The organisms in the phylum Cnidaria represent some of the oldest living venomous creatures on the planet, including jellyfish, hydroids, sea anemones, and corals (Rachamim et al., 2015). The phylum is primarily defined by the presence of nematocytes, or stinging cells, in the tissue of these organisms (Ozbek, 2011). Nematocyte cells contain a tubule with a capsule of venom that, when stimulated, is everted, striking the prey/predator, penetrating the outer membrane and delivering the venom (Ozbek, 2011). These stinging cells have a variety of purposes but are mainly used for prey capture and defense (Greenwood, 2009).

Venoms often contain a complex mixture of compounds, including small molecules, peptides and proteins. These compounds can be highly potent and specific for biological targets, and the peptides in venoms are generally stable because of the presence of disulfide bonds making them of interest in drug design (Vetter et al., 2011; Utkin, 2015). Venomous creatures, such as spiders, scorpions, and cone snails have been well-studied and several databases have been established to collate the data on the toxins present (Kaas et al., 2008, 2012; Kuzmenkov et al., 2016; Pineda et al., 2018). Although cnidarians are generally less well-studied (Macrander et al., 2018), information about the toxins present is currently expanding.

Perhaps the most well-known of the cnidarian organisms are jellyfish. Their venom can be extremely potent and act, not only on small marine prey organisms, but can also have severe physiological effects on humans (Tibballs, 2006; Tibballs et al., 2011; Remigante et al., 2018). Although not as harmful as some jellyfish, other cnidarians, such as select sea anemones can elicit a stinging sensation in humans when the nematocytes in the tentacles are stimulated (Lubbock et al., 1981; Garcia-Arredondo et al., 2016). Several sea anemone toxins have been well-characterized, including an analog of a ShK toxin from Stichodactyla helianthus, which has entered Phase 2 trials for autoimmune diseases (Pennington et al., 2009; Chi et al., 2012; Prentis et al., 2018). There have been several recent reviews of sea anemone toxins regarding their bioactivity as well as their potential uses in the field of pharmaceutical development (Prentis et al., 2018; Thangaraj et al., 2018; Madio et al., 2019; Utkin et al., 2019). Corals are often overshadowed by the highly potent and potentially life-threatening toxins from jellyfish and clinically relevant sea anemones, but they too possess toxins of interest.

Much of the research on corals has focused on climate change impacts and secondary metabolites. In the past year alone there have been more than 3,750 journal articles published on “corals and climate change” (GoogleScholar) while there are around 388 articles published on “corals and toxins” (2 August 2019). The majority of research on corals and their secondary metabolites is not necessarily venom related. For example, metabolites from the gorgonian coral Erythropodium caribaeorum have been shown to act as a deterrent against reef fishes predating on the coral (Fenical and Pawlik, 1991). However, more recent studies have characterized venom derived coral toxins, with potential in the field of drug development (Radwan et al., 2002; Frazao et al., 2012; Rodriguez et al., 2012; Garcia-Arredondo et al., 2016). There is significant scope for future studies aimed at characterizing coral toxins, and in this mini review we highlight some of the structural and functional diversity that has already been uncovered.

Corals, primarily grouped into stony corals and soft corals, are members of the Anthozoa class of the phylum Cnidaria as shown in the phylogenetic tree in Figure 1. Toxins have been characterized from four of the Anthozoa order and examples of these toxins are given in Table 1 to highlight the structural diversity, range of bioactivities and potential applications. The majority of research into toxins from organisms in the Anthozoa class has focused on sea anemones, because of the exciting therapeutic potential of some of the toxins, and several recent reviews have been published in this area (Prentis et al., 2018; Liao et al., 2019; Madio et al., 2019). Although there are distinct differences between sea anemones and corals, with stony corals having calcium carbonate skeletons in contrast to sea anemones (Shick, 1991; Stanley, 2003), the two organisms are in the same class and might have similar compounds to each other. We are only just beginning to appreciate the diversity of compounds present in the nematocysts of corals and potentially toxins present elsewhere in the tissue of these organisms. There is evidence that toxins can be delivered from anatomical structures other than nematocytes in sea anemones, with differences in localization between species (Moran et al., 2012; Bastos et al., 2016). It is possible a similar phenomenon also occurs in corals. While sea anemone toxins, such as the ShK toxins have not been found in corals to date, there are examples of other toxins and toxin families as outlined below for stony corals and soft corals and highlights the importance of characterizing coral toxins.

Insight into the evolution of coral toxins is primarily based on the SCRiP family of peptides, as these are the most well-characterized to date. As mentioned above, in contrast to the original suggestion, SCRiPS are not only found in corals but have been found in the sea anemones Anemonia viridis and Metridium senile (Jouiaei et al., 2015b). The toxin τ-AnmTx Ueq 12-1 isolated from the sea anemone Urticina eques also shows similarity to SCRiPs, in particular one cDNA matched the SCRiP Anthopleura elegantissima comp63456_c0_seq1 (Logashina et al., 2017). The presence of SCRiPs in corals and sea anemones suggests that these proteins evolved more than 500 million years ago, the estimated time when coral diverged from