Causes and Consequences of Snake Venom Variation

Trends in Pharmacological Sciences, Journal Year: 2020, Volume and Issue: 41(8), P. 570 - 581

Published: June 19, 2020

Venom is an ecologically important functional trait in venomous snakes and its composition activity often coevolve with the physiology of prey animals it deployed against.Variation toxin venom components occurs both inter- intraspecifically as result various processes, including gene duplication action positive selection.The consequences this variation generation functionally diverse venoms that cause distinct pathologies snakebite victims which undermine efficacy antivenom treatments.Knowledge varying toxins found across medically enabling new therapeutic approaches to circumvent better treat worlds 1.8 million annual victims. Snake are mixtures vary extensively between within snake species. This variability has serious for management world's Advances 'omic' technologies have empowered toxinologists comprehensively characterize compositions, unravel molecular mechanisms underpin variation, elucidate ensuing consequences. In review, we describe how such mechanistic processes resulted suites isoforms human detail can treatment failure. Finally, outline current designed deliver next-generation treatments most lethal neglected tropical disease. a remarkable evolutionary innovation scattered animal tree life [1.Schendel V. et al.The diversity venom: importance behavior system morphology understanding ecology evolution.Toxins. 2019; 11: 666Crossref Scopus (92) Google Scholar]. Due their histories consequent variability, proven be fascinating models number fundamental duplication, genotype–phenotype mapping, convergent evolution, cell tissue development [2.Dowell N.L. deep origin recent loss genes rattlesnakes.Curr. Biol. 2016; 26: 2434-2445Abstract Full Text PDF PubMed (96) Scholar, 3.Post Y. al.Snake gland organoids.Cell. 2020; 180: 233-247Abstract (50) 4.Casewell N.R. al.Solenodon genome reveals evolution eulipotyphlan mammals.Proc. Natl. Acad. Sci. U. S. A. 116: 25745-25755Crossref (27) 5.Sunagar K. al.Cell type-specific expression profiling unravels stinging cells sea anemone.BMC 2018; 16: 108Crossref (34) 6.Columbus-Shenkar Y.Y. al.Dynamics complex cycle.Elife. 7e35014Crossref Scholar], while bioactivities many make them promising leads discovery therapeutics [7.Clark G.C. al.Friends or foes? Emerging impacts biological toxins.Trends Biochem. 44: 365-379Abstract (29) The well-studied systems those snakes. All 'advanced snakes' (superfamily: Colubroidea) pair homologous oral glands located behind eye on either side upper jaw [8.Jackson T.N.W. al.Endless forms beautiful: ophidian glands, system, use appropriate terminology structures.Zoomorphology. 2017; 136: 107-130Crossref (26) Scholar,9.Jackson venom-delivery snakes.Zool. J. Linnean Soc. 2003; 137: 337-354Crossref (70) These connected ducts transfer secreted base morphologically teeth referred 'fangs'. For snakes, greatest medical importance, these fangs at front mouth, contain enclosed canal, highly efficient mechanism facilitates rapid injection bolus venom. Although predominantly assist acquisition prey, they may also deploy defensive bites deter potential predators aggressors, people. snakebites severe. Current estimates suggest up 138 000 deaths worldwide each year perhaps 500 additional cases venom-induced morbidity [10.Gutiérrez J.M. al.Snakebite envenoming.Nat. Rev. Dis. Primers. 3: 1-21Google Snakebite envenomings affect rural impoverished populations tropics consequently World Health Organization (WHO) listed priority disease (NTD) (see Glossary) [11.Chippaux J.-P. envenomation turns again into disease!.J. Venom. Anim. Toxins Incl. Trop. 23: 38Crossref (263) pathological effects include neuromuscular paralysis (neurotoxicity), hemorrhage coagulopathy (hemotoxicity), and/or local swelling, blistering, necrosis (cytotoxicity) around bite site variable clinical signs direct consequence venom; extensive [12.Massey D.J. al.Venom envenoming severity outcomes Crotalus scutulatus (Mojave rattlesnake) from Southern Arizona.J. Proteome. 