Therapeutics with a Sting: Venoms and Toxins
What nature has intricately and expertly designed to inflict harm can be harnessed as a force for good and a remedy for disease. With over 220,000 venomous animal species worldwide, a complex cocktail of natural pharmacologically active components is at our disposal.?Many animals and insects produce venom as part of a defense mechanism used in immobilizing, capturing, killing, and digesting prey. Venoms are not just made up of a single toxin but are instead made up of a natural pool of bioactive molecules, including enzymes, proteins, peptides, carbohydrates, metal ions, and lipids.
Why are venom-derived bioactive molecules?of scientific interest??
These components have sparked an interest in scientific research and drug development. This is due to their pharmacological properties and their natural ability to target G protein-coupled receptors and ion channels, important drug targets that a large portion of on-the-market drugs currently target. They are also attractive due to their variety, specificity, and efficiency. Many venom components are peptides that target enzymes, hemostatic pathways, ion channels, and membrane receptors with high selectivity and affinity. For example, in snake venoms, there are proteins such as cysteine-rich secretory proteins (CRISPs), phospholipases A2, phosphodiesterases and nerve growth factors (NGFs), and bioactive peptides like neuropeptides, antimicrobial, analgesic, cell-penetrating, hypotensive, cytotoxic and anti-cancer peptides. Despite the possibility that venoms have the potential to contain 100 to 500 pharmacologically active compounds, many have not been identified and characterized due to reliable sources of venoms being challenging to obtain. Furthermore, purifying and characterizing a toxin in detail is complex, and until now, there have not been many research teams interested in this field. However, with advancements in scientific techniques and more recognition of the potential of toxins, interest in this field is increasing. That is why Biosynth has a venoms and toxins category within our catalog of over a million research products. We offer various animal-derived venoms and toxins with potential for biotechnological and pharmacological applications. We can meet our customers' needs, including snakes, scorpions, spiders, cone snails, and reptiles.
Snake venom in clinical pharmacology and therapeutics
The discovery of snake venom as a therapeutic stems from the 18th century, when scientist?Abbé Felice Fontana, now described as the founder of modern toxicology, was working on?European viper venom. Remarkably, Fontana found that this venom was myotoxic and produced coagulation of blood as well as its fluidity?(Hawgood, 1995). Fast forward to the 21st century, and there are now many venom-derived drugs in different clinical stages, even those approved by the FDA. Prime examples of snake venom-derived drugs approved by the FDA are?Captopril? (Enalapril), Aggrastat? (Tirofiban), and Integrilin? (Eptifibatide).
Enalapril
Taken from the venom of a Brazilian jararaca pit viper,?Captopril??(Enalapril) has been commercially successful in treating high blood pressure.?Captopril? is based on the nonapeptide bradykinin potentiating factor (BPF), found in?Bothrops jararaca?snake venom, that blocks the angiotensin-converting enzyme (ACE). During its development as a drug, the native peptide was expensive to make and difficult to administer orally. Therefore a 'miniaturization' of BPF was made and a succinyl group was added to a proline residue, enabling its oral administration. The proline residue at the c-terminal is responsible for interacting with ACE and making it a successful treatment for hypertension.?
Tirofiban and?Eptificatide
Aggrastat? (Tirofiban) is an antiplatelet drug based on the RGD motif in the echistatin venom protein from saw-scaled viper Echis carinatus.?Tirofiban?mimics the RGD sequence and competes with fibrinogen for RGD recognition sites on the platelet glycoprotein GPIIb/IIIa receptor.?Tirofibin has an enhanced interaction due to a (S)-NHSO2-C4H9 group. This leads to the prevention of platelet aggregation and other antithrombotic properties and demonstrates its use for acute coronary syndrome treatment. Interestingly,?echistatin?(from?Echis carinatus) has anti-cancer properties in human ovarian, glioma, and prostate cancer. Integrilin? (Eptifibatide) is another antiplatelet drug that inhibits glycoprotein IIb/IIIa. Derived from disintegrin protein in southeastern pygmy rattlesnake venom, eptifibatide is a cyclic heptapeptide used to decrease the risk of acute cardiac ischemic events.?
