An analgesic preparation containing cobratide and oxycodone for cancer-related pain CN and a keluoqu tablet preparation method using tramadol hydrochloride, ibuprofen and cobratide also known as ketongning and cobrotoxin CN have been patented.
The anti-nociceptive effects of cobrotoxin the N. RPIM has 71 amino acid residues with five disulfide bonds and completed phase I of clinical trials for multiple sclerosis, while RPI-MN presents 62 amino acid residues and four disulfide bonds King, Both molecules show analgesic applications and present the nAChRs as molecular target Chan et al. Although RPI-MN is parenterally administered via subcutaneous injection, RPIM can be orally administered, since its absorption through the oral mucosa occurs when it is formulated with benzalkonium chloride Reid and Raymond, Chemical modifications that detoxify these molecules can alter their affinity to nAChRs.
They may include their oxidation with ozone, formate also known as methanoate and hydrogen peroxide, being the latter more adopted Reid, However, its mechanism of action has not been elucidated yet Reid and Raymond, Crotamine, a highly cationic and cysteine-rich CPP from C. This toxin is specifically uptaken by actively proliferating cells, being able to permeate several lineages in vitro Nascimento et al.
Additionally, several molecules based on crotamine structure, including fluorescent derivatives Tansi et al. Crotamine and its analogues have been tested in healthy and tumorous cell lines, and the results indicate they can be used as selective delivery tools of anticancer molecules Mambelli-Lisboa et al. Another component isolated from C. It acts at peripheral opioid receptors Gutierrez et al. The potent and long lasting opioid-mediated antinociception of crotalphine has been evaluated in cancer pain Brigatte et al.
This toxin strongly attenuates brain damage after stroke and could be used to protect the brain from ischemic injury Chassagnon et al. Purotoxin-1 PT1 , obtained from the central Asian spider Geolycosa sp. Characterized as a specific antagonist of P2X3 purinergic receptor, which is the most-studied subtype of P2X receptor related to pain, PT1 was able to inhibit nociceptive effect in different rat pain models Grishin et al. Phoneutria nigriventer the armed spider presents different toxins with potential pharmaceutical application and under preclinical tests Peigneur et al.
Interestingly, a minimum dose of 0. PnPP is a promising candidate for erectile dysfunction treatment in patients that do not respond to the usual therapies Silva et al. Biozeus Biopharmaceutical S. A performed pilot tests with the topical peptide renamed BZ on healthy human beings and has been performing a pilot test with voluntary men with erectile dysfunction associated to hypertension or diabetes.
The regulatory toxicological preclinical tests have already started. Tetrodotoxin TTX , a guanidinium neurotoxin with high affinity for voltage-gated sodium Na v channels, had traditionally been known for many years as the main toxin from Tetraodontidae pufferfish Lago et al.
However, the toxin was present not only in other marine animals such as octopuses, gobies and sea stars, but also in phylogenetically unrelated terrestrial and aquatic organisms, including a dinoflagellate Alexandrium tamarense , red calcareous algae, arthropods, echinoderms, molluscs, worms, newts, frogs, and bacteria Actinomyces , Aeromonas , Alteromonas , Bacillus and Pseudomonas Lago et al. TTX has been used for the development of analgesic and anesthetic drugs Assuncao et al.
The salivary secretion from different animals, such as bats, leeches, lizards, shrews and ticks are considered important sources of biologically active compounds. Other animals, such as caterpillars, have biologically active compounds in their bristles. Many of these compounds are still underexploited, lacking information on their chemical structure, physiological role and therapeutic application.
Thus, the study of these compounds increases the chances of discovering new compounds with great pharmaceutical potential. The subsections Bats to Ticks will address some potential therapeutic molecules found in the saliva or bristles of these animals.
A phase III randomized study in participants with acute ischemic stroke was completed in Currently, there is no drug based on desmoteplase available for commercialization. Caterpillars from different South American countries, such as Venezuela, Brazil, French Guyana, Peru, Paraguay, Argentina and Colombia, are responsible for a severe bleeding syndrome in humans who touch their bristles Arocha-Pinango and Guerrero, Lonomia obliqua is the main species of caterpillar found in Southern Brazil and its venom is comprised of molecules with antiviral, procoagulant, fibrinolytic and wound healing activities Veiga et al.
Some compounds with potential therapeutic applications were identified in Lonomia sp, e. Lonofibrase , protease inhibitors, serpins, lipocalins, and lectins Veiga et al. Currently, there are three clinical studies on caterpillars recorded at the Clinical Trials website US National Library of Medicine, However, these studies are related to their use as a source of protein in the diet and none of them involves the genus Lonomia.
