Between a Stonefish and a hard place
Stonefish (Genus: Synanceia) are notorious for their venomous dorsal spines and their unique camouflage that gives them a mottled color similar to sea rocks, hence their name. Stonefish (like the majority of venomous fish) use their toxins for defensive purposes. A particular toxin known as stonustoxin (SNTX) is a potent component of the venom and can lead to cardiovascular collapse in any potential predators, including humans.
Recent research has identified that in fact SNTX is an ancient relative of the human immune protein Perforin. In humans, Perforin is used to destroy virally infected and cancerous cells. Perforin attaches to diseased cells and creates a formation of pores on the cell surface membrane. Once these pores are formed, toxins can enter the cell and destroy it from the inside. Excessive Perforin activity in humans however can lead to a rejection of bone marrow transplants in leukemia treatments among many other medical problems.
Until recently, the mechanisms of Perforin pore formations were a mystery to science, but the analysis of SNTX has revealed key aspects of the pore formation. Understanding of its mechanism has lead researchers on the pursuit to develop Perforin inhibitors to act as immunosuppressants to improve the success rates of transplants.
(Last updated 17/03/16)
Ellisdon, A. M., Reboul, C. F., Panjikar, S., Huynh, K., Oellig, C. A., Winter, K. L., Dunstone, M. A., Hodgson, W. C., Seymour, J., Dearden, P. K., Tweten, R. K., Whisstock, J. C. & McGowan, S. (2015) Stonefish toxin defines an ancient branch of the perforin-like superfamily. Proc. Nat. Acad. Sci. 112(50). 15360-15365.
How to stop yourself bleeding to death in 6 seconds
A nanofiber hydrogel infused with Batroxobin (an isolated toxin produced by Bothrops atrox and Bothrops moojeni), has been developed to halt excessive bleeding and very quickly. Although, technically this is not a ‘drug’, it is still a significant medical advancement using venom toxins.
The venom hydrogel is named SB50, which is injected into a wound as a liquid, wherein it transforms into gel to aid clotting rapidly within 6 seconds. Batroxobin is a class of haemotoxins that has various coagulant properties, and when infused with the nanofiber hydrogel, it keeps it coagulant properties, even in the presence of anti-coagulant drugs such as heparin. This is an important find as it can still allow for wounds to clot even in patients with medical conditions that require them taking heparin.
The Batroxobin is not directly isolated from the South American pit vipers, they are synthetically created using bacteria, this avoids contamination from other toxins within the snake venoms when purified. SB50 has also been subject to comparable testing against other clinical clotting gels and Batroxobin itself, by where SB50 outperformed them all.
The potential for SB50 as both, a casual gel for small cuts and wounds to a surgical gel; rapidly stopping internal bleeding during operations and surgery, is something in which is needed as a pharmaceutical product. Although still in its research infancy, SB50 has great promise, but could still be years away from FDA approval.
(Last updated 26/10/15)
Kumar, V. A., Wickremasinghe, N. C., Shi, S. & Hartgerink, J. D. (2015). Nanofibrous Snake Venom Hemostat. ACS Biomater. Sci. Eng. DOI:10.1021/ascbiomaterials.5b00356.
An Insomniacs best friend
We have already spoke about how deadly the infamous Cone Snail venom actually is and how their venom is a ‘gold mine’ for therapeutic peptides. New research on the venom peptides of Conus araneosus (Cob web cone snail) – an endemic cone snail to the coastal regions southeast of India and Sri Lanka, showed highly selective sleep-inducing properties. The isolated peptides were injected into mice, initially putting them asleep for two hours. When the dosage was increased (x2.5) it allowed the mice to fall asleep for even longer, up to 5 hours.
The impact of this research could have profound therapeutic uses for many sleeping disorders such as insomnia, sleep apnea, delayed sleep phase disorder (DSPD) etc. The next stage of the research is to understand the biological mechanisms of the sleep-inducing peptides, and how they can potentially be used in drugs development.
From an evolutionary perspective, it is clear as to why these peptides have evolved based on the molluscs prey items. Fast moving fish is a main food source, and the sluggish (no pun intended) speed of cone snails means that fast swimming prey need to be immobilised within seconds before they escape and become some other predators lunch.
