Atractaspis aterrima Toxins: The First Insight into the Molecular Evolution of Venom in Side-Stabbers

Terrat, Yves; Sunagar, Kartik; Fry, Bryan G.; Jackson, Timothy N. W.; Scheib, Holger; Fourmy, Rudy; Verdenaud, Marion; Blanchet, Guillaume; Antunes, Agostinho; Ducancel, Frédéric

doi:10.3390/toxins5111948

Cited by 20 publications

(15 citation statements)

References 47 publications

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“…The only other characterized toxin type from Atractaspis venom has been a hemorrhagic metalloprotease (Ovadia, 1987). Transcriptome sequencing has shown that toxin types present in the venom include peptides (three finger, AVIT, beta-defensin, c-type lectin, cystatin, sarafotoxin, waprin), nonenzymatic proteins (CRiSP, lipocalin, nerve growth factor) and enzymes (acetylcholinesterase, kallikrein-type serine protease, metalloprotease, phospholipase A2) (Terrat et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Factor X activating Atractaspis snake venoms and the relative coagulotoxicity neutralising efficacy of African antivenoms

et al. 2018

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Atractaspis snake species are enigmatic in their natural history, and venom effects are correspondingly poorly described. Clinical reports are scarce but bites have been described as causing severe hypertension, profound local tissue damage leading to amputation, and deaths are on record. Clinical descriptions have largely concentrated upon tissue effects, and research efforts have focused upon the blood-pressure affecting sarafotoxins. However, coagulation disturbances suggestive of procoagulant functions have been reported in some clinical cases, yet this aspect has been uninvestigated. We used a suite of assays to investigate the coagulotoxic effects of venoms from six different Atractaspis specimens from central Africa. The procoagulant function of factor X activation was revealed, as was the pseudo-procoagulant function of direct cleavage of fibrinogen into weak clots. The relative neutralization efficacy of South African Antivenom Producer's antivenoms on Atractaspis venoms was boomslang>>>polyvalent>saw-scaled viper. While the boomslang antivenom was the most effective on Atractaspis venoms, the ability to neutralize the most potent Atractaspis species in this study was up to 4-6 times less effective than boomslang antivenom neutralizes boomslang venom. Therefore, while these results suggest cross-reactivity of boomslang antivenom with the unexpectedly potent coagulotoxic effects of Atractaspis venoms, a considerable amount of this rare antivenom may be needed. This report thus reveals potent venom actions upon blood coagulation that may lead to severe clinical effects with limited management strategies.

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Section: Introductionmentioning

confidence: 99%

Factor X activating Atractaspis snake venoms and the relative coagulotoxicity neutralising efficacy of African antivenoms

et al. 2018

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“…[15,16,17,18,19,20,21,22,23,24,25,26]). The results of this study not only contribute to our understanding of the molecular evolution of Australian elapid snake venom, particularly the influence of feeding ecology on venom composition, but will also constitute a platform for biodiscovery.…”

