397.Google Scholar
Hollecker, M. & Creighton, T. E. 1983. Evolutionary conservation and variation of protein folding pathways. Two protease inhibitor homologues from black mamba venom. Journal of Molecular Biology 168, 409–37.Google Scholar
Hollecker, M. & Creighton, T. E. 1982. Protease inhibitor homologues from mamba venoms: facilitation of acetylcholine release and interactions with prejunctional blocking toxins. British Journal of Pharmacology 11, 153–61.Google Scholar
Hollecker, M. & Larcher, D. 1989. Conformation forces affecting the folding pathways of dendrotoxins I and K from black mamba venom. European Journal of Biochemistry 179, 87–94.Google Scholar
Hughes, R. 1986. Atracurium. In New neuromuscular blocking agents. Handbook of experimental pharmacology, vol. 79, pp 529–43, ed. Kharkevich, D. A. Berlin: Springer-Verlag.CrossRefGoogle Scholar
Kornalik, F. 1985. The influence of snake venom proteins on blood coagulation. Pharmacology and Therapeutics 29, 353–405.CrossRefGoogle ScholarPubMed
Kornalik, F. 1991. The influence of snake venom proteins on blood coagulation. In Snake toxins, pp. 323–83, ed. Harvey, A. L. New York: Pergamon Press.Google Scholar
Marshall, D. L. & Harvey, A. L. 1990. Re-examination of the protease inhibitor activities of the dendrotoxins from mamba venoms. Toxicon 28, 157–8.Google Scholar
Rehm, H. & Lazdunski, M. 1988. Purification and subunit structure of a putative K+ channel protein identified by its binding properties for dendrotoxin I. Proceedings of the National Academy of Sciences USA 85, 4919–23.CrossRefGoogle ScholarPubMed
Rehm, H., Pelzer, S., Cochet, C., Chambaz, E., Tempel, B. L., Trautwein, W., Pelzer, D. & Lazdunski, M. 1989. Dendrotoxin-binding brain membrane protein displays a K+ channel activity that is stimulated by both cAMP-dependent and endogenous phosphorylations. Biochemistry 28, 6455–60.CrossRefGoogle Scholar
Rowan, E. G., Ducancel, F., Doljansky, Y., Harvey, A. L., Boulain, J.-C. & Ménez, A. 1990. Nucleotide sequence encoding a ‘synergistic-like’ protein from the venom glands of Dendroaspis angusticeps. Nucleic Acids Research 18, 1639.CrossRefGoogle ScholarPubMed
Rudy, B. 1988. Diversity and ubiquity of K channels. Neuroscience 25, 729–49.CrossRefGoogle ScholarPubMed
Scarborough, R. M., Rose, J. W., Hsu, M. A., Phillips, D. A., Fried, V. A., Campbell, A. M., Nannizzi, L. & Charo, I. F. 1991. Barbourin. A GPIIB-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri. Journal of Biological Chemistry 266, 9359–62.CrossRefGoogle ScholarPubMed
Stenlake, J. B. 1986. Biodegradation and elimination of neuromuscular blocking agents. In New neuromuscular blocking agents. Handbook of experimental pharmacology, vol. 79, pp. 263–76, ed. Kharkevich, D. A. Berlin: Springer-Verlag.Google Scholar
Stuhmer, W., Stocker, M., Sakmann, B., Seeburg, P., Baumann, A., Grupe, A. & Pongs, O. 1988. Potassium channels expressed from rat brain cDNA have delayed rectifier properties. FEBS Letters 242, 199–206.CrossRefGoogle ScholarPubMed
Thomas, K. B. 1964. Curare. Its history and usage. London: Pitman Medical.Google Scholar
Weller, U., Bernhardt, U., Siemen, D., Dreyer, F., Vogel, W. & Habermann, E. 1985. Electrophysiological and neurobiochemical evidence for the blockade of a potassium channel by dendrotoxin. Naunyn-Schmiedeberg's Archives of Pharmacology 330, 77–83.CrossRefGoogle ScholarPubMed