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Difficult drug targets are becoming the normal course of business in drug discovery, sometimes due to large interacting surfaces or only small differences in selectivity regions. For these, a different approach is merited: compounds lying somewhere between the small molecule and the large antibody in terms of many properties including stability, biodistribution and pharmacokinetics. Venoms have evolved over millions of years to be complex mixtures of stable molecules derived from other somatic molecules, the stability comes from the pressure to be ready for delivery at a moment's notice. Snakes, spiders, scorpions, jellyfish, wasps, fish and even mammals have evolved independent venom systems with complex mixtures in their chemical arsenal. These venom-derived molecules have been proven to be useful tools, such as for the development of antihypotensive angiotensin converting enzyme (ACE) inhibitors and have also made successful drugs such as Byetta® (Exenatide), Integrilin® (Eptifibatide) and Echistatin. Only a small percentage of the available chemical space from venoms has been investigated so far and this is growing. In a new era of biological therapeutics, venom peptides present opportunities for larger target engagement surface with greater stability than antibodies or human peptides. There are challenges for oral absorption and target engagement, but there are venom structures that overcome these and thus provide substrate for engineering novel molecules that combine all desired properties. Venom researchers are characterising new venoms, species, and functions all the time, these provide great substrate for solving the challenges presented by today's difficult targets.
Carol M. Trim; Lee J. Byrne; Steven A. Trim. Utilisation of compounds from venoms in drug discovery. Progress in Medicinal Chemistry 2021, 60, 1 -66.
AMA StyleCarol M. Trim, Lee J. Byrne, Steven A. Trim. Utilisation of compounds from venoms in drug discovery. Progress in Medicinal Chemistry. 2021; 60 ():1-66.
Chicago/Turabian StyleCarol M. Trim; Lee J. Byrne; Steven A. Trim. 2021. "Utilisation of compounds from venoms in drug discovery." Progress in Medicinal Chemistry 60, no. : 1-66.
Following a bite from a juvenile Russell’s viper (Daboia russelii), a priapism (painful erection) developed rapidly in a 16-year-old male and only subsided after administration of antivenom 3 hours later. Potential mechanisms for this snakebite-induced priapism are unclear but likely due to venom toxins causing nitric oxide (NO) release and subsequent vasodilation of endothelium in the corpus cavernosum, although the possible involvement of other mechanisms cannot be ruled out. We strongly believe that this unusual case report may lead to further scientific research in order to improve the clinical understanding of the pathophysiology of envenomation due to Russell’s viper bites. Although it is too early to speculate, further research may also discover the possibilities of developing venom-based candidate molecules to treat sexual dysfunction in males and females.
Subramanian Senthilkumaran; Harry F. Williams; Ketan Patel; Steven A. Trim; Ponniah Thirumalaikolundusubramanian; Sakthivel Vaiyapuri. Priapism following a juvenile Russell’s viper bite: An unusual case report. PLOS Neglected Tropical Diseases 2021, 15, e0009242 .
AMA StyleSubramanian Senthilkumaran, Harry F. Williams, Ketan Patel, Steven A. Trim, Ponniah Thirumalaikolundusubramanian, Sakthivel Vaiyapuri. Priapism following a juvenile Russell’s viper bite: An unusual case report. PLOS Neglected Tropical Diseases. 2021; 15 (3):e0009242.
Chicago/Turabian StyleSubramanian Senthilkumaran; Harry F. Williams; Ketan Patel; Steven A. Trim; Ponniah Thirumalaikolundusubramanian; Sakthivel Vaiyapuri. 2021. "Priapism following a juvenile Russell’s viper bite: An unusual case report." PLOS Neglected Tropical Diseases 15, no. 3: e0009242.
