Venomics as a drug discovery platform

Escoubas, Pierre; King, Glenn F.

doi:10.1586/epr.09.45

Cited by 158 publications

(117 citation statements)

References 31 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…Considering that around 44,000 terrestrial venomous species (scorpions, snakes, spiders), 20,000 marine species (cone snails, turrids, and Cnidarians) and 103,000 flying species (hymenopterans) have already been reported, and that each of their venoms is composed of approximately 250 different toxins, this natural pool consists of more than 40 million peptide toxins, biochemically stable and with particular pharmacologic properties [1,2]. From this impressive number of toxins, only 1600 have been identified corresponding to less than 0.01% of the whole bank.…”

Section: Introductionmentioning

confidence: 99%

An Unusual Family of Glycosylated Peptides Isolated from Dendroaspis angusticeps Venom and Characterized by Combination of Collision Induced and Electron Transfer Dissociation

Quinton

Gilles

Smargiasso

et al. 2011

J. Am. Soc. Mass Spectrom.

View full text Add to dashboard Cite

This study describes the structural characterization of a totally new family of peptides from the venom of the snake green mamba (Dendroaspis angusticeps). Interestingly, these peptides differ in several points from other already known mamba toxins. First of all, they exhibit very small molecular masses, ranging from 1.3 to 2.4 kDa. The molecular mass of classical mamba toxins is in the range of 7 to 25 kDa. Second, the new peptides do not contain disulfide bonds, a posttranslational modification commonly encountered in animal toxins. The third difference is the very high proportion of proline residues in the sequence accounting for about one-third of the sequence. Finally, these new peptides reveal a carbohydrate moiety, indicating a glycosylation in the sequence. The last two features have made the structural characterization of the new peptides by mass spectrometry a real analytical challenge. Peptides were characterized by a combined use of MALDI-TOF/TOF and nanoESI-IT-ETD experiments to determine not only the peptide sequence but also the composition and the position of the carbohydrate moiety. Anyway, such small glycosylated and proline-rich toxins are totally different from any other known snake peptide and form, as a consequence, a new family of peptides.

show abstract

Section: Introductionmentioning

confidence: 99%

An Unusual Family of Glycosylated Peptides Isolated from Dendroaspis angusticeps Venom and Characterized by Combination of Collision Induced and Electron Transfer Dissociation

Quinton

Gilles

Smargiasso

et al. 2011

J. Am. Soc. Mass Spectrom.

View full text Add to dashboard Cite

show abstract

“…Only full tryptic peptides were considered with a maximum of two missed cleavages. Mass tolerances for MS 1 and MS 2 were set at 70 and 550 ppm, respectively. XCorr was determinate as a primary score, and ZScore was used as a secondary one.…”

Section: Methodsmentioning

confidence: 99%

“…The toxic secretions of venomous animals have long been a source of biologically active molecules, yet remain a promising source of new drugs (1,2). Snake venoms in particular are widely studied and contain a mixture of small molecules, peptides, proteins, and protein complexes which are used to incapacitate prey and to defend against predators (3)(4)(5).…”

mentioning

confidence: 99%

“…Most current techniques for venom protein analysis and toxin identification are based on bottom-up (BU) 1 proteomics approaches where toxins are enzymatically digested and the peptides are analyzed by tandem mass spectrometry (MS/ MS) (8 -11). Although this technique can generate a comprehensive overview of toxin families present in the venom, such peptide-based toxin studies do not provide isoform-specific identifications and/or distributions and stoichiometries of post-translational modifications (PTMs).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mapping Proteoforms and Protein Complexes From King Cobra Venom Using Both Denaturing and Native Top-down Proteomics

Melani¹,

Skinner

Fornelli

et al. 2016

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

Characterizing whole proteins by top-down proteomics avoids a step of inference encountered in the dominant bottom-up methodology when peptides are assembled computationally into proteins for identification. The direct interrogation of whole proteins and protein complexes from the venom of Ophiophagus hannah (king cobra) provides a sharply clarified view of toxin sequence variation, transit peptide cleavage sites and post-translational modifications (PTMs) likely critical for venom lethality. A tube-gel format for electrophoresis (called GELFrEE) and solution isoelectric focusing were used for protein fractionation prior to LC-MS/MS analysis resulting in 131 protein identifications (18 more than bottom-up) and a total of 184 proteoforms characterized from 14 protein toxin families. Operating both GELFrEE and mass spectrometry to preserve non-covalent interactions generated detailed information about two of the largest venom glycoprotein complexes: the homodimeric L-amino acid oxidase (ϳ130 kDa) and the multichain toxin cobra venom factor (ϳ147 kDa). The L-amino acid oxidase complex exhibited two clusters of multiproteoform complexes corresponding to the presence of 5 or 6 N-glycans moieties, each consistent with a distribution of N-acetyl hexosamines. Employing top-down proteomics in both native and denaturing modes provides unprecedented characterization of venom proteoforms and their complexes. A precise molecular inventory of venom proteins will propel the study of snake toxin variation and the targeted development of new antivenoms or other biotherapeutics. Molecular &

