Figure 1: Adult frog neuromuscular junction stained using toxins. Courtesy Professor Stephen D. Meriney, PhD, Department of Neuroscience, University of Pittsburgh, PA (USA).

Toxins Acting On Receptors

A number of toxins are used to investigate the functions of receptors. Thereby, many toxins act on G-protein coupled receptors (GPCRs), which fulfill about 80 % of the signal transduction across cellular membranes and are drug targets of remarkably high relevance [6].

Mammalian endothelins, the endogenous activators for a family of GPCRs, are highly potent vasoconstrictors. In addition, the endothelin system plays an important role in pain, hypertension, atherosclerosis, cancer and inflammation. Sarafotoxins, discovered in the venom of burrowing asps of the genus Atractaspis, have high structural similarity with mammalian endothelins and function as efficient and selective agonists for endothelin receptors [7].

Other examples for toxic peptides acting on GPCRs are exendin-4 or exenatide, an FDA-approved synthetic drug derived from it. Exendin-4 was isolated from the venom of the lizard Heloderma suspectum. Exendin-4 and exenatide activate glucagon-like peptide-1 (GLP-1) receptors and thus stimulate insulin secretion, slow gastric emptying, and inhibit the production of glucose by the liver. Since exendin-4 (exenatide) is resistant to degradation by the enzyme dipeptidyl peptidase 4, it is of high therapeutic value in the treatment of diabetes [8].

Like the ion channel blocking conotoxins, conopressins were found in the venom of fish-hunting cone snails. Conopressins show structural and functional similarity to the peptide hormone vasopressin, which physiologically activates three subtypes of GPCRs. Conopressins could be beneficial for the development of vasopressin or oxytocin receptor antagonists with tailored selectivity [3].

Lipid Bilayer Interacting and Mast Cell Degranulating Toxins

A number of bee and wasp toxins have effects, which are of substantial scientific interest. Melittin for example is a surface-active, highly cytolytic peptide, making up about 50 % of the peptide fraction in the venom of the European honey bee Apis mellifera. Melittin is extensively used for monitoring mechanisms of pore formation and lipid–protein interactions in membranes. Melittin also induces histamine release, presumably by lysis of mast cells, and potentially has anti-viral activity [9, 10].

Mast cell degranulating peptide (MCD or MCDP), also found in European honey bee venom, has antagonistic immunological properties: It is a powerful anti-inflammatory agent, but also induces mast cell degranulation and hence inflammation. In addition, MCD has been shown to function as a neurotoxin with the ability to block a certain class of K_v channels, and to have a cardiovascular effect with the potential to significantly lower blood pressure [10]. 

Mastoparans, isolated from the venoms of several wasp species, can increase the lipid bilayer permeability for hydrophilic molecules and can form pore-like lesions in lipid membranes [11]. They furthermore promote secretion from mast cells by interacting with intracellular, trimeric G-proteins, thus mimicking the action of activated GPCRs [11, 12]. Other effects conferred by wasp toxins include vascular smooth muscle contraction (mastoparan-7) [13] as well as potential anti-tumor properties (mastoparan-7 and polybia) [13, 14].

Actin Filament Binding Toxins

Actin filaments are involved in intracellular transport, secretion, cellular motility and cancer transformation in eukaryotic cells. Phalloidin, a bicyclic poisonous heptapeptide of the mushroom Amanita phalloides, tightly binds to F-actin. This is beneficial for the visualization of actin in light microscopy: Binding of phalloidin stabilizes actin filaments against harsh experimental treatment, which facilitates sample preparation. In addition, actin filaments can be stained very specifically with fluorophore-conjugated phalloidins [15].

Conclusions

Manifold applications employing toxic peptides in biomedical research exist, rendered possible by the intriguing diversity of toxins in nature. Toxins are used for example to selectively block channels, to activate receptors, to specifically label biomolecules and to study peptide-membrane interactions. Furthermore, toxic peptides can serve as blue prints for drug development.

For experimental work, a broad offering of catalog peptides including numerous natural, conjugated, or modified toxic peptides can be purchased from stock or are commercially available as custom peptides. This significantly improves the availability of the toxins for bench scientists and is of great value for obtaining meaningful and reproducible results in shorter time.

Explore our broad offering of catalog toxic peptides, our custom peptide synthesis service as well as further technical information

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References

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[2]           B. A. Simms and G. W. Zamponi. Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron 82, 24-45 (2014)
[3]           R. J. Lewis et al. Conus venom peptide pharmacology. Pharmacological Reviews 64, 259-298 (2012)

[4]           H. Wulff et al. Voltage-gated potassium channels as therapeutic targets. Nature Reviews Drug Discovery 8, 982-1001 (2009)

[5]           K. G. Chandy et al. K⁺ channels as targets for specific immunomodulation. Trends in Pharmacological Sciences 25, 280 (2004)

[6]           R. P. Millar and C. L. Newton. The year in G protein-coupled receptor research. Molecular Endocrinology 24, 261-274 (2010)

[7]           F. Ducancel. Endothelin-like peptides. Cellular and Molecular Life Sciences 62, 2828-2839 (2005)

[8]           B.D. Green and P.R. Flatt. Incretin hormone mimetics and analogues in diabetes therapeutics. Best Practice & Research Clinical Endocrinology & Metabolism. 21, 497-516 (2007)

[9]           H. Raghuraman and A. Chattopadhyay. Melittin: a membrane-active peptide with diverse functions. Bioscience Reports 27, 189-223 (2007)

[10]         M. R. Ziai et al. Mast cell degranulating peptide: a multi-functional neurotoxin. Journal of Pharmacy and Pharmacology 42, 457-461 (1990)

[11]         A. Arbuzova and G. Schwarz. Pore-forming action of mastoparan peptides on liposomes: a quantitative analysis. Biochimica et Biophysica Acta 1420, 139-152 (1999)

[12]         T. Higashijima et al. Mastoparan, a peptide toxin from wasp venom, mimics receptors by activating GTP-binding regulatory proteins (G proteins). Journal of Biological Chemistry 263, 6491-6494 (1988)

[13]         G. Grzesk et al. Direct regulation of vascular smooth muscle contraction by mastoparan-7. Biomedical Reports 2, 34-38 (2014)

[14]         K.R. Wang et al. Antitumor effects, cell selectivity and structure-activity relationship of a novel antimicrobial peptide polybia-MPI. Peptides 29, 963-968 (2008)

[15]         J. Small et al. Visualising the actin cytoskeleton. Microscopy Research and Technique 47, 3-17 (1999)