These sleep-inducing peptides are the first peptides of this type isolated from cone snail toxins, and therefore extend the current knowledge and resourcefulness of molluscivorous venoms.
(Last updated 26/10/15)
Franklin, J. B. & Rajesh, R. P. (2015). A sleep-inducing peptide from the venom of the Indian cone snail Conus araneosus. Toxicon. 103, 39-47.
No drugs for the arachnophobes
Strokes & Brain damage
Strokes are caused by a blockage on the brain resulting in a deprivation of O2 to brain cells, ensuing cell death and brain damage. Under these circumstances a neurotransmitter is released called Glutamate in large concentrations, which ultimately also causes death to neighboring cells. Hololena curta (Funnel-web spider) contains neurotoxic venom, with an identified active agent, named HF-7, which has been found to block nerve cell receptors that prevent glutamate production. There is ongoing research into using HF-7 as a pharmaceutical to limit damage to brain cells in stroke victims, and other illnesses caused by O2 deprivation to the brain.
The Chilean Rose tarantula (Grammostola rosea) is most widely known as a popular docile pet for many exotic pet keepers. However, an active compound in the spider’s venom (GsMtx-4) has been isolated and currently being researched to potentially aid in controlling Atrial Fibrillation (AF). AF is a heart condition that causes fast and abnormal heart rates, leading the upper chambers of the heart (atria) to contract rapidly, preventing blood from entering the lower chambers (ventricles). Stretch activated ion channels control the muscle contraction and co-ordination of the heartbeat. When these ion channels open (during a heart attack) there is an influx of chemicals which interfere with the hearts rhythm leading to AF. GsMtx-4 blocks these stretch activated ion channels, returning the heart to a normal rhythm, and GsMtx-4 is ineffective to unstretched ion channels, therefore there are no side effects to normal hearts. This makes the novel compound a prime candidate as a potential pharmaceutical.
Erectile dysfunction (ED) affects approx. 40% of men at some stage in their life, and there are currently a plethora of drugs that already deal with this problem. So why are we still searching for new drugs to deal with this problem? Well, the current drugs such as sildenafil (Viagra®), tadalafil (Cialis®) and vardenafil (Levitra®) are not without their side effects such as headaches, flushing, dyspepsia, nasal congestion, impaired and blurred vision. This is were one of the deadliest spiders known to man comes into the equation; the Brazilian wandering spider (Phoneutria nigriventer). When P. nigriventer bites a male human it was noticed that along with shortness of breath, excessive salivation, tremors, paralysis, asphyxiation and death, the males have an uncontrolled penile erection. This has lead researchers to actively seek out the toxin that causes this effect, and they found δ-ctenitoxin-Pn2a (δ-CNTX-Pn2a; Tx2-6) was the culprit. The compound was tested on mice, resulting in mice with ED (Who knew even mice could even have ED) being able to attain an erect penis with no side effects. Thus up to now, δ-ctenitoxin-Pn2a has all the desired traits for a perfect drug that could potentially see some of the old drugs being blown off the market.
Do spiders hold the cure for chronic pain? Well researchers in Australia think they might just hold the key. 205 species of spiders had their venoms analysed, resulting in 40% of species having some form of peptide in which contained pain blocking affects. The venoms were then thoroughly scrutinised and there were seven novel peptides identified with promising hNav1.7 inhibition (refer to ‘pain therapeutics’ section for what hNav1.7 is and why it is important in chronic pain therapeutics).
The peptide Hd1a from the venom of Borneo orange-fringed tarantula (Haplopelma doriae), was the most promising peptide out of the seven. Its stability, potency and high level of selectivity to inhibit hNav1.7 make it an ideal candidate for a potential chronic pain therapeutic.
Aside from the discovery of these novel peptides, the overall important result of the research is how promising spider venoms may be in drugs development. Only 205 species of spider venoms were analysed in this study, however there are around ~45000 species known to science. The potential catalogue of peptides is remarkable, and as previously shown, there are many other diseases and conditions that have the potential to be cured by spider venom peptides.
