Large-scale discovery of conopeptides and conoproteins in the injectable venom of a fish-hunting cone snail using a combined proteomic and transcriptomic approach

Violette, Aude; Biass, Daniel; Dutertre, Sébastien; Koua, Dominique; Piquemal, David; Pierrat, Fabien; Stöcklin, Reto; Favreau, Philippe

doi:10.1016/j.jprot.2012.06.001

Cited by 75 publications

(73 citation statements)

References 42 publications

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“…However, using traditional protein-centric drug discovery approaches has been a tedious and time-consuming task that allows only superficial mining of the huge chemical diversity of natural products and that usually leads to the identification of only a few bioactive peptides per experiment (77). During the past decade, several studies focusing solely on cone snail venom duct (43,44,49,(78)(79)(80) or salivary gland (9,43,44,49,(78)(79)(80) transcriptomes, and later complemented by proteome profiling (46,47,50,59,81), have allowed the report of no more than only a hundred (47 on average) full-length precursor conotoxins each. The great majority of these studies used the ROCHE 454 next-generation sequencing platform because it produced low amounts of long reads that were possible to annotate by performing simple homology BLAST searches.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, improvement of de novo assembly programs dedicated to the treatment of datasets with numerous conserved sequences and repeats would open the way to the identification of new classes of longer polypeptides with original modes of action (81). However, de novo transcriptome assembly still remains a challenging task (87-91) requiring dedicated highdepth sequencing strategies and extensive optimization steps (92) especially when performed in nonmodel organisms expressing highly similar transcripts.…”

Section: Discussionmentioning

confidence: 99%

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Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks

Lavergne

Harliwong

Jones

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cone snails are predatory marine gastropods characterized by a sophisticated venom apparatus responsible for the biosynthesis and delivery of complex mixtures of cysteine-rich toxin peptides. These conotoxins fold into small highly structured frameworks, allowing them to potently and selectively interact with heterologous ion channels and receptors. Approximately 2,000 toxins from an estimated number of >70,000 bioactive peptides have been identified in the genus Conus to date. Here, we describe a high-resolution interrogation of the transcriptomes (available at www.ddbj.nig.ac.jp) and proteomes of the diverse compartments of the Conus episcopatus venom apparatus. Using biochemical and bioinformatic tools, we found the highest number of conopeptides yet discovered in a single Conus specimen, with 3,305 novel precursor toxin sequences classified into 9 known superfamilies (A, I1, I2, M, O1, O2, S, T, Z), and identified 16 new superfamilies showing unique signal peptide signatures. We were also able to depict the largest population of venom peptides containing the pharmacologically active C-C-CC-C-C inhibitor cystine knot and CC-C-C motifs (168 and 44 toxins, respectively), as well as 208 new conotoxins displaying odd numbers of cysteine residues derived from known conotoxin motifs. Importantly, six novel cysteine-rich frameworks were revealed which may have novel pharmacology. Finally, analyses of codon usage bias and RNA-editing processes of the conotoxin transcripts demonstrate a specific conservation of the cysteine skeleton at the nucleic acid level and provide new insights about the origin of sequence hypervariablity in mature toxin regions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks

Lavergne

Harliwong

Jones

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Cone snails, as the other members of the superfamily Conoidea, are characterized by a venom apparatus. The venom, comprising up to 200 different toxins ("conotoxins"), specific to each species of cone snails (Dutertre et al 2013;Violette et al 2012), is injected in the prey (worms, molluscs or fish) by a highly modified harpoon-shaped radular tooth. The relatively recent discovery of conotoxins and their therapeutical applications is also fueling the enthusiasm of the scientific community for cone snails, and the discovery of a new species is always a warranty to discover new toxins.…”

Section: Introductionmentioning

confidence: 99%

Conus hughmorrisoni, a new species of cone snail from New Ireland, Papua New Guinea (Gastropoda: Conidae)

Lorenz¹,

Puillandre

2015

EJT

735

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Abstract. Based on newly collected material from the Kavieng Lagoon Biodiversity Survey, we describe a new species of cone snail, Conus hughmorrisoni sp. nov., from the vicinity of Kavieng, New Ireland, Papua New Guinea. It closely resembles the New Caledonian C. exiguus and the Philippine C. hanshassi, but differs from these species by having more numerous shoulder tubercles, by the shell's sculpturing and details of the color pattern. We also sequenced a fragment of the mitochondrial COI gene of five specimens collected alive. All possessed very similar sequences (genetic distances < 0.3%), different from all the COI sequences of cone snails available in GenBank (genetic distances > 10%).

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“…This review will not cover this area in significant depth due to the wealth of reviews already available on conotoxins and pain. [33][34][35] However, cone snails have yielded the first toxin-derived analgesic approved for clinical use -Prialt ® (Ziconotide, Elan Pharmaceuticals). 36 This 25 amino acid peptide is a synthetic form of the natural snail venom that blocks N-type calcium channels in the dorsal horn of the spinal cord.…”

Section: Pain-relevant Speciesmentioning

confidence: 99%

Venom: the sharp end of pain therapeutics

Trim

2013

British Journal of Pain

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Adequate pain control is still a significant challenge and largely unmet medical need in the 21st century. With many small molecules failing to reach required levels of potency and selectivity, drug discovery is once again turning to nature to replenish pain therapeutic pipelines. Venomous animals are frequently stereotyped as inflictors of pain and distress and have historically been vilified by mankind. Yet, ironically, the very venoms that cause pain when directly injected by the host animal may actually turn out to contain the next generation of analgesics when injected by the clinician. The last 12 months have seen dramatic discoveries of analgesic tools within venoms. Spiders, snakes and even centipedes are yielding peptides with immense therapeutic potential. Significant advances are also taking place in delivery methods that can improve bioavailability and pharmacokinetics of these exciting natural resources. Turning proteinaceous venom into pharmaceutical liquid gold is the goal of venomics and the focus of this article.

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Large-scale discovery of conopeptides and conoproteins in the injectable venom of a fish-hunting cone snail using a combined proteomic and transcriptomic approach

Cited by 75 publications

References 42 publications

Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks

Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks

Conus hughmorrisoni, a new species of cone snail from New Ireland, Papua New Guinea (Gastropoda: Conidae)

Venom: the sharp end of pain therapeutics

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