The new COST Action European Venom Network (EUVEN)—synergy and future perspectives of modern venomics

Abstract Venom research is a highly multidisciplinary field that involves multiple subfields of biology, informatics, pharmacology, medicine, and other areas. These different research facets are often technologically challenging and pursued by different teams lacking connection with each other. This lack of coordination hampers the full development of venom investigation and applications. The COST Action CA19144–European Venom Network was recently launched to promote synergistic interactions among different stakeholders and foster venom research at the European level.

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Background
Venomous species represent about 15% of the global estimated animal biodiversity, are omnipresent in aquatic and terrestrial habitats, and evolved independently in all metazoan lineages in more than 100 instances [1]. Venoms are complex mixtures of bioactive compounds, mostly peptides and proteins, that evolved through millions of years of natural selection predominantly for predation and defense. Venom toxins are adaptive and highly convergent traits, extremely useful to understand the evolutionary mechanisms that link genotype, phenotype, and protein function.
In addition, toxins are streamlined to act fast at very low concentrations, being highly specific with key physiological targets of prey and/or predators (ion channels, enzymes and cellular membrane components) [2]. Many toxins target the neuromuscular system, while others possess anticoagulant, cytolytic, anesthetic and hypotensive activities [3]. These characteristics make them ideal candidates for biotechnological applications. Ten animal-derived drugs have been so far approved and several others are in various stages of clinical trials to treat a wide array of diseases including cancer, hypertension, acute coronary syndromes and chronic pain [4]. Besides medicine, venoms toxins have great potential in other biotechnological fields: spider toxins to develop ecofriendly insecticides and other agrochemicals [4]; ion channel blockers from cone snails and bees for cosmeceutical applications [5]; and pore-forming toxins for sequencing and sensing technologies [6].

Venomics as a multidisciplinary playground
Venom investigation involves many scientific disciplines that in recent years have undergone great technological improvements ( Figure 1). These fast-evolving technologies foster venomics research, but also bring new challenges, requiring considerable integrative expertise.
High-throughput techniques have facilitated the characterization of complex venoms even in non-model organisms [7]. Transcriptomic data obtained by latest RNA-Seq technologies are often integrated with bottom-up proteomics, in which high-performance liquid chromatography is coupled with tandem mass spectrometry. This proteo-transcriptomics approach allows the detection of lowcopy transcripts and post-translational modifications, and a precise relative quantification of expressed proteins. Integration of genomic data is still uncommon, despite its promise for understanding evolutionary and regulatory patterns of venom compounds.
Bioinformatics pipelines are used for similarity-based screening and identification of promising candidates. Afterwards, the peptide and protein toxins are synthesized via solid-phase peptide synthesis and regioselective folding, or by a variety of different recombinant expression systems to obtain a realistic folding pattern. When separation and isolation of each compound is not achievable due to the low quantity of raw venom, these procedures can yield amounts of proteins suitable for subsequent activity testing, although they require extensive optimization for each component.
Activity screening mostly relies on electrophysiology that is applied on multiple neuroreceptors, ligand-gated and voltage-gated ion channels involved in neurodegenerative and drug dependency disorders, in immune system regulation, anesthesia and neuropathic pain. Electrophysiology also includes ex vivo assays and bi-dimensional array assays on tissue preparations for neurological disorders and trauma. Other activity screening tests target hormonal pathways, cancer, cardiovascular or inflammatory disorders; diabetes and obesity, infectious diseases. Bioactivitydriven identification of novel compounds is further tested by in vivo phenotypic screens [8].
In addition, biophysical approaches such as, X-ray crystallography, nuclear magnetic resonance spectroscopy, surface plasmon resonance spectroscopy, isothermal titration calorimetry and micro-computer tomography have become key components of drug discovery platforms and venom systems identification. In silico approaches, such as molecular modeling, have also become widely used for studying venom components, providing structural information and theoretical understanding of the molecular mechanisms of toxin action [9].

The COST Action EUVEN: from fragmentation to integration
The different facets of venomics are typically pursued by different research groups, whose level of collaboration in EU is not adequate to face the increasing challenges in venomics research, as

Conclusion
The new COST Action EUVEN provides a flexible platform for scientists to overcome the lack of coordination, tools, and resources, and develop a fully synergistic network. To guarantee the coverage of the diverse topics of interest in EUVEN, and build an effective network across Europe and beyond, it is fundamental to engage the broadest participation possible from all COST participating countries. Near-neighbor and international partner countries can also request to join EUVEN, and participate in networking activities.
We believe that building an effective network, able to bridge different scientific disciplines and sectors, constitutes a fundamental prerequisite to fully develop the extraordinary transformative potential of venom research.

Funding:
The authors acknowledge support from the European Cooperation in Science and Technology (COST) through the Action CA19144 EUVEN.

Conflicts of Interest:
The authors declare no conflict of interest.