2012; 75: 2576-2587Crossref (111) 13.Casewell al.Medically differences dictated by postgenomic mechanisms.Proc. 2014; 111: 9205-9210Crossref (182) 14.Durban al.Integrated venomics transcriptome analysis juvenile adult Mexican rattlesnakes simus, C. tzabcan, culminatus revealed miRNA-modulated ontogenetic shifts.J. Proteome Res. 3370-3390Crossref (75) 15.Pla D. al.Phylovenomics Daboia russelii Indian subcontinent. Bioactivities comparative vivo neutralization vitro third-generation antivenomics antivenoms against India, Bangladesh Sri Lanka.J. 207: 103443Crossref (53) 16.Laxme R.S. al.Beyond 'big four': yet disturbing deficiencies.PLoS Negl. 13e0007899PubMed 17.Jackson T.N. al.Rapid radiations race redundancy: investigation Australian elapid venoms.Toxins (Basel). 8: 309Crossref (47) 18.Jackson Fry B.G. A tricky trait: applying fruits "function debate" philosophy biology "venom science toxinology.Toxins 263Crossref (23) impact (antivenom), resulting different having manufactured species [19.Williams al.Ending drought: strategies improving flow affordable, effective Asia Africa.J. 2011; 74: 1735-1767Crossref (177) Despite complexity, advances (e.g., proteomics, transcriptomics) enabled characterization over 125 relevant [20.Tasoulis T. Isbister G.K. review database proteomes.Toxins. 9: 290Crossref (256) Here, data transformed our generated context pathology treatment. We highlight rational application will enable broadly therapies envenoming, essential step mitigating devastating NTD inflicts upon vulnerable [21.Williams al.Strategy globally coordinated response disease: envenoming.PLoS 13e0007059Crossref (173) used one organism interfere homeostatic another, generally facilitate feeding competitors [18.Jackson therefore intrinsically ecological; mediates outcome interactions two more organisms [22.Jackson context: clades concepts.Front. Ecol. Evol. 7: 332Crossref (36) 'Venomous' not synonymous 'dangerous', majority organisms, pose no threat humans, because rarely, if ever, envenom trivial. Indeed, widespread amongst snakes', but almost all 'medically important' (those capable causing harm humans via envenoming) members only three clades: families Elapidae (cobras, mambas, taipans, relatives) Viperidae (vipers pit vipers, adders, rattlesnakes, subfamily Atractaspidinae (mole vipers/stiletto snakes). As coevolves and, certain extent, [23.Holding M.L. al.Coevolution function resistance rattlesnake predator squirrel prey.Proc. R. B 283: 20152841Crossref (80) 24.Ji X.H. al.Receptor variability-driven toxins.Zool. 39: 431-436PubMed 25.Daltry J.C. al.Diet evolution.Nature. 1996; 379: 537-540Crossref (501) 26.Jorge da Silva N. Jr Aird, S.D. Prey specificity, lethality compositional coral venoms.Comp. Physiol. C Toxicol. Pharmacol. 2001; 128: 425-456Crossref 27.Barlow diet prey-specific supports role selection evolution.Proc. 2009; 276: 2443-2449Crossref (238) primates been since time immemorial exclusively defensive, unlikely exerted any major selective pressure venoms. Rather, best viewed collateral damage chemical arms taking place (mammalian) prey. exists multiple phylogenetic levels contingent divergent lineages ecological deployment specific toxins. At deepest general level, of, example, viperid (Box 1); recruited utilized become central lineage other [28.Fry structural diversification Toxicofera reptile system.Toxicon. 60: 434-448Crossref (100) Similarly, broad exist compositions genera family genus [13.Casewell Scholar,20.Tasoulis Scholar,29.Ainsworth paraspecific neutralisation induced antivenoms.Commun. 1: 1-14Crossref (62) Scholar]). much long understood why manufacturers developed products given region viper- elapid-specific antivenoms).Box 1Toxin Gene Family Expansion Coevolution Delivery MechanismsVenom varies history selection. undergone expansion neofunctionalization lineages. Three-finger (3FTxs) component expanded considerably lineage-specific duplications, facilitated emergence novel functions addition ancestral neurotoxic antagonism nicotinic acetylcholine receptors [52.Sunagar al.Three-fingered RAVERs: accumulation variations exposed residues toxins.Toxins. 