Section: Introductionmentioning

confidence: 99%

Venom Down Under: Dynamic Evolution of Australian Elapid Snake Toxins

Jackson

Sunagar

Undheim

et al. 2013

Toxins

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Despite the unparalleled diversity of venomous snakes in Australia, research has concentrated on a handful of medically significant species and even of these very few toxins have been fully sequenced. In this study, venom gland transcriptomes were sequenced from eleven species of small Australian elapid snakes, from eleven genera, spanning a broad phylogenetic range. The particularly large number of sequences obtained for three-finger toxin (3FTx) peptides allowed for robust reconstructions of their dynamic molecular evolutionary histories. We demonstrated that each species preferentially favoured different types of α-neurotoxic 3FTx, probably as a result of differing feeding ecologies. The three forms of α-neurotoxin [Type I (also known as (aka): short-chain), Type II (aka: long-chain) and Type III] not only adopted differential rates of evolution, but have also conserved a diversity of residues, presumably to potentiate prey-specific toxicity. Despite these differences, the different α-neurotoxin types were shown to accumulate mutations in similar regions of the protein, largely in the loops and structurally unimportant regions, highlighting the significant role of focal mutagenesis. We theorize that this phenomenon not only affects toxin potency or specificity, but also generates necessary variation for preventing/delaying prey animals from acquiring venom-resistance. This study also recovered the first full-length sequences for multimeric phospholipase A2 (PLA2) ‘taipoxin/paradoxin’ subunits from non-Oxyuranus species, confirming the early recruitment of this extremely potent neurotoxin complex to the venom arsenal of Australian elapid snakes. We also recovered the first natriuretic peptides from an elapid that lack the derived C-terminal tail and resemble the plesiotypic form (ancestral character state) found in viper venoms. This provides supporting evidence for a single early recruitment of natriuretic peptides into snake venoms. Novel forms of kunitz and waprin peptides were recovered, including dual domain kunitz-kunitz precursors and the first kunitz-waprin hybrid precursors from elapid snakes. The novel sequences recovered in this study reveal that the huge diversity of unstudied venomous Australian snakes are of considerable interest not only for the investigation of venom and whole organism evolution but also represent an untapped bioresource in the search for novel compounds for use in drug design and development.

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“…However, although the use of venoms for drug discovery is rapidly emerging, it is still mostly an unrealized prospect due to recurrent technical bottlenecks that represent venom exploration. The advent of -omic techniques [5–7] lead to an explosion of the number of toxin sequences known, which are available for biomedical and biotechnological exploitation [8]. High-throughput production of these highly biologically-relevant molecules using recombinant technologies is currently the major limiting step between sequencing and biological screening and represents nowadays a considerable challenge.…”

Section: Introductionmentioning

confidence: 99%

High-throughput expression of animal venom toxins in Escherichia coli to generate a large library of oxidized disulphide-reticulated peptides for drug discovery

et al. 2017

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BackgroundAnimal venoms are complex molecular cocktails containing a wide range of biologically active disulphide-reticulated peptides that target, with high selectivity and efficacy, a variety of membrane receptors. Disulphide-reticulated peptides have evolved to display improved specificity, low immunogenicity and to show much higher resistance to degradation than linear peptides. These properties make venom peptides attractive candidates for drug development. However, recombinant expression of reticulated peptides containing disulphide bonds is challenging, especially when associated with the production of large libraries of bioactive molecules for drug screening. To date, as an alternative to artificial synthetic chemical libraries, no comprehensive recombinant libraries of natural venom peptides are accessible for high-throughput screening to identify novel therapeutics.ResultsIn the accompanying paper an efficient system for the expression and purification of oxidized disulphide-reticulated venom peptides in Escherichia coli is described. Here we report the development of a high-throughput automated platform, that could be adapted to the production of other families, to generate the largest ever library of recombinant venom peptides. The peptides were produced in the periplasm of E. coli using redox-active DsbC as a fusion tag, thus allowing the efficient formation of correctly folded disulphide bridges. TEV protease was used to remove fusion tags and recover the animal venom peptides in the native state. Globally, within nine months, out of a total of 4992 synthetic genes encoding a representative diversity of venom peptides, a library containing 2736 recombinant disulphide-reticulated peptides was generated. The data revealed that the animal venom peptides produced in the bacterial host were natively folded and, thus, are putatively biologically active.ConclusionsOverall this study reveals that high-throughput expression of animal venom peptides in E. coli can generate large libraries of recombinant disulphide-reticulated peptides of remarkable interest for drug discovery programs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-016-0617-1) contains supplementary material, which is available to authorized users.

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Atractaspis aterrima Toxins: The First Insight into the Molecular Evolution of Venom in Side-Stabbers

Cited by 20 publications

References 47 publications

Factor X activating Atractaspis snake venoms and the relative coagulotoxicity neutralising efficacy of African antivenoms

Factor X activating Atractaspis snake venoms and the relative coagulotoxicity neutralising efficacy of African antivenoms

Venom Down Under: Dynamic Evolution of Australian Elapid Snake Toxins

High-throughput expression of animal venom toxins in Escherichia coli to generate a large library of oxidized disulphide-reticulated peptides for drug discovery

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