Cone Snail Venomics: From Novel Biology to Novel Therapeutics

Abstract

Peptide neurotoxins from cone snails called conotoxins are renowned for their therapeutic potential to treat pain and several neurodegenerative diseases. Inefficient assay-guided discovery methods have been replaced by high-throughput bioassays integrated with advanced MS and next-generation sequencing, ushering in the era of 'venomics'. In this review, we focus on the impact of venomics on the understanding of cone snail biology as well as the application of venomics to accelerate the discovery of new conotoxins. We also discuss the continued importance of medicinal chemistry approaches to optimize conotoxins for clinical use, with a descriptive case study of MrIA featured.

An efficient transcriptome analysis pipeline to accelerate venom peptide discovery and characterisation

“…The adoption of next-generation sequencing technology has accelerated the discovery of new venom peptides and helped inform mechanistic aspects of envenomation (Prashanth et al, 2014). Advances in sequencing throughput have gradually shifted the rate-limiting step in venom analysis from data collection to analysis (Wang et al, 2009).…”

“…This approach can also uncover rare peptides that maybe missed by traditional assay-guided fractionation (Prashanth et al, 2012). In particular, transcriptome sequencing has been used extensively to study of cone snail venoms because a single read of the 454-Pyrosequencing platform can cover the entire conotoxin precursor cDNA (~300 bp) thus circumventing the issue of assembly and this sequencing platform has been used to uncover the venome of various Conidae (Prashanth et al, 2014). Recent technological advances have increased sequence read lengths generated by the Illumina platform allowing better quality assemblies, which M A N U S C R I P T…”

“…However, this method requires large quantities of venom, and is time and resource intensive (Prashanth et al, 2012). Recent advances in transcriptomic and proteomic approaches, and the development of complementary bioinformatics tools have established 'venomics' as an accelerated method for studying venoms, with several seminal discoveries reported using this approach (Pineda et al, 2014;Prashanth et al, 2014;Zelanis and Tashima, 2014). In addition to novel toxin discoveries Viala et al, 2015), venomics has helped uncover the mechanisms governing toxin diversification Jin et al, 2013), distinct defensive and predatory venom gland specialisation in Conidae , and the morphological constraints driving the evolution of centipede venoms (Undheim et al, 2015).…”

“…In addition to novel toxin discoveries Viala et al, 2015), venomics has helped uncover the mechanisms governing toxin diversification Jin et al, 2013), distinct defensive and predatory venom gland specialisation in Conidae , and the morphological constraints driving the evolution of centipede venoms (Undheim et al, 2015). In the absence of reference genomes for many venomous animals, transcriptome sequencing of venom glands has come to underpin the venomics approach and has enabled novel toxin discovery at an unprecedented level from snakes (Durban et al, 2011), spiders (Pineda et al, 2014), scorpions (Rendón-Anaya et al, 2015), cone snails (Prashanth et al, 2014), and even relatively poorly characterised animals such as ants (Bouzid et al, 2013).…”

“…Thus, our pipeline approach has demonstrated utility and efficiency for the analysis of large venom gland transcriptomes from Conidae. Although this method was designed to identify conotoxins from next generation data sets due to the availability of standalone programs such as ConoSorter and large volumes of next-generation sequencing data (Prashanth et al, 2014), it is adaptable to the study of other venomous animals such as snakes or spiders.…”