(Last updated 06/05/15)
Andrade, E., Villanova, F., Borra, P., Leite, K., Troncone, L., Cortez, I., Messina, L., Paranhos, M., Claro, J. & Srougi, M. (2008) Penile erection induced in vivo by a purified toxin from the Brazilian spider Phoneutria nigriventer. BJU Int. 102, 835–837.
Cordeiro, M. N., Diniz, C. R., Valentim, A. C., von Eickstedt, V. R. D., Gilroy, J. & Richardson, M. (1992). The purification and amino acid sequences of four Tx2 neurotoxins from the venom of the Brazilian ‘armed’ spider Phoneutria nigriventer. FEBS Lett. 310, 153–156.
Escoubas, P., Diochot, S. & Corzo, G. (2000). Structure and pharmacology of spider venom neurotoxins. Biochimie. 82 (10), 893-907.
Klint, J. K., Smith, J. J., Vetter, I., Rupasinghe, D. B., Er, Y. S., Senff, S., Herzig, V., Mobil, M., Lewis, R. J., Bosmans, F. & King, G. F. (2015). Seven novel modulators of the analgesic target Nav1.7 uncovered using a high-throughput venom-based discovery approach. Brit. Jour. of Pharm. 172 (10), 2445-2458.
McCormick, J., Li, Y., McCormick, K., Duynstee, H. I., van Engen, A. K., van der Marel, G. A., Ganem, B., van Boom., J. H. & Mainwald, J. (1999). Structure and Total Synthesis of HF-7, a Neuroactive Glyconucleoside Disulfiate from the Funnel-Web Spider Hololena curta. Jour. Amer. Chem. Soc. 121 (21), 5661-5665.
Nunes, K. P., Costa-Goncalves, A., Lanza, L. F., Cortes, S. F., Cordeiro, M. N., Richardson, M., Pimenta, A. M., Webb, R. C., Leite, R. & De Lima, M. E. (2008). Tx2-6 toxin of the Phoneutria nigriventer spider potentiates rat erectile function. Toxicon 2008, 51, 1197–1206.
Oswald, R.E., Suchyna, T.M., McFeeters, R., Gottlieb, P. & Sachs, F. (2002) Solution structure of peptide toxins that block mechanosensitive ion channels. J. Biol. Chem. 277, 34443–34450.
Saez, N. J., Senff, S., Jensen, J. E., Er, S. Y., Herzig, V., Rash, L. D. & King, G. F. (2010). Spider-Venom Peptides as Theraputics. Toxins. 2, 2851-2871.
Schouten, B. W., Bohnen, A. M., Groeneveld, F. P., Dohle, G. R., Thomas, S. & Bosch, J. L. (2010). Erectile dysfunction in the community: trends over time in incidence, prevalence, GP consultation and medication use—the Krimpen study: trends in ED. J. Sex. Med. 7 (7), 2547–53.
Suchyna, T. M., Johnson, J. H., Hamer, K., Leykam, J. F., Gage, D. A., Clemo, H. F., Baumgarten, C. M. & Sachs, F. (2000). Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation-selective stretch-activated channels. J. Gen. Physiol. 115, 583–598.
Mental disorders cured by a worm?
Schizophrenia is a mental disorder that can cause abnormal social behavior and/ or a failure to recognise the difference between reality and hallucinations etc. The disease is thought to be caused by dysfunctional NMDA-glutamate receptors that play an important role in cellular plasticity, learning and memory processes within the brain. NDMA receptors are found on dendrites of the cortical and hippocampal neurons and produce excitatory postsynaptic effects which make them highly permeable to calcium (Ca2+). Therefore, dysfunctional NMDA receptors reduce Ca2+ influx and signalling in these dendrites, which ultimately brings about the known symptoms of schizophrenia.
