Tissue damaging toxins in snake venoms: mechanisms of action, pathophysiology and treatment strategies

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: March 22, 2024

Snakebite envenoming is an important public health issue responsible for mortality and severe morbidity. Where mainly caused by venom toxins that induce cardiovascular disturbances, neurotoxicity, acute kidney injury, morbidity directly or indirectly destroy cells degrade the extracellular matrix. These are referred to as 'tissue-damaging toxins' have previously been classified in various ways, most of which based on tissues being affected (e.g., cardiotoxins, myotoxins). This categorisation, however, primarily phenomenological not mechanistic. In this review, we propose alternative way classifying cytotoxins their mechanistic effects rather than using a description organ- tissue-based. The mechanisms toxin-induced tissue damage clinical implications discussed. review contributes our understanding fundamental biological processes associated with snakebite envenoming, may pave knowledge-based search novel therapeutic options.

Language: Английский

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Genetic variability in snake venom and its implications for antivenom development in sub-Saharan Africa

Transactions of the Royal Society of Tropical Medicine and Hygiene, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Abstract Snake venom, a complex mixture of proteins, has attracted human attention for centuries due to its associated mortality, morbidity and other therapeutic properties. In sub-Saharan Africa (SSA), where snakebites pose significant health risk, understanding the genetic variability snake venoms is crucial developing effective antivenoms. The wide geographic distribution venomous species in SSA countries demonstrates need develop specific broad However, development antivenoms been hindered by different factors, such as antivenom cross-reactivity polygenic paratopes. While have numerous across region, current antivenoms, SAIMR polyvalent Premium Serums & Vaccines, exhibit varying degrees cross-reactivity. Such ability cross-react enables target multiple components from species. advent biotechnological innovations, including recombinant antibodies, small-molecule drugs, monoclonal antibodies synthetic presents options eliminating limitations with traditional plasma-derived challenges still persist, especially SSA, addressing variability, evidenced inadequate testing capacity limited genomic research facilities. This comprehensive review explores emphasizing venom composition various their interactions. information critical strategies during development. Finally, it offers concerning extensive collaborative engagements, technological advancements evaluations produce targeted

Language: Английский

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Snakebite drug discovery: high-throughput screening to identify novel snake venom metalloproteinase toxin inhibitors

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 11, 2024

Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration clinical setting. Next-generation snakebite are being widely investigated the aim improve efficacy, safety. In recent years small molecule drugs shown considerable promise indication, oral bioavailability particularly promising community delivery rapidly after snakebite. However, only two such entered development To offset risk of attrition during trials better explore chemical space venom toxin inhibitors, here we describe first throughput drug screen against snake metalloproteinases (SVMPs)—a pathogenic family responsible causing haemorrhage coagulopathy. Following validation 384-well fluorescent enzymatic assay, screened repurposed library 3,547 compounds five geographically distinct venoms. Our resulted identification 14 pan-species inhibitory activity. secondary potency testing, SVMP inhibitors were identified nanomolar EC 50 s comparable previously matrix metalloproteinase inhibitor marimastat superior metal chelator dimercaprol, doubling current global portfolio inhibitors. analysis their structure ADME properties, hit-to-lead identified. These clear starting points initiation medicinal chemistry campaigns provide basis ever designer specific molecules.

Language: Английский

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Revolutionizing snakebite care with novel antivenoms: Breakthroughs and barriers

Heliyon, Journal Year: 2024, Volume and Issue: 10(3), P. e25531 - e25531

Published: Jan. 30, 2024

Snakebite envenoming (SBE) is a global public health concern, primarily due to the lack of effective antivenom for treating snakebites inflicted by medically significant venomous snakes prevalent across various geographic locations. The rising demand safe, cost-effective, and potent snakebite treatments highlights urgent need develop alternative therapeutics targeting relevant toxins. This development could provide promising discoveries create novel recombinant solutions, leveraging human monoclonal antibodies, synthetic peptides nanobodies. Such technologies as DNA, peptide epitope mapping phage display etc) have potential exceed traditional use equine polyclonal which long been used in production. Recombinant can be engineered target certain toxins that play critical role pathology. approach has produce with improved efficacy safety profiles. However, there are limitations challenges associated these emerging technologies. Therefore, identifying overcoming optimizing antivenoms. review aimed at presenting thorough overview diverse antivenom, emphasizing their offering insights into prospects advancing

Language: Английский

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Differential effects of the venoms of Russell’s viper and Indian cobra on human myoblasts

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 7, 2024

Abstract Local tissue damage following snakebite envenoming remains a poorly researched area. To develop better strategies to treat snakebites, it is critical understand the mechanisms through which venom toxins induce envenomation effects including local damage. Here, we demonstrate how venoms of two medically important Indian snakes (Russell's viper and cobra) affect human skeletal muscle using cultured myoblast cell line. The data suggest that both viability myoblasts. Russell’s reduced total number cells, their migration, area focal adhesions. It also suppressed myogenic differentiation induced atrophy. While cobra decreased viability, did not largely migration Cobra affected formation myotubes venom-induced atrophy could be reversed by small molecule inhibitors such as varespladib (a phospholipase A 2 inhibitor) prinomastat metalloprotease inhibitor), soluble activin type IIb receptor used promote regeneration muscle), although antivenom (raised against ‘Big Four’ snakes) has attenuated effects. However, all these molecules rescued from This study demonstrates key steps in process are offers insights into potential causes clinical features displayed envenomed victims. Further research required investigate molecular myotoxicity under vivo settings therapies for snakebite-induced