The lack of public awareness surrounding the dangers of snakebite envenomation (SBE) is one of the most critical factors contributing to SBE-induced complications, and subsequently exacerbating the number of deaths and disabilities resulting from SBE. In this study, we deployed a multifaceted community education programme to educate students, healthcare professionals and members of the public in rural areas of Tamil Nadu, India about the dangers of SBE, appropriate first aid measures and the ‘do’s and don’ts’ following a snakebite. An assessment of prior knowledge within these communities identified several misconceptions concerning snakes and SBE. Using a combination of direct engagement (estimated to reach over 200,000 people), information leaflets (200,000 distributed), posters, video documentaries, media and social media (>2.8 million engagements), over the course of one year (January to December 2019) we reached over 3 million people in rural Tamil Nadu (around 8% of population). Evaluation of community-based assemblies indicated that at least 90% of attendees were able to recall the key messages at the end of the events, and at least 85% were able to recall the key messages even after 12 months. Due to high demand, a one-day symposium was organised to provide clinical knowledge and training on SBE to 250 healthcare professionals in rural Tamil Nadu. Notably, an assessment of patient data (291 victims) collected from a snakebite referral hospital over the same 12-month period (2019) indicated that arrival time at hospital following a snakebite was significantly faster and the effective first aid measures were administered to patients who were aware of our activities compared to those that were not. Overall, our approach provides a framework on how to educate rural communities about the dangers of SBE and thereby, mitigate delayed SBE treatment leading to an overall reduction in SBE-induced mortality, morbidity, treatment costs and other socio-economic ramifications.
Stephen Paul Samuel; Soundararaj Chinnaraju; Harry F. Williams; Elamaran Pichamuthu; Mangaiyarkkarasai Subharao; Mohanraj Vaiyapuri; Sundhararajan Arumugam; Rajendran Vaiyapuri; M. Fazil Baksh; Ketan Patel; Steven A. Trim; Tracey E. Duncombe; Sakthivel Vaiyapuri. Venomous snakebites: Rapid action saves lives—A multifaceted community education programme increases awareness about snakes and snakebites among the rural population of Tamil Nadu, India. PLOS Neglected Tropical Diseases 2020, 14, e0008911 .
AMA StyleStephen Paul Samuel, Soundararaj Chinnaraju, Harry F. Williams, Elamaran Pichamuthu, Mangaiyarkkarasai Subharao, Mohanraj Vaiyapuri, Sundhararajan Arumugam, Rajendran Vaiyapuri, M. Fazil Baksh, Ketan Patel, Steven A. Trim, Tracey E. Duncombe, Sakthivel Vaiyapuri. Venomous snakebites: Rapid action saves lives—A multifaceted community education programme increases awareness about snakes and snakebites among the rural population of Tamil Nadu, India. PLOS Neglected Tropical Diseases. 2020; 14 (12):e0008911.
Chicago/Turabian StyleStephen Paul Samuel; Soundararaj Chinnaraju; Harry F. Williams; Elamaran Pichamuthu; Mangaiyarkkarasai Subharao; Mohanraj Vaiyapuri; Sundhararajan Arumugam; Rajendran Vaiyapuri; M. Fazil Baksh; Ketan Patel; Steven A. Trim; Tracey E. Duncombe; Sakthivel Vaiyapuri. 2020. "Venomous snakebites: Rapid action saves lives—A multifaceted community education programme increases awareness about snakes and snakebites among the rural population of Tamil Nadu, India." PLOS Neglected Tropical Diseases 14, no. 12: e0008911.
Snakebite envenomation (SBE) is a high-priority, neglected tropical disease. This devastating occupational health hazard disproportionately affects rural farming communities in tropical countries. This is exacerbated by the distribution and densities of venomous snakes, incidence of encounters, and limited access to advanced healthcare, including antivenom. Before the development of antivenom, desperation and spiritual beliefs led patients to experiment with a wide range of traditional treatments. Many of these treatments still survive today, particularly in regions where access to healthcare is limited. Plants are a major source of bioactive molecules, including several lifesaving medications that are widely used to this day. However, much of the research into the use of traditional plant treatments for SBE are limited to preliminary analysis or have focused on techniques used to confirm antibody efficacy that are not suitable for non-antibody-containing treatments. Modern drugs are developed through a robust pharmaceutical drug discovery and development process, which applies as much to SBE as it does to any other disease. This review discusses specifically why research into ethnobotanical practices has failed to identify or develop a novel treatment for SBE and proposes specific approaches that should be considered in this area of research in the future.