Sarafotoxins
Sarafotoxins (SRTXs) are a selection of toxins taken from the venom of Atractaspis engaddensis?and exist as different substances, namely?SRTX-a, SRTX-b, and SRTX-c.?Due to their structural and functional homology to the endothelin peptides?(ET), Sarafotoxins can enhance vasoconstriction by stimulating the class A G-protein-coupled endothelin ETA and ETB receptors. This, in turn, leads to left ventricular dysfunction and bronchoconstriction. As the most potent sarafotoxin, sarafotoxin S6b binds to both ETA and ETB receptors with a similar affinity to endothelin-1 (ET-1). This is evident as when given to mice intravenously, sarafotoxin S6b caused cardiac arrest and death in mice almost immediately. Another characteristic of S6b is its matrix metalloproteinase inhibitory activity due to it exhibiting a fold found in the core region of tissue inhibitors of metalloproteinases (TIMPs). Sarafotoxin S6b can be used as a pharmacological reagent to study the interactions of endothelins and their corresponding receptors.?
Compared to the sarafotoxin isopeptide S6b, sarafotoxin S6c is less toxic, with a 100 to 10,000-fold reduced affinity for the ETA receptor. It, therefore, acts as a selective agonist to the ETB receptor. One study demonstrated that when sarafotoxin 6c was used to activate ETB receptors in rats, arterial pressure increased, known as S6c-induced hypertension. As the upregulation of ET-1?is related to circulatory-system diseases, the interaction between ET-1 and its receptors is highly important for developing endothelin receptor antagonist treatments. Sarafotoxins can be used as a pharmacological reagent to study these interactions. As part of our catalog, Biosynth offers other?sarafotoxin isopeptides such as Sarafotoxin A,?Sarafotoxin B,?Sarafotoxin C,?Sarafotoxin S6d, and?Sarafotoxin S6a1.
Other snake venom-derived products available at Biosynth are:
Toxins sourced from the Black Mamba, Dendroaspis polylepis
Sourced from the Green Mamba, Dendroaspis angusticeps
Sourced from C. durissus terrificus snake venom
Crotamine When used in nanosystems such as gold NPs (PEG linker), they are used in anti-cancer and cellular imaging.
How can bee venom contribute to therapeutics?
Honey bees, although tiny, contribute significantly to the human population, with 'a third of our food... produced directly or indirectly by honeybees' (Bava, 2023). Recent studies on bee venom have also found it has many therapeutic properties, such as antimicrobial, anti-inflammatory, antioxidant, and radioprotective properties. Even since 3000 BC, bee venom has been used as an inflammatory illness treatment in traditional Eastern medicine. Hippocrates, the 'father of medicine', wielded the power of bee venom to treat arthritis. Now, bee venom is known to be important in therapeutics, treating asthma, infectious diseases like malaria, and neurological disorders, and even in veterinary medicine.?
Melittin
Melittin?is a peptide and one of the most abundant elements found in honey bee venom (Apis mellifera). It exhibits anti-inflammatory, anti-cancer, antiviral, antibacterial, and neuroprotective properties. One key feature of melittin's therapeutic properties is the ability to damage cell membranes by integrating into the phospholipid bilayer. This ultimately changes the phospholipid composition, leading to cell lysis. Nanobiotechnology is used because many of these molecules found in venom have low bioavailability or stability in in vivo treatments or biological media. This helps protect and target these molecules to their pharmacological destination, improving their activity and effectiveness. Melittin is one such example. It can be used in liposome nanotechnology, which is tested in anti-hepatocellular carcinoma activity and the prevention of metastatic lesions.
Apamin
Another component of bee venom is apamin. One of the smallest neurotoxins in bee venom, apamin is an allosteric inhibitor and a selective?small-conductance Ca2+-activated?K+?channel blocker. As these channels are responsible for resting action potentials and neuronal signal transmission, their inhibition by apamin results in long-term afterhyperpolarization in muscle cells and neurons. Apamin can also affect the central nervous system, as demonstrated in rats, where it has neurotoxic effects that cause convulsions and hyperactivity. However, this bee venom component has potential as an atherosclerosis treatment, in that it can prevent the proliferation and migration of vascular smooth muscle cells, through Erk and Akt signaling pathways.