show abstract

“…Utilising these new and improved techniques has significantly increased our understanding of the remarkable venom complexity of several jellyfish species [14] (see chapter 3 and 4). When genomic database (and therefore theoretical protein databases) is not available, activity-guided fractionation can be useful to facilitate characterisation of active toxins (bioactivies) in whole venom [146,285]. For example, screening of the fractioned crude venom from Conus sp.…”

Section: Introductionmentioning

confidence: 99%

Evolution and diversification of the cnidarian venom system

Jouiaei¹

View full text Add to dashboard Cite

The phylum Cnidaria (corals, sea pens, sea anemones, jellyfish and hydroids) is the oldest venomous animal lineage (~750 million years old), making it an ideal phylum to understand the origin and diversification of venom. Cnidarians are characterised by specialised cellular structures called cnidae, which they utilise to inject mixtures of bioactive compounds or venom for predation and defence. In recent years cnidarian venoms have begun to be investigated as a potential source of novel bioactive therapeutics. However, in comparison with several venomous lineages that are relatively younger, such as snakes, cone snails and spiders, the diversification and molecular evolutionary regimes of toxins encoded by these fascinating and ancient animals remain poorly understood.The first experimental part of this thesis (Chapter 2) is comprised of the phylogenetic and molecular evolutionary histories of pharmacologically characterised cnidarian toxin families. These include peptide neurotoxins (voltage-gated Na + and K + channel-targeting toxins: NaTxs and KTxs, respectively), pore-forming toxins (actinoporins, aerolysin-related toxins, and jellyfish toxins) and small cysteine-rich peptides (SCRiPs). Our analyses show that most cnidarian toxins remain conserved under the strong influence of negative selection. A deeper analysis of the molecular evolutionary histories of neurotoxins demonstrates that type III KTxs have evolved from NaTxs under the regime of positive selection and likely represent a unique evolutionary innovation of the Actinioidea lineage. We also identify a few functionally important sites in other classes of neurotoxins and pore-forming toxins that experienced episodic adaptation. In addition, we describe the first family of neurotoxic peptides (SCRiPs) in reef-building corals, Acropora millepora, that are likely involved in the envenoming function.The third chapter describes the development of a novel venom extraction technique which is rapid, repeatable and cost effective. This technique involves using ethanol to both induce cnidae discharge and to recover venom contents in one step. Our model species is the notorious Australian box jellyfish (Chironex fleckeri) which has a notable impact on public health. By using the complementary approaches of transcriptomics, proteomics, mass spectrometry, histology, and scanning electron microscopy, this study compares the proteome profile of the new ethanol recovery based method to a previously reported protocol, based upon density purified intact cnidae and pressure induced disruption. This work not only results in the expansion of identified Australian box jellyfish venom components but also illustrates that ethanol extraction method could greatly augment future cnidarian venom proteomics research efforts.The forth chapter is constituted by previously described venom extraction technique, ethanolinduced discharge of cnidae, to rapidly and efficiently characterise venom components of the Jelly Blubber or Blue Blubber Jellyfish, Catostylus mosaicus. By us...

show abstract

Venomics as a drug discovery platform

Cited by 158 publications

References 31 publications

An Unusual Family of Glycosylated Peptides Isolated from Dendroaspis angusticeps Venom and Characterized by Combination of Collision Induced and Electron Transfer Dissociation

An Unusual Family of Glycosylated Peptides Isolated from Dendroaspis angusticeps Venom and Characterized by Combination of Collision Induced and Electron Transfer Dissociation

Mapping Proteoforms and Protein Complexes From King Cobra Venom Using Both Denaturing and Native Top-down Proteomics

Evolution and diversification of the cnidarian venom system

Contact Info

Product

Resources

About