Biogeographic venom variation in Russell’s viper (Daboia russelii) and the preclinical inefficacy of antivenom therapy in snakebite hotspots

PLoS neglected tropical diseases, Journal Year: 2021, Volume and Issue: 15(3), P. e0009247 - e0009247

Published: March 25, 2021

Background Snakebite in India results over 58,000 fatalities and a vast number of morbidities annually. The majority these clinically severe envenomings are attributed to Russell’s viper ( Daboia russelii ), which has near pan-India distribution. Unfortunately, despite its medical significance, the influence biogeography on composition potency venom from disparate D . populations, repercussions variation neutralisation efficacy marketed Indian antivenoms, remain elusive. Methods Here, we employ an integrative approach comprising proteomic characterisation, biochemical analyses, pharmacological assessment, toxicity profiling elucidate varying ecology environment pan-Indian populations We then conducted vitro recognition experiments vivo assays evaluate commercial antivenoms against geographically populations. Findings reveal significant intraspecific composition, activities potencies venoms sourced five distinct biogeographic zones across India. Contrary our understanding consequences effectiveness snakebite therapy, antivenom exhibited surprisingly similar investigated with exception low preclinical semi-arid population northern However, ability counter morbid effects envenoming remains be evaluated. Conclusion concerning lack north , as well two other ‘big four’ snake species nearby locations, underscores pressing need develop effective improved high burden locales.

Language: Английский

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Old World Vipers—A Review about Snake Venom Proteomics of Viperinae and Their Variations

Toxins, Journal Year: 2021, Volume and Issue: 13(6), P. 427 - 427

Published: June 17, 2021

Fine-tuned by millions of years evolution, snake venoms have frightened but also fascinated humanity and nowadays they constitute potential resources for drug development, therapeutics antivenoms. The continuous progress mass spectrometry techniques latest advances in proteomics workflows enabled toxinologists to decipher modern omics technologies, so-called ‘venomics’. A tremendous upsurge reporting on venom proteomes could be observed. Within this review we focus the highly venomous widely distributed subfamily Viperinae (Serpentes: Viperidae). detailed public literature database search was performed (2003–2020) extensively reviewed all compositional studies Old-World Vipers. In total, 54 resulted 89 proteomes. are dominated four major, secondary, six minor several rare toxin families peptides, respectively. multitude different venomics approaches complicates comparison composition datasets therefore differentiated between non-quantitative three groups quantitative workflows. resulting direct comparisons within these show remarkable differences intra- interspecies level across genera with a regional differences. summary, present compilation is first comprehensive up-to-date differentiating analytical methods

Language: Английский

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Investigating Toxin Diversity and Abundance in Snake Venom Proteomes

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 12

Published: Jan. 14, 2022

Understanding snake venom proteomes is becoming increasingly important to understand biology, evolution and especially clinical effects of venoms approaches antivenom development. To explore the current state proteomics transcriptomics we investigated proteomic methods, associations between methodological biological variability diversity abundance protein families. We reviewed available studies on from September 2017 April 2021. This included 81 characterising 79 species, providing data relative toxin for 70 species (number different toxins) 37 species. Methodologies utilised in these were summarised compared. Several comparative showed that preliminary decomplexation crude by chromatography leads increased identification, as does use transcriptomics. Combining strategies venomic appears maximize proteome coverage. 48% used RP-HPLC →1D SDS-PAGE → in-gel trypsin digestion ESI -LC-MS/MS pathway. Protein quantification MS1-based spectral intensity was twice commonly MS2-based counting (33–15 studies). Total 25–225 toxins/species, with a median 48. The mean four dominant families elapids; 3FTx–52%, PLA 2 –27%, SVMP–2.8%, SVSP–0.1%, vipers: 3FTx–0.5%, –24%, SVMP–27%, SVSP–12%. Viper compositionally more complex than elapid terms number making up most venom, contrast, made fewer, but diverse, No relationship observed abundance. For equivalent comparisons be studies, there need clarify differences acceptance standardised classification, nomenclature reporting procedure. Correctly measuring comparing essential understanding biological, evolutionary implications composition.

Language: Английский

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A current perspective on snake venom composition and constituent protein families

Archives of Toxicology, Journal Year: 2022, Volume and Issue: 97(1), P. 133 - 153

Published: Nov. 27, 2022

Language: Английский

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Snake Venomics: Fundamentals, Recent Updates, and a Look to the Next Decade

Toxins, Journal Year: 2022, Volume and Issue: 14(4), P. 247 - 247

Published: March 30, 2022

Venomic research, powered by techniques adapted from proteomics, transcriptomics, and genomics, seeks to unravel the diversity complexity of venom through which knowledge can be applied in treatment envenoming, biodiscovery, conservation. Snake proteomics is most extensively studied, but methods varied widely, creating a massive amount information complicates data comparison interpretation. Advancement mass spectrometry technology, accompanied growing databases sophisticated bioinformatic tools, has overcome earlier limitations protein identification. The progress, however, remains challenged limited accessibility samples, non-standardized quantitative methods, biased interpretation -omic data. Next-generation sequencing (NGS) technologies enable high-throughput venom-gland transcriptomics complementing providing deeper insights into structural diversity, differential expression, regulation functional interaction toxin genes. tissue sampling is, difficult due strict regulations on wildlife use transfer biological materials some countries. Limited resources for funding are among other pertinent issues that impede progress venomics, particularly less developed regions neglected species. Genuine collaboration between international researchers, recognition regional experts global organizations (e.g., WHO), improved distribution research support, should embraced.