Understanding what causes schizophrenia; scientists have spent years developing a model drug which has the potential to aid in alleviating the symptoms of this mental disorder. The novel drug developed is called GTS-21, which has been developed from the toxins of the marine nemertean Amphiporus angulatus. GTS-21 binds to Nicotinic α7 acetylcholine receptors (α7-nAChRs), which are located on glutamate neurons and are involved in the regulation of neurotransmitter release. One of the neurotransmitters that α7-nAChRs receptors release is Ca2+. Thus activation of α7-nAChRs receptors enhances Ca2+ influx, potentially restoring the dysfunctional system affected by NMDA receptor suppression.
Studies have tested the effects of GTS-21 on model organisms as rats and rhesus monkeys, resulting in an improvement in cognitive impairment. Human trials of GTS-21 are still currently in progress, and are in phase 3 (Final confirmation of safety and efficacy), which could potentially see this drug being available for market in the not so distant future.
However, GTS-21 is not just a one trick pony, there have been developments by which the drug could also be used to aid in Alzheimer’s disease and nicotine dependence. So keep your eyes peeled for this potential wonder drug, developed from a nemertean, that most people wouldn’t even notice lying on the Atlantic shores of North America to Greenland.
(Last updated 03/09/14)
Briggs, C. A., Anderson, D. J., Brioni, J. D., Buccafusco, J. J., Buckley, M. J., Campbell, J. E., Decker, M. W., Donnelly-Roberts, D., Elliott, R. L., Gopalakrishnan, M., Holladay, M. W., Hui, Y. H., Jackson, W. J., Kim, D. J., Marsh, K. C., O’Neill, A., Prendergast, M. A., Ryther, K. B., Sullivan, J. P. & Arneric, S. P. (1997). Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo. Pharmacology, Biochem. & Behav. 57(1), 231-41.
Callahan, P. M., Terry Jr, A. V. & Tehim, A. (2014). Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDA-glutamatergic receptor related deficits in
sensorimotor gating and recognition memory in rats. Psychopharma. 231, 3695-3706.
Cannon, C. E., Puri, V., Vivian, J. A., Egbertson, M. S., Eddins. D. & Uslaner, J. M. (2013). The nicotinic α7 receptor agonist GTS-21 improves cognitive performance in ketamine impaired rhesus monkeys. Neuropharma. 64, 191-196.
Mayer, A. M. S., Glaser, K. B., Cuevas, C., Jacobs, R. S., Kem, W., Little, D. R., McIntosh, M. J., Newman, D. J., Potts, B. C. & Shuster, D. E. (2010). The odyssey of marine pharmaceuticals: a current pipeline perspective. Cell. 31 (6), 255-265.
Zawieja, P., Kornprobst, J. M. & Métias, P. (2012). 3-(2,4-Dimethoxybenzylidene)-anabasine: A promising candidate drug for Alziemer’s disease?. Geriatr. Gerontol. Int. 12, 365-371.
Fighting cancer with a sting!
Cancer is a disease that every one of us fears, just the word is enough to strike distress into a person. Approximately 7.6 million people worldwide die from cancer each year, with around 200 different types of known cancers. However, there are treatment such as radio- and chemotherapy, but they conceal a dark side. Many adverse side effects are caused by these treatments, such as nausea, vomiting, fatigue, hair loss, anaemia, lymphedema, fertility side effects and also an increased chance of other cancers developing; which all seem to defeat the purpose of the word ‘therapy’. These side effects are solely caused by the treatments not being able to distinguish between normal healthy cells and cancerous cells. There does however seem to be a silver lining to this problem, from research using the venom of the Deathstalker scorpion (Leiurus quinquestriatus).
An active compound of the scorpion venom, named Chlorotoxin (CTX) was identified, and its main role is to block chloride-gated ion channels. These channels are known to have a key involvement in cancer cell mobility and growth. The characterisation of CTX has lead researchers to delve into its potential cancer fighting properties.
CTX actively seeks out tumour cells with 90% of 262 patients having shown a significant reduction in tumour growth and size. In vitro experiments revealed that healthy tissue cells remained unaffected by CTX, thus reducing the risk of side effects. This has lead researchers to believe that the toxin is a highly reliable histopathological marker for killing tumours.