Other components found in bee venom
Toxins found in scorpion venom
Humans have quite rightly labeled scorpions as 'dangerous', with scorpion stings having the ability to cause pain, inflammation, and even death. Neurotoxins?in the scorpion venom can block targeted ion channels, resulting in autonomic excitation. Those stung by a scorpion could be subjected to?arrhythmia, unconsciousness,?heart failure, pulmonary edema, and death. On the other hand, scorpion venom is another natural venom carrying a whole host of molecules with therapeutic potential. It is home to peptides with a range of antimicrobial activities (possible candidates in antimicrobial drug development) and components with the potential as anti-cancer drugs. Below are some scorpion venom components available at Biosynth.
Chlorotoxin?- A synthetic scorpion toxin sourced from the scorpion, Leiurus quinquestriatus. It has the potential application as a small-conductance Cl-channel blocker. Research has shown that this toxin preferentially binds to glioma cells rather than normal brain cells and non-neoplastic cells and, therefore, may benefit cancer diagnostics and therapeutics.
Martentoxin I?- A?synthetic scorpion toxin sourced from the?Scorpion, Buthus martensi.
HsTX1 - A peptide toxin with a sequence derived from the scorpion, Heterometrus spinifer, which blocks the Kv1.3 potassium channel.?
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Kaliotoxin?- A synthetic scorpion toxin (derived from the Androctonus mauretanicus?scorpion) can be used as a high conductance Ca2+ activated K+ channel blocker.
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Kurtoxin?- A synthetic scorpion toxin from Parabuthus transvaalicus can be applied as a?T-type Ca2+ channel blocker.?
Tityustoxin Ka?- A synthetic scorpion toxin sourced from the Scorpion, Tityus serrulatus. This product is a voltage-dependent K+ channel (A channel) blocker.
Peptide T?- Displays?bradykinin-potentiating activities. For example, in a rat model, it increased the depressor effect of bradykinin on arterial blood pressure.
See also our scorpion toxins?Imperatoxin A?and?Agitoxin 2.
Spider venom's important clinical and pharmacological role
Spider venom is another crucial factor in clinical pharmacology and therapeutics. Take, for example, the Fraser Island funnel-web spider found in Australia. This spider provides a venom-derived drug containing a protein called HiLA that can stop cell death after a heart attack. It does this by preventing heart cells from sensing acid. If successful in clinical trials, it could be used by emergency medical workers and could help reduce the damage caused by heart attacks. Some more examples of spider toxins are listed below.
Purotoxin-1? Synthetic Purotoxin-1 peptide sourced from the Wolf Spider Geolycosa species. During studies, Purotoxin-1 has been found to operate within the sensory neurons, showing antinociceptive properties in its inhibition of P2X3 Purinoreceptors. P2X3 receptors, which act as ATP-gated cation channels, are located primarily within the nociceptive system in some epithelial cells, small-diameter sensory neurons, taste buds, enteric neurons, and carotid body afferent neurons. Their detection of noxious stimuli and pain sensation has made P2X3 receptors, alongside Purotoxin-1 (as a manipulative tool of purinoreceptors), a therapeutic interest for research into pain and visceral sensory function disorder treatments.
Guangxitoxin-1E? Guangxitoxin-1E is a tarantula spider toxin sourced from the tarantula, Plesiophrictus guangxiensis. It can be used as a Kv2.1/Kv2.2 channel blocker and an enhancer of glucose-dependent insulin secretion. Guangxitoxin-1E, in particular, has a high affinity for the Kv2.1 channel and binds to a voltage-sensing motif located on Kv2.1. Its inhibitory activity towards Kv2 channels allows the mechanisms of these channels to be researched. Additionally, it can act as a scaffold for fluorescent probes, allowing the localization and function of Kv2 channels to be further understood.
Huwentoxin- IV -?This product's sequence was?originally discovered from the venom of the Chinese bird spider, Selenocosmia huwena, and is sourced from the Chinese bird spider, Ornithoctonus huwena. It can be used as a neuronal tetrodotoxin-sensitive Na+- channel blocker.