Steven A. Trim; Carol M. Trim; Harry F. Williams; Sakthivel Vaiyapuri. The Failures of Ethnobotany and Phytomedicine in Delivering Novel Treatments for Snakebite Envenomation. Toxins 2020, 12, 774 .
AMA StyleSteven A. Trim, Carol M. Trim, Harry F. Williams, Sakthivel Vaiyapuri. The Failures of Ethnobotany and Phytomedicine in Delivering Novel Treatments for Snakebite Envenomation. Toxins. 2020; 12 (12):774.
Chicago/Turabian StyleSteven A. Trim; Carol M. Trim; Harry F. Williams; Sakthivel Vaiyapuri. 2020. "The Failures of Ethnobotany and Phytomedicine in Delivering Novel Treatments for Snakebite Envenomation." Toxins 12, no. 12: 774.
Snakebite envenomation causes over 140,000 deaths every year, predominantly in developing countries. As a result, it is one of the most lethal neglected tropical diseases. It is associated with incredibly complex pathophysiology due to the vast number of unique toxins/proteins present in the venoms of diverse snake species found worldwide. Here, we report the purification and functional characteristics of a Group I (PI) metalloprotease (CAMP-2) from the venom of the western diamondback rattlesnake, Crotalus atrox. Its sensitivity to matrix metalloprotease inhibitors (batimastat and marimastat) was established using specific in vitro experiments and in silico molecular docking analysis. CAMP-2 shows high sequence homology to atroxase from the venom of Crotalus atrox and exhibits collagenolytic, fibrinogenolytic and mild haemolytic activities. It exerts a mild inhibitory effect on agonist-induced platelet aggregation in the absence of plasma proteins. Its collagenolytic activity is completely inhibited by batimastat and marimastat. Zinc chloride also inhibits the collagenolytic activity of CAMP-2 by around 75% at 50 μM, while it is partially potentiated by calcium chloride. Molecular docking studies have demonstrated that batimastat and marimastat are able to bind strongly to the active site residues of CAMP-2. This study demonstrates the impact of matrix metalloprotease inhibitors in the modulation of a purified, Group I metalloprotease activities in comparison to the whole venom. By improving our understanding of snake venom metalloproteases and their sensitivity to small molecule inhibitors, we can begin to develop novel and improved treatment strategies for snakebites.
Harry J. Layfield; Harry F. Williams; Divyashree Ravishankar; Amita Mehmi; Medha Sonavane; Anika Salim; Rajendran Vaiyapuri; Karthik Lakshminarayanan; Thomas M. Vallance; Andrew B. Bicknell; Steven A. Trim; Ketan Patel; Sakthivel Vaiyapuri. Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox. Toxins 2020, 12, 309 .
AMA StyleHarry J. Layfield, Harry F. Williams, Divyashree Ravishankar, Amita Mehmi, Medha Sonavane, Anika Salim, Rajendran Vaiyapuri, Karthik Lakshminarayanan, Thomas M. Vallance, Andrew B. Bicknell, Steven A. Trim, Ketan Patel, Sakthivel Vaiyapuri. Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox. Toxins. 2020; 12 (5):309.
Chicago/Turabian StyleHarry J. Layfield; Harry F. Williams; Divyashree Ravishankar; Amita Mehmi; Medha Sonavane; Anika Salim; Rajendran Vaiyapuri; Karthik Lakshminarayanan; Thomas M. Vallance; Andrew B. Bicknell; Steven A. Trim; Ketan Patel; Sakthivel Vaiyapuri. 2020. "Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox." Toxins 12, no. 5: 309.