Language: Английский

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Prospect of using ethnobotanicals to manage snakebites in a cost-effective manner: validating Senegalia mellifera extract's inhibitory potential on Naja nigricincta nigricincta (zebra cobra) venom

Transactions of the Royal Society of Tropical Medicine and Hygiene, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Abstract Background Despite Naja nigricincta being responsible for most snake envenomation in remote Namibian regions, an effective intervention against its venom remains undiscovered. This study aimed to scientifically validate folklore claims about Senegalia mellifera extract's efficacy envenomation. Methods In vitro assays were conducted assess the inhibitory potential of S. stem bark extract on phospholipase A2 (svPLA2) activity from N. n. venom. Gas chromatography-mass spectrometry (GC-MS) and molecular docking predicted phytochemicals effects proteins. Results The svPLA2 assay demonstrated significant extract, reducing enzyme 100% as low 66.99%. GC-MS analysis indicated abundant presence terpenes having antisnake activity. Molecular identified capable neutralizing prevalent cobra toxins, that is, stigmasterol acetate, beta-Sitosterol vitamin E, kaur-15-ene, squalene 4,6-Cholestadien-3beta-ol. Conclusions plant cannot be considered a discrete treatment It may serve transient remedy impede toxic or supplement action antivenoms. Future research should at finding other plants with greater antivenom increase prospect using ethnobotanicals manage snakebites cost-effective manner.

Language: Английский

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Inflammation and Oxidative Stress in Snakebite Envenomation: A Brief Descriptive Review and Clinical Implications

Toxins, Journal Year: 2022, Volume and Issue: 14(11), P. 802 - 802

Published: Nov. 18, 2022

Snakebite envenoming is a pathological condition which may occur in response to the injection of venom. Snake venoms contain complex mixture biologically active molecules are responsible for broad spectrum clinical manifestations, ranging from local tissue injuries fatal complications. venom administration commonly provokes injury often associated with systemic effects, including neurotoxic and cardiotoxic bleeding, acute kidney injury, rhabdomyolysis. An important pathogenesis snake envenomation generation reactive oxygen species (ROS), can directly provoke damage also potentiate deleterious consequences inflammation at bite site. components known induce oxidative stress include phospholipases A2, metalloproteinases, three-finger toxins, L-amino acid oxidase. Clear evidence mounting suggesting that participate destructive effects envenoming, renal failure, necrosis, unusual susceptibility bleed (hemorrhage), mostly due hypocoagulability, neuro/cardio toxicity, myonecrosis. Impaired regulation set stage secondary/long-term complications snakebite such as musculoskeletal disabilities. Some aspects natural antioxidant therapeutic options discussed this review.

Language: Английский

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Plant-Derived Toxin Inhibitors as Potential Candidates to Complement Antivenom Treatment in Snakebite Envenomations

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: May 9, 2022

Snakebite envenomations (SBEs) are a neglected medical condition of global importance that mainly affect the tropical and subtropical regions. Clinical manifestations include pain, edema, hemorrhage, tissue necrosis, neurotoxic signs, may evolve to functional loss affected limb, acute renal and/or respiratory failure, even death. The standard treatment for snake is antivenom, which produced from hyperimmunization animals with toxins. inhibition effects SBEs using natural or synthetic compounds has been suggested as complementary particularly before admission hospital antivenom treatment, since these alternative molecules also able inhibit Biodiversity-derived molecules, namely those extracted medicinal plants, promising sources toxin inhibitors can minimize deleterious consequences SBEs. In this review, we systematically synthesize literature on plant metabolites be used toxin-inhibiting agents, well present potential mechanisms action derived sources. These findings aim further our understanding products provide new lead auxiliary therapies

Language: Английский

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Molecular dissection of cobra venom highlights heparinoids as an antidote for spitting cobra envenoming

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(756)

Published: July 17, 2024

Snakebites affect about 1.8 million people annually. The current standard of care involves antibody-based antivenoms, which can be difficult to access and are generally not effective against local tissue injury, the primary cause morbidity. Here, we used a pooled whole-genome CRISPR knockout screen define human genes that, when targeted, modify cell responses spitting cobra venoms. A large portion modifying that conferred resistance venom cytotoxicity was found control proteoglycan biosynthesis, including

Language: Английский

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In vitro and in vivo preclinical venom inhibition assays identify metalloproteinase inhibiting drugs as potential future treatments for snakebite envenoming by Dispholidus typus

Toxicon X, Journal Year: 2022, Volume and Issue: 14, P. 100118 - 100118

Published: March 18, 2022

Snakebite envenoming affects more than 250,000 people annually in sub-Saharan Africa. Envenoming by

Language: Английский

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