See our full range of spider toxins in our catalog.
Reptiles
Exenatide?– Peptide taken from Heloderma suspectum (Gila monster) and can be applied to glycemic modulation when used in a nanosystem such as mesoporous silica NPs. It can also be used for the treatment of Type 2 diabetes.
Alyteserin-1c –?Peptide is found in the venom of the common midwife toad (Alytes obstetricans), which can be used in a polymer-coated liposomes nanosystem and has antibacterial activity against Listeria monocytogenes.
Cone snail
Conotoxins are a diverse group of peptides found in the venom of cone snails (genus Conus). These small peptides have evolved to target specific receptors and ion channels in the nervous systems of prey animals, allowing cone snails to immobilize or kill their prey. Conotoxins have attracted significant interest from scientists due to their potential applications in therapeutics, diagnostics, neuroscience, and research. They have been studied for their ability to block or modulate various receptors and ion channels involved in pain transmission, making them promising candidates for developing new pain medications. Additionally, conotoxins have shown potential in other areas, such as neurological disorders and cancer research.
Discover Biosynth's range of conotoxins sourced from cone snails.?
The pharmacological properties of venoms and toxins make them indispensable in drug discovery and development, providing potential treatments for various human health conditions. From pain relief to hypertension to diabetes, these natural pharmacologically active compounds contribute significantly to therapeutics, diagnostics, and research. Explore Biosynth's collection of venoms and toxins,?complemented by our outstanding?custom peptide synthesis services.?Our experts can synthesize your peptide tailored to specific applications on a large scale and at GMP. Use our peptide quotation tool or contact our team for more information.
References
Bava, R., Castagna, F., Musella, V., Lupia, C., Palma, E., Britti, D. (2023). Therapeutic Use of Bee Venom and Potential Applications in Veterinary Medicine. Veterinary Science, 10(2): 119.
Bordon, K. C. F., Cologna, C. T., Fornari-Baldo, E. C., Pinheiro-Júnior, E. L., Cerni, F. A., Amorim, F. G., Anjolette, F. A. O., Cordeiro, F. A., Wiezel, G. A., Cardoso, L. A., Ferreira, I. G., Sousa de Oliveira, I., Boldrini-Fran?a, J., Pucca, M. B., Baldo, M. A., Arantes, E. C. (2020). From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery. Frontiers in Pharmacology, 11: 1132.
Ca?as, C. A., Casta?o-Valencia, S., Castro-Herrera, F., Ca?as, F., Tobón, G. J. (2021). Biomedical applications of snake venom: from basic science to autoimmunity and rheumatology. Journal of Translational Autoimmunity, 4, 100076.
El-Aziz, T. M. A., Soares, A. G., Stockand, J. D. (2019). Snake Venoms in Drug Discovery: Valuable Therapeutic Tools for Life-Saving. Toxins (Basel). 11(10): 564.
Greener, M. (2020). The next generation of venom-based drugs. Prescriber.
Hawgood, B. J. (1995). Abbé Felice Fontana (1730-1805): founder of modern toxinology. Toxicon. 33(5), 591-601.
Oliveira, A. L., Viegas, F. M., da Silva, S. L., Soares, A. M., Ramos, M. J., Fernandes, P. A. (2022). The chemistry of snake venom and its medicinal potential. Nature Reviews Chemistry, 6, 451-469.
Ortiz, E., Gurrola, G. B., Schwartz, E. F., Possani, L. D. (2015). Scorpion venom components as potential candidates for drug development. Toxicon. 93: 125-135.
Robbins, J. (2022). Deadly Venom From Spiders and Snakes May Also Cure What Ails You. The New York Times. https://www.nytimes.com/2022/05/03/science/venom-medicines.html
Roque-Borda, C. A., de Lima Gualque, M. W., da Fonseca, F. H., Pavan, F. R., Santos-Filho, N. A. (2022). Nanobiotechnology with Therapeutically Relevant Macromolecules from Animal Venoms: Venoms, Toxins, and Antimicrobial Peptides. Pharmaceutics, 14(5): 891.