Venomics-Accelerated Cone Snail Venom Peptide Discovery

Abstract

Cone snail venoms are considered a treasure trove of bioactive peptides. Despite over 800 species of cone snails being known, each producing over 1000 venom peptides, only about 150 unique venom peptides are structurally and functionally characterized. To overcome the limitations of the traditional low-throughput bio-discovery approaches, multi-omics systems approaches have been introduced to accelerate venom peptide discovery and characterisation. This “venomic” approach is starting to unravel the full complexity of cone snail venoms and to provide new insights into their biology and evolution. The main challenge for venomics is the effective integration of transcriptomics, proteomics, and pharmacological data and the efficient analysis of big datasets. Novel database search tools and visualisation techniques are now being introduced that facilitate data exploration, with ongoing advances in related omics fields being expected to further enhance venomics studies. Despite these challenges and future opportunities, cone snail venomics has already exponentially expanded the number of novel venom peptide sequences identified from the species investigated, although most novel conotoxins remain to be pharmacologically characterised. Therefore, efficient high-throughput peptide production systems and/or banks of miniaturized discovery assays are required to overcome this bottleneck and thus enhance cone snail venom bioprospecting and accelerate the identification of novel drug leads.

Venomics: A Mini-Review

“…Currently, genome sequencing is typically performed using third-generation next-generation sequencing (NGS) technologies, having moved forward from the second-generation NGS technologies (e.g., 454 pyrosequencing, sequencing by oligonucleotide ligation and detection (SOLiD), and Illumina reversible terminator chemistry) (reviewed in [ 2 ]). The “short-read” sequencing technologies, such as Illumina platforms, have lower error rates and can provide highly accurate genotyping in non-repetitive regions but do not allow contiguous de novo assemblies which restricts the ability to reconstruct repetitive sequences and detect complex structural variation [ 18 ].…”

“…Both approaches have been fundamentally transformed by the revolution in powerful mass spectrometry-based instrumentation and protocols with the capability to identify and accurately quantify expressed proteins [ 49 ]. For the study of venoms, proteomics provides a comprehensive, multi-faceted approach for the analysis of venom proteins, including sequence, post-translational modifications (PTMs), quantity, regionalisation, and stimulus-dependence of venom protein mobilisation [ 2 ]. PTMs are particularly common in venom.…”

“…PTMs are particularly common in venom. For example, cone snail venom peptides are notorious for undergoing a diverse range of PTMs, with up to 75% of amino acids post-translationally modified in individual conopeptides [ 2 , 15 ]. Disulfide bonds and C-terminal amidation are common PTMs found in spider venom peptides, and examples of common PTMs observed in cone snail venom peptides include C-terminal amidation, disulfide bonds, N-terminal pyroglutamylation, proline hydroxylation, valine hydroxylation, tryptophan bromination, γ-carboxylation of glutamic acid, tyrosine sulfation, and O -glycosylation [ 2 , 15 ].…”

“…The complex mixtures of diverse, selective and potent natural products found in the venom of venomous creatures has garnered significant interest and is well-published as a source of potential therapeutic leads [ 1 , 2 , 3 , 4 ]. This interest stems from >50% of all approved drugs arising from natural products or their derivatives [ 5 ], including six venom-derived drugs approved by the Food and Drug Administration (FDA) [ 6 ].…”

“…Limited quantities of venom have also hindered attempts to characterise venom components [ 12 ]. Accessing this expansive peptide reserve requires the broad implementation of multidimensional miniaturised high-throughput strategies [ 2 ].…”