Two phase II randomized studies involving leech therapy in NCT and 60 participants NCT with knee osteoarthritis were completed in and , respectively. Additional information on FDA-approved hirudin analogues from H. Exenatide is the synthetic version of the native peptide exendin-4 isolated from the saliva of Gila monster lizard H. According to the Clinical Trials website, there are more than clinical studies about exenatide. So far, there are completed studies, 12 terminated, 25 whose status has not changed for 2 years, 47 recruiting volunteers, 11 that are not yet recruiting, and three enrolled by invitation.
For an extensive review regarding clinical trials involving this drug, please see Odegard and Desantis, ; Bhavsar et al. It is comprised of 13 amino acids derived from the C-terminal region of the paralytic peptide soricidin UniProtKB—P0C2P6 , from the submaxillary and sublingual salivary glands of the Northern Short-tailed shrew Blarina brevicauda Bowen et al. A phase I of study NCT in 23 advanced cancer patients with TRPV6 channel overexpression was completed in and a phase I study NCT started recruiting patients with advanced refractory solid tumors in There are several studies addressing the importance of tick saliva components.
The use of evasins in the treatment of heart diseases, such as myocarditis Singh et al. However, although tick saliva contains many components with therapeutic and biotechnological potentials, there are neither clinical studies involving the use of substances isolated from tick saliva nor drugs available for therapeutic purposes.
The clinical studies currently registered on the Clinical Trial website in respect to ticks are related to the development of vaccines against ticks or the use of different antibiotics in Lyme disease.
Animal poisons and venoms are comprised of a cocktail of bioactive components with a gamut of different activities. Company pipelines worldwide are expanding the number of peptide-based products currently in development mainly because of the diversity of their application and activity. To overcome these limitations, the main options are the chemical synthesis of peptides and the production of biopharmaceuticals via heterologous expression using biotechnological tools.
The industry has focused on heterologous expression systems as an interesting alternative for manufacturing biopharmaceuticals of high molecular mass Merlin et al.
Recombinant protein production processes require extensive design and regulatory control before therapeutic products become commercially available. Regarding heterologous expression, the accurate cysteine bond formation and the proper incorporation of post-translational modifications remain a challenge, and new technologies to assess and mitigate immunogenicity risk of engineered proteins are becoming more common. Therefore, a special attempt should be made to ensure that the recombinant protein presents comparable three-dimensional folding and consistent pharmacological properties when compared to its corresponding native form.
Native chemoselective reaction has been employed in the production of animal toxins with potential therapeutic application, such as mambalgin-2, a amino acid analgesic peptide from three-finger toxins family, from Dendroaspis polylepis polylepis venom Diochot et al.
This approach allows the synthesis of large proteins, since it is based in the production of different unprotected linear peptide fragments, which are condensed in solution via chemoselective reactions to originate the entire polypeptide Kent et al. Studies to improve the protecting groups, resins, linkers, and activation and coupling reagents may enable the manufacture of larger peptides and even small proteins for therapeutic applications. However, the development of cheaper reagents and methods for the synthesis and purification of peptides are necessary.
Concerning the limitations of peptides in terms of their biopharmaceutical properties, designed approaches that will find molecules with intrinsically more favorable properties will need to be devised. As mentioned earlier in section Achievements With Animal Toxin-Based Molecules , the drug design of captopril made oral administration possible. Additionally, designed cationicity-enhanced analogues of natural antimicrobial peptides have exhibited higher potency and spectra of antimicrobial activity Luna-Ramirez et al.
Achievements towards successful oral delivery of proteins and peptides by protecting them against degradation and increasing their absorption remain as an active area of research. Regarding toxin-based formulations, intranasal inoculation of hyaluronidase from T. Some approaches to improve biopharmaceuticals delivery, such as alternative delivery routes, PEGylation and conjugation to nano carriers, represent a relevant step towards targeted delivery of toxin-based drugs.
It is sobering to realize how little alternative delivery routes and bioconjugation strategies have been exploited to deliver toxin-based drugs, suggesting that studies on routes of distribution, delivery vehicles, cargo molecules, and targeting strategies are fruitful fields for future research.
Collinein-1, a thrombin-like serine protease from C. The PEGylated peptide HsTX1[R14A] from Heterometrus spinnifer scorpion venom showed higher plasma circulating half-life in rodents compared to the native peptide, which resulted in sustained efficacy in rodent models of multiple sclerosis and rheumatoid arthritis Tanner et al.