Current chemotherapy methods use a chemical compound known as Cisplatin, which triggers cell death (apoptosis) by binding to the cells and causing crosslinking of DNA. A team of researchers lead by Prof. Nora Graf at the Massachusetts Institute of Technology, Department of Chemistry, have had on-going efforts to implement a ’tolerant’ form of Cisplatin into the body without side effects. A breakthrough eventually occurred with the creation of Pt-CTX which is in essence the combination of Cisplatin with the cancer targeting toxin CTX. In the presence of CTX the Cisplatin derived Pt-CTX has very little cell toxicity; therefore the potential side effects from chemotherapy are greatly reduced. The testing of this drug is still in the human trial phase, so it’s only a matter of time before it could be available.
(Last updated 24/11/13)
Graf, N., Mokhtari, T. E., Papayannopoulos, I. A. & Lippard, S. J. (2012). Platinum(IV)-chlorotoxin (CTX) conjugates for targeting cancer cells. Jour. of Inorg. Biochem. 110, 58-63.
Hmed, B. N., Serria, H. T. & Mounir, Z. K. (2013). Scorpion Peptides: Potential Use for New Drug Development. Jour. of Tox. 2013, 1-15.
Lyons, S.A., O’Neal, J. & Sontheimer, H. (2002). Chlorotoxin, a Scorpion-Derived Peptide, Specifically Binds to Gliomas and Tumors of Neiroectodermal Origin. GLIA. 39, 162-173.
Omran, M. A. A. (2003a). Cytotoxic and apoptotic effects of scorpion Leiurus quinquestriatus venom on 293T and C2C12 eukaryotic cell lines. Jour. of Ven. Anim. & Tox. incl. Trop. Dis. 9, 255-278.
Omran, M. A. A. (2003b). In vitro Anticancer effect of Scorpion Leiurus quinquestriatus and Egyptian Cobra venom on Human Breast and Prostate Cancer cell lines. Jour. Med. Sci. 3, 66-86.
Shen, S., Khazaeli, M. B., Gillespie, G. Y. & Alvarez, V. L. (2005). Radiation dosimetry of 131I-chlorotoxin for targeted radiotherapy in glioma-bearing mice. Jour. of Neuro-Onco. 71, 113-119.
Soroceanu, L., Gillespie, Y., Khazaeli, M. B. & Sontheimer, H. (1998). Use of Chlorotoxin for Targeting of Primary Brain Tumors. Cancer Research. 58, 4871-4879.
The life saving sea anemone
Research into the venom of the Sun anemone (Stichodactyla helianthus) has brought about the discovery of a unique peptide named ShK. ShK inhibits T-lymphocyte potassium channel Kv1.3 which essentially allows DNA to code for T-cells which help fight off infection. It was initially thought that ShK could be a useful molecule to aid in autoimmune diseases; diseases by where the antibodies of a person attacks their own tissues. One problem with ShK is that it also blocks potassium channel Kv1.1, this protein allows nerve impulses to be passed through neurones; thus it would be disasterous if it was used on humans as it could cause paralysis.
A breakthrough came about when a team of molecular biologists at Bayor college of Medicine developed a synthetically dervied compound called ShK-186. This still has the inhibiting ability to block Kv1.3 channels but not Kv1.1, ultimately allowing it to be subject to many pharmaceutical applications in autoimmune disorders without the potential of paralysis.
Due to ShK-186 having huge implications to cure autoimmune disorders, it was found that it was able to cure multiple sclerosis (MS); a disorder that causes inflammation of the nerve cells and eventually leads to paralysis. The testing was initially completed on mice and it completely reversed paralysis whilst also still allowing the immune system to maintain function, as the mice test subjects were still able to fight off influenza and chlamydia. ShK-186 is also being use with effective results in potentially curing other diseases as psoriasis, psoriatic arthritis, rheumatoid arthritis, uveitis, dry eye, lupus and type I diabetes.
The biotechnology company Kineta have completed phase 1a and 1b clinical trials for Psoriasis, in healthy volunteers and results indicate that there are no major safety concerns – Further clinical trials involving patients with active plaque psoriasis are currently under assessment. The evaluation of biweekly injections of ShK-186 are monitored and tested for safety endpoints, inflammatory activity in the blood and also skin biopsy. The results will be available later in 2015 and published on the Kineta webpage.