Snakebite envenoming (SBE) is a priority neglected tropical disease, which kills in excess of 100,000 people per year. Additionally, many millions of survivors also suffer through disabilities and long-term health consequences. The only treatment for SBE, antivenom, has a number of major associated problems, not least, adverse reactions and limited availability. This emphasises the necessity for urgent improvements to the management of this disease. Administration of antivenom is too frequently based on symptomatology, which results in wasting crucial time. The majority of SBE-affected regions rely on broad-spectrum polyvalent antivenoms that have a low content of case-specific efficacious immunoglobulins. Research into small molecular therapeutics such as varespladib/methyl-varespladib (PLA2 inhibitors) and batimastat/marimastat (metalloprotease inhibitors) suggest that such adjunctive treatments could be hugely beneficial to victims. Progress into toxin-specific monoclonal antibodies as well as alternative binding scaffolds such as aptamers hold much promise for future treatment strategies. SBE is not implicit during snakebite, due to venom metering. Thus, the delay between bite and symptom presentation is critical and when symptoms appear it may often already be too late to effectively treat SBE. The development of reliable diagnostical tools could therefore initiate a paradigm shift in the treatment of SBE. While the complete eradication of SBE is an impossibility, mitigation is in the pipeline, with new treatments and diagnostics rapidly emerging. Here we critically review the urgent necessity for the development of diagnostic tools and improved therapeutics to mitigate the deaths and disabilities caused by SBE.
Harry F. Williams; Harry J. Layfield; Thomas Vallance; Ketan Patel; Andrew B. Bicknell; Steven A. Trim; Sakthivel Vaiyapuri. The Urgent Need to Develop Novel Strategies for the Diagnosis and Treatment of Snakebites. Toxins 2019, 11, 363 .
AMA StyleHarry F. Williams, Harry J. Layfield, Thomas Vallance, Ketan Patel, Andrew B. Bicknell, Steven A. Trim, Sakthivel Vaiyapuri. The Urgent Need to Develop Novel Strategies for the Diagnosis and Treatment of Snakebites. Toxins. 2019; 11 (6):363.
Chicago/Turabian StyleHarry F. Williams; Harry J. Layfield; Thomas Vallance; Ketan Patel; Andrew B. Bicknell; Steven A. Trim; Sakthivel Vaiyapuri. 2019. "The Urgent Need to Develop Novel Strategies for the Diagnosis and Treatment of Snakebites." Toxins 11, no. 6: 363.
Snakebite envenomation is an affliction currently estimated to be killing upwards of 100,000 people annually. Snakebite is associated with a diverse pathophysiology due to the magnitude of variation in venom composition that is observed worldwide. The haemolytic (i.e., lysis of red blood cells) actions of snake venoms are well documented, although the direct impact of venoms on haemoglobin is not fully understood. Here we report on the varied ability of a multitude of snake venoms to oxidise haemoglobin into methaemoglobin. Moreover, our results demonstrate that the venom of an elapid, the black necked spitting cobra, Naja nigricollis, oxidises oxyhaemoglobin (Fe2+) into methaemoglobin (Fe3+) in a time- and concentration-dependent manner that is unparalleled within the 47 viper and elapid venoms evaluated. The treatment of venom with a reducing agent, dithiothreitol (DTT) is observed to potentiate this effect at higher concentrations, and the use of denatured venom demonstrates that this effect is dependent upon the heat-sensitive proteinaceous elements of the venom. Together, our results suggest that Naja nigricollis venom appears to promote methaemoglobin production to a degree that is rare within the Elapidae family, and this activity appears to be independent of proteolytic activities of venom components on haemoglobin.
Harry F. Williams; Paul Hayter; Divyashree Ravishankar; Anthony Baines; Harry J. Layfield; Lorraine Croucher; Catherine Wark; Andrew B. Bicknell; Steven Trim; Sakthivel Vaiyapuri. Impact of Naja nigricollis Venom on the Production of Methaemoglobin. Toxins 2018, 10, 539 .
AMA StyleHarry F. Williams, Paul Hayter, Divyashree Ravishankar, Anthony Baines, Harry J. Layfield, Lorraine Croucher, Catherine Wark, Andrew B. Bicknell, Steven Trim, Sakthivel Vaiyapuri. Impact of Naja nigricollis Venom on the Production of Methaemoglobin. Toxins. 2018; 10 (12):539.