In the drug development process, formulation patents using advanced drug release systems extend the market exclusivity of drugs, because of the high technical barrier to be overcome by generic manufacturers after the expiration of patents.
Focusing on competitiveness, pharmaceutical companies have established strategic partnerships with leading academic institutions that have deep scientific expertise in novel concepts in the main areas of biology or chemistry. Some reports have shown the antitumor potential, among other applications, of animal venoms or their toxins conjugated with a wide variety of nanomaterials, such as silica, gold, chitosan, poly D,L-Lactide -based, and supermagnetic iron oxide nanoparticles Badr et al. Studies on cell penetrating peptides CPPs have open unprecedented possibilities for vector applications in several fields, such as basic research, therapeutics, technology, and medical imaging.
WaTx, a cell-penetrating toxin from the Australian black rock scorpion U. Another field in ever-growing demand is the cosmeceutical industry, especially in Asia, where Korea is at the forefront of cosmeceutical development. Animal poisons and venoms are rich sources of molecules with a wide range of applications.
However, to make the use of these molecules feasible, extensive preclinical trials are necessary, with some applications also requiring clinical trials Figure 2.
Figure 2 Animal poisons and venoms as sources of candidate molecules for wide-ranging applications, after extensive characterization during preclinical and clinical trials. Although the research in the field of toxinology tends to be quite challenging and time-consuming, the high selectivity of animal toxins for their targets turns them into promising leads for the development of effective therapeutic drugs.
Studies on new engineered molecules with reduced side effects can be reached by untangling the interaction of venom peptides with their target. Therefore, we are still at a beginning phase in comprehending the complexity of animal venoms and poisons.
While very few species have been extensively studied, we still have thousands of unexploited organisms, especially marine ones. Novel methods to produce and deliver biopharmaceuticals are expected to be developed in the near future. With that in mind, we can get a glimpse of how much work on toxinology and drug discovery is yet to come in the next years.
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That venom is now by definition a poison, because it is absorbed rather than injected through a wound,' explains Ronald. But the deadly nature of this cephalopod comes from tetrodotoxin, a poison acquired from bacteria that live in various places in the body, including venom glands.
Tetrodotoxin can act as either a poison if a predator eats the octopus, or as venom if injected through a bite. The blue-ringed octopus steals tetrodotoxin from bacteria living on and in its body, making it venomous and poisonous. This technique is also used by other animals, including some newts, flatworms and arrow worms. Not all venoms and poisons are fatal to humans.
An envenomation can just be painful, as the substances may be being used as a deterrent. The bullet ant is regarded as having the most painful sting of all insects. The pain can last up to 24 hours, but a human victim is likely to walk away otherwise unharmed.
Bees and wasps can both provide an uncomfortable sting, but for the most part, neither is deadly - except in cases of anaphylactic shock, an extreme allergic reaction to the venom. Similarly, some poisons will cause swelling, nausea or other unpleasant side effects if the toxins are absorbed.
Some animals are so frequently at risk from venom and poison that they have developed a total resistance to them. Meerkats prey mainly on insects but are also known to feast on lizards, snakes and spiders. Because of their varied diet, they tend to come up against some venomous bites and stings. Meerkats are part of the mongoose family Herpestidae , several members of which have evolved resistance to venom.
This means they can freely hunt venomous prey with limited risk. Almost all animals have receptors that transmit chemical messages around the body. Venom works by binding itself to these receptors, blocking vital impulse conduction pathways that allow the body to function normally, such as nerve-muscle communication. Animals that have developed venom resistance have evolved mechanisms to stop the toxins from binding to the receptors. This results in an animal that can withstand venom with little or no side effect.
If you have to choose between being bit by a venomous snake or touching a poisonous frog, you might want to go with the snake. As it turns out, snakes don't always inject venom when they bite: Some 20 percent or more of bites from venomous snakes are "dry bites" that create a wound but don't include venom. Poisonous animals can't choose when to apply their toxins. But what would happen if you drank venom rather than having it injected?
While there have not been many people willing to submit to this experiment, it is theoretically possible to swallow venom and not notice any effects unless of course you had cuts in your mouth, in which case it could enter your bloodstream. This is because the acids in your stomach would break down the venom like any other protein before it could reach your bloodstream—at least, that's the theory. Venom What's the difference? Poison vs.
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