2013; 5: 2172-2208Crossref (83) Scholar,86.Kessler P. three-finger fold: multifunctional scaffold able modulate cholinergic functions.J. Neurochem. 142: 7-18Crossref (59) Contrastingly, metalloproteinases (SVMP) [17.Jackson Scholar] group II phospholipase A2 (PLA2) [38.Koludarov I. al.Family saga: reconstructing complexity genetic origins novelty.bioRxiv. (Published online March 20, 2019. https://doi.org/10.1101/583344)Google expansions, facilitating activities. events redundant arrays form hotspots Scholar,17.Jackson Scholar,44.Giorgianni M.W. protein snakes.Proc. 117: 10911-10920Crossref (37) Scholar,87.Suryamohan cobra reference enables comprehensive identification toxins.Nat. Genet. 52: 106-117Crossref Scholar,88.Schield D.R. chromosomes, dosage compensation, underlying regulation snakes.Genome 29: 590-601Crossref (66) lineages, expansions sequence diversifications occurred following front-fanged, high-pressure delivery systems, highlighting coevolutionary relationship Scholar,52.Sunagar More recently, extent begun recognized. Such (i.e., regional variation) age/size classes Scholar,14.Durban dynamically evolving trait, stands reason whenever groups differ ecology, there corresponding difference composition. Juvenile consume adults same exhibit foraging prey-handling juveniles nocturnal, whereas diurnal; employ bite-and-hold strategy, 'bite release', etc.). dynamism documented level later), further evidenced existence linked variance neutral pervasive work tandem [30.Aird al.Population genomic pitviper microevolutionary forces chemistry.Genome 2640-2649Crossref (43) itself generates another prediction based first principles: evolve rapidly, must considerable heritable [31.Lewontin R.C. units selection.Annu. Syst. 1970; 1-18Crossref single population beginning investigated, preliminary evidence suggests likely confirmed [32.Smiley-Walters S.A. al.High divergence toxicity towards among individual pigmy rattlesnakes.Biol. Lett. 15: 20180876Crossref (12) Scholar,33.Petras al.Intact mass spectrometry intraspecies Vipera kaznakovi Northeastern Turkey.J. 199: 31-50Crossref (13) encoding originate code endophysiological proteins salivary, immunological, pancreatic proteins, etc.) [34.Reyes-Velasco al.Expression homologs python tissues model venom.Mol. 2015; 32: 173-183Crossref (60) Numerous proposed explain thereby, domain loss, tinkering levels, alternative- trans-splicing, under Darwinian [35.Casewell al.Complex cocktails: novelty venoms.Trends 28: 219-229Abstract (539) (Figure 1). plays key phenotypic innovation, implicated theorized undergo duplications 'birth death' [36.Fry al.Molecular phylogeny toxins.J. Mol. 57: 110-129Crossref (273) According model, repeated lead copies, pseudogenization dysfunctional time, some subsequently retained [37.Ohno Evolution Duplication. Springer-Verlag, 1970Crossref assumptions original questionable led formation multi-locus extraordinary Scholar,39.Vonk F.J. king dynamic adaptation system.Proc. U.S. 110: 20651-20656Crossref (322) later). does always introduce though increased levels. Concerted contrast maintains high conservation duplicates through recombination, strategy increase encoded [40.Moran al.Concerted anemone neurotoxin Nematostella vectensis genome.Mol. 2008; 25: 737-747Crossref (64) concerted noted recurrent do types [41.Margres M.J. al.Selection expression, diversity, precedes venom.Genetics. 206: 1569-1580Crossref (33) Since relative alter [16.Laxme shifts seem adaptations. Stochastic degeneration reported significant [42.Shibata H. habu accelerated genes.Sci. Rep. 1-11Crossref (38) several lost genes, were once present common ancestor, shifted hemotoxic profile Partial segments genes. Domain shown mediate 1), notable examples truncations structurally subclasses