Language: Английский

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The molecular mechanism of snake short-chain α-neurotoxin binding to muscle-type nicotinic acetylcholine receptors

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 4, 2022

Bites by elapid snakes (e.g. cobras) can result in life-threatening paralysis caused venom neurotoxins blocking neuromuscular nicotinic acetylcholine receptors. Here, we determine the cryo-EM structure of muscle-type Torpedo receptor complex with ScNtx, a recombinant short-chain α-neurotoxin. ScNtx is pinched between loop C on principal subunit and unique hairpin F complementary subunit, thereby access to neurotransmitter binding site. adopts mode that tilted toward forming wider network interactions than those seen long-chain α-Bungarotoxin complex. Certain mutations at toxin-receptor interface eliminate inhibition neuronal α7 nAChRs, but not human These observations explain why binds more tightly receptors Together, these data offer framework for understanding subtype-specific actions α-neurotoxins inspire strategies design new snake antivenoms.

Language: Английский

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Discovery and optimization of a broadly-neutralizing human monoclonal antibody against long-chain α-neurotoxins from snakes

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 8, 2023

Abstract Snakebite envenoming continues to claim many lives across the globe, necessitating development of improved therapies. To this end, broadly-neutralizing human monoclonal antibodies may possess advantages over current plasma-derived antivenoms by offering superior safety and high neutralization capacity. Here, we report establishment a pipeline based on phage display technology for discovery optimization affinity antibodies. This approach yielded recombinant antibody with capacities in vitro vivo against different long-chain α-neurotoxins from elapid snakes. prevents lethality induced Naja kaouthia whole venom at an unprecedented low molar ratio one per toxin prolongs survival mice injected Dendroaspis polylepis or Ophiophagus hannah venoms.

Language: Английский

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What Are the Neurotoxins in Hemotoxic Snake Venoms?

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2919 - 2919

Published: Feb. 2, 2023

Snake venoms as tools for hunting are primarily aimed at the most vital systems of prey, especially nervous and circulatory systems. In general, snakes Elapidae family produce neurotoxic comprising toxins targeting system, while Viperidae rear-fanged hemotoxic directed mainly on blood coagulation. However, it is not all so clear. Some bites by viperids results in signs now known that do contain components. For example, viperid phospholipases A2 may manifest pre- or/and postsynaptic activity be involved pain analgesia. There other neurotoxins belonging to diverse families ranging from large multi-subunit proteins (e.g., C-type lectin-like proteins) short peptide waglerins azemiopsin), which found venoms. Other include baptides, crotamine, cysteine-rich secretory proteins, Kunitz-type protease inhibitors, sarafotoxins three-finger toxins. these exhibit activity, others affect functioning voltage-dependent ion channels. This review represents first attempt systematize data “non-neurotoxic” snake venom. The structural functional characteristic affecting targets system considered.

Language: Английский

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Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 14, 2023

Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by current antivenoms. Repurposed small molecule drugs that inhibit specific snake venom toxins show considerable promise for tackling this neglected tropical disease. Using human skin cell assays as an initial model snakebite-induced dermonecrosis, we 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, varespladib, alone or in combination, cytotoxicity of a broad range medically important venoms. Thereafter, using preclinical mouse models demonstrate dual therapeutic combinations DMPS marimastat varespladib significantly dermonecrotic activity geographically distinct venoms, even when drug are delivered one hour after envenoming. These findings strongly support future translation repurposed broad-spectrum therapeutics preventing morbidity caused snakebite.

Language: Английский

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Micro and macroevolution of sea anemone venom phenotype

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 16, 2023

Abstract Venom is a complex trait with substantial inter- and intraspecific variability resulting from strong selective pressures acting on the expression of many toxic proteins. However, understanding processes underlying toxin dynamics that determine venom phenotype remains unresolved. By interspecific comparisons we reveal in sea anemones evolves rapidly each species different family dictates by massive gene duplication events. In-depth analysis anemone, Nematostella vectensis , revealed striking variation dominant ( Nv1 ) diploid copy number across populations (1-24 copies) independent expansion/contraction events, which generate distinct haplotypes. correlates at both transcript protein levels one population having near-complete loss production. Finally, establish hypothesis incorporates observations other venomous lineages animals have convergently evolved similar strategy shaping their venom.

Language: Английский

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