ShK-186 is taken via subcutaneous injection on a twice-per-week basis. However, Kineta are developing a steady release formulation that has the potential to be taken once every 3 months.
(Last updated 23/02/15)
Beeton, C., Pennington, M. W. & Norton, W. (2011). Analogs of the Sea Anemone Potassium Channel Blocker ShK for the Treatment of Autoimmune Diseases. Inflam. Alle. Dru. Tar.. 10 (5), 313-321
Chi V., Pennington M.W., Norton R.S., Tarcha E., Londono L., Sims-Fahey B., Upadhyay S.K., Lakey J.T., Iadonato S., Wulff H., Beeton C. & Chandy K.G. (2012) Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases. Toxicon. 59:529-546.
Jin, L. & Wu, Y. (2007). Molecular mechanism of the sea anemone toxin ShK recognizing the Kv1. 3 channel explored by docking and molecular dynamic simulations. Jour. of Chem. Info. & Mod.. 47 (5), 1967-1972.
Pennington, M., Rashid, M. H., Tajhya, R. B., Beeton, C., Kuyucak, S. & Norton, R. S. (2012). A C-terminally amidated analogue of ShK is a potent and selective blocker of the voltage-gated potassium channel Kv1.3. FEBS Letters. 586 (22), 3996-4001.
Tarcha E.J., Chi V., Munoz-Elias E., Bailey D., Londono L.M., Upadhyay S.K., Norton K., Olson A., Tjong I., Nguyen H., Hu X., Rupert G.W., Boley S.E., Slauter R., Sams J., Knapp B., Pennington M.W., Beeton C., Chandy K.G. & Iadonato S.P. (2012) Durable pharmacological responses from the peptide ShK-186, a specific Kv1.3 channel inhibitor that suppresses T cell mediators of autoimmune diseases. J. Pharmacol. Exp. Ther. 342, 642-653.
Chronic pain is a serious health issue with around 15% of adults suffering from it. However, current analgesics have limited efficacy and does-limiting side effects, sometimes adding more problems than pain relief. Traditional painkillers such as opiates can also be highly addictive, which can lead to drug abuse and other problems deriving from them. These problems have caused an increased interest in the search for new and better developed pain theraputics.
The discovery of the gene – SCN9A has been crucial in the development of pain theraputics because when a rare mutation occurs on this gene, the ability to feel pain is eliminated, whilst all tactile functions remain active. The gene is responsible for making one part of a sodium channel alpha subunit called NaV1.7.
So far to date there has only been one drug development that acts on the nervous system and causes pain relief – that is Prialt® derived from the toxin of the cone snail; Conus magnus. Drugs that act on the nervous system can be somewhat outcast because of how sensitive the nervous system is; a simple nerve being damaged can be disastrous and cause paralysis.
However, more recently there has been research into pain alleviating drugs that act on the nervous system using toxins from the Black Mamba (Dendroaspis polylepis). The peptides derived are known as mambalgins and they have been shown to have high analgesic effects as they block neuronal acid-sensing ion channels (ASICs). These mambalgins are more powerful than morphine but have an induced tolerance, thus they are not as deadly as morphine in higher dosages.
It’s not just the Black Mamba that is being utilised for pain relief; there are efforts to bring about similar drugs using peptides from King Cobra (Ophiophagus hannah) venom. The pharmaceutical company Theralpha have derived a peptide known as THA903 that can be taken orally, rather than being injected into the blood stream.
Another drug is being developed from the biotechnology company Kineta to treat chronic pain and it is also based on the conopeptides from the venom of cone snails (previously mentioned). The drug targets α9/α10 nicotinic acetylcholine receptors located in the peripheral nervous system. The drug does not have any dependence (unlike opioids) and has no intolerable side effects. Chemotheraphy-induced pain, nerve injury, burn pain, cancer pain and lower back pain are just some of the alleviated pain symptoms that are targeted. Preliminary animal safety tests have identified no toxicity results, and further trials will be completed in the near future.
(Last updated 22/04/15)