Chicago/Turabian StyleHarry F. Williams; Paul Hayter; Divyashree Ravishankar; Anthony Baines; Harry J. Layfield; Lorraine Croucher; Catherine Wark; Andrew B. Bicknell; Steven Trim; Sakthivel Vaiyapuri. 2018. "Impact of Naja nigricollis Venom on the Production of Methaemoglobin." Toxins 10, no. 12: 539.
There have been increasing reports of cases of erratic movements and ataxia followed by death in tarantula species. This paper covers a brief review of what we know about the condition and what to look for in a tarantula patient. This is the first paper on this syndrome and thus hypotheses on causality and treatment options are in their infancy. The paper concludes with a call for more case reports to be published or sent to the attention of the authors such that we can continue to build on the data we already have to seek a better treatment option.
Emily Draper; Steven A. Trim. Dyskinetic syndrome in tarantula spiders (Theraphosidae). Veterinary Nursing Journal 2018, 33, 230 -232.
AMA StyleEmily Draper, Steven A. Trim. Dyskinetic syndrome in tarantula spiders (Theraphosidae). Veterinary Nursing Journal. 2018; 33 (8):230-232.
Chicago/Turabian StyleEmily Draper; Steven A. Trim. 2018. "Dyskinetic syndrome in tarantula spiders (Theraphosidae)." Veterinary Nursing Journal 33, no. 8: 230-232.
Adequate pain control is still a significant challenge and largely unmet medical need in the 21st century. With many small molecules failing to reach required levels of potency and selectivity, drug discovery is once again turning to nature to replenish pain therapeutic pipelines. Venomous animals are frequently stereotyped as inflictors of pain and distress and have historically been vilified by mankind. Yet, ironically, the very venoms that cause pain when directly injected by the host animal may actually turn out to contain the next generation of analgesics when injected by the clinician. The last 12 months have seen dramatic discoveries of analgesic tools within venoms. Spiders, snakes and even centipedes are yielding peptides with immense therapeutic potential. Significant advances are also taking place in delivery methods that can improve bioavailability and pharmacokinetics of these exciting natural resources. Turning proteinaceous venom into pharmaceutical liquid gold is the goal of venomics and the focus of this article.
Steven A Trim; Carol M Trim. Venom: the sharp end of pain therapeutics. British Journal of Pain 2013, 7, 179 -188.
AMA StyleSteven A Trim, Carol M Trim. Venom: the sharp end of pain therapeutics. British Journal of Pain. 2013; 7 (4):179-188.
Chicago/Turabian StyleSteven A Trim; Carol M Trim. 2013. "Venom: the sharp end of pain therapeutics." British Journal of Pain 7, no. 4: 179-188.
Summary As scientific understanding of invertebrate life increases so does the concern for how to end that life in a way that not only minimises (potential) suffering and is non-recoverable, but is also safe for those carrying out the procedure. There is increasing debate on the most appropriate euthanasia methods for invertebrates as their use in experimental research and zoological institutions grows. Their popularity as pet species has also lead to an increase in the need for greater veterinary understanding. Through the use of a local injection of potassium chloride (KCl) initially developed for use in American lobsters, this manuscript describes a safe and effective method for euthanasia in terrestrial invertebrates. Initial work focused on empirically determining the dose for cockroaches then extrapolating to other arthropod species. For this method of euthanasia, we propose the term 'targeted hyperkalosis' to describe death through terminal depolarisation of the thoracic ganglia as a result of high potassium concentration.
Neil A. C. Bennie; Christopher D. Loaring; Mikaella M. G. Bennie; Steven A. Trim. An effective method for terrestrial arthropod euthanasia. Journal of Experimental Biology 2012, 215, 4237 -4241.
AMA StyleNeil A. C. Bennie, Christopher D. Loaring, Mikaella M. G. Bennie, Steven A. Trim. An effective method for terrestrial arthropod euthanasia. Journal of Experimental Biology. 2012; 215 (24):4237-4241.
Chicago/Turabian StyleNeil A. C. Bennie; Christopher D. Loaring; Mikaella M. G. Bennie; Steven A. Trim. 2012. "An effective method for terrestrial arthropod euthanasia." Journal of Experimental Biology 215, no. 24: 4237-4241.