Language: Английский

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From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery

Frontiers in Pharmacology, Journal Year: 2020, Volume and Issue: 11

Published: July 24, 2020

Animal poisons and venoms are comprised of different classes molecules displaying wide-ranging pharmacological activities. This review aims to provide an in-depth view toxin-based compounds from terrestrial marine organisms used as diagnostic tools, experimental validate postulated therapeutic targets, drug libraries, prototypes for the design drugs, cosmeceuticals agents. However, making these applicable requires extensive preclinical trials, with some applications also demanding clinical in order their molecular target, mechanism action, effective dose, potential adverse effects, well other fundamental parameters. Here we go through pitfalls a become eligible trials marketing. The manuscript presents overview current picture several animal (such those amphibians, cone snails, hymenopterans, scorpions, sea anemones, snakes, spiders, tetraodontiformes, bats shrews) that have been trials. Advances perspectives on underexploited animals, such caterpillars ticks, reported. challenges faced during lengthy costly studies how overcome hindrances discussed candidates going bedside. It covers most drugs developed using toxins, failed currently article detailed toxins agents, including discovery, formulation, dosage, indications, main effects pregnancy breastfeeding prescription warnings. Toxins diagnosis, atypical therapies (bee venom leech therapies) level cumulative information provided this may help pharmacists, physicians, biotechnologists, pharmacologists scientists interested toxinology, discovery development products.

Language: Английский

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ToxinPred2: an improved method for predicting toxicity of proteins

Briefings in Bioinformatics, Journal Year: 2022, Volume and Issue: 23(5)

Published: April 20, 2022

Proteins/peptides have shown to be promising therapeutic agents for a variety of diseases. However, toxicity is one the obstacles in protein/peptide-based therapy. The current study describes web-based tool, ToxinPred2, developed predicting proteins. This an update ToxinPred mainly peptides and small method has been trained, tested evaluated on three datasets curated from recent release SwissProt. To provide unbiased evaluation, we performed internal validation 80% data external remaining 20% data. We implemented following techniques protein toxicity; (i) Basic Local Alignment Search Tool-based similarity, (ii) Motif-EmeRging with Classes-Identification-based motif search (iii) Prediction models. Similarity motif-based achieved high probability correct prediction poor sensitivity/coverage, whereas models based machine-learning balance sensitivity specificity reasonably accuracy. Finally, hybrid that combined all approaches maximum area under receiver operating characteristic curve around 0.99 Matthews correlation coefficient 0.91 dataset. In addition, alternate realistic datasets. best machine learning web server named 'ToxinPred2', which available at https://webs.iiitd.edu.in/raghava/toxinpred2/ standalone version https://github.com/raghavagps/toxinpred2. general proteins regardless their source origin.

Language: Английский

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Benchmarking AlphaFold2 on peptide structure prediction

Structure, Journal Year: 2022, Volume and Issue: 31(1), P. 111 - 119.e2

Published: Dec. 15, 2022

Language: Английский

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Modern venomics—Current insights, novel methods, and future perspectives in biological and applied animal venom research

GigaScience, Journal Year: 2022, Volume and Issue: 11

Published: Jan. 1, 2022

Abstract Venoms have evolved >100 times in all major animal groups, and their components, known as toxins, been fine-tuned over millions of years into highly effective biochemical weapons. There are many outstanding questions on the evolution toxin arsenals, such how venom genes originate, contributes to fitness venomous species, which modifications at genomic, transcriptomic, protein level drive evolution. These received particularly little attention outside snakes, cone snails, spiders, scorpions. Venom compounds further become a source inspiration for translational research using diverse bioactivities various applications. We highlight here recent advances new strategies modern venomics discuss technological innovations multi-omic methods dramatically improve animals. The study genomes through CRISPR knockdown technologies will increase our understanding toxins evolve functions they different ontogenetic stages during development Mass spectrometry imaging combined with spatial transcriptomics, situ hybridization techniques, computer tomography gives us insights distribution system function apparatus. All these evolutionary biological contribute more efficiently identify compounds, can then be synthesized or produced adapted expression systems test bioactivity. Finally, we critically agrochemical, pharmaceutical, therapeutic, diagnostic (so-called translational) aspects venoms from humans benefit.

Language: Английский

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Snake Venom Gland Organoids

Cell, Journal Year: 2020, Volume and Issue: 180(2), P. 233 - 247.e21

Published: Jan. 1, 2020

Language: Английский

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Predicted Aflatoxin B1 Increase in Europe Due to Climate Change: Actions and Reactions at Global Level

Toxins, Journal Year: 2021, Volume and Issue: 13(4), P. 292 - 292

Published: April 20, 2021

Climate change (CC) is predicted to increase the risk of aflatoxin (AF) contamination in maize, as highlighted by a project supported EFSA 2009. We performed comprehensive literature search using Scopus engine extract peer-reviewed studies citing this study. A total 224 papers were identified after step

Language: Английский

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Substances of Natural Origin in Medicine: Plants vs. Cancer

Cells, Journal Year: 2023, Volume and Issue: 12(7), P. 986 - 986

Published: March 23, 2023

Continuous monitoring of the population’s health is main method learning about disease prevalence. National and international data draw attention to persistently high rates cancer incidence. This necessitates intensification efforts aimed at developing new, more effective chemotherapeutic chemopreventive drugs. Plants represent an invaluable source natural substances with versatile medicinal properties. Multidirectional activities exhibited by their ability modulate key signaling pathways, mainly related cell death, make these important research direction. review summarizes information regarding plant-derived drugs, including mechanisms action, a special focus on selected anti-cancer drugs (paclitaxel, irinotecan) approved in clinical practice. It also presents promising plant-based drug candidates currently being tested preclinical trials (betulinic acid, resveratrol, roburic acid).

Language: Английский

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Nanomaterial-mediated self-calibrating biosensors for ultra-precise detection of food hazards: Recent advances and new horizons

Coordination Chemistry Reviews, Journal Year: 2024, Volume and Issue: 522, P. 216204 - 216204

Published: Sept. 10, 2024

Language: Английский

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Therapeutic Applications of Aptamers

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6742 - 6742

Published: June 19, 2024

Affinity reagents, or target-binding molecules, are quite versatile and major workhorses in molecular biology medicine. Antibodies the most famous frequently used type they have been for a wide range of applications, including laboratory techniques, diagnostics, therapeutics. However, antibodies not only available affinity reagents do significant drawbacks, laborious costly production. Aptamers one potential alternative that variety unique advantages. They single stranded DNA RNA molecules can be selected binding to many targets proteins, carbohydrates, small molecules-for which typically low affinity. There also cost-effective methods producing modifying nucleic acids vitro without cells, whereas require cells even whole animals. While there drawbacks using aptamers therapeutic vivo stability, had success clinical trials treating diseases two aptamer-based drugs gained FDA approval. Aptamer development is still ongoing, could lead additional applications aptamer therapeutics, antitoxins, combinatorial approaches with nanoparticles other acid therapeutics improve efficacy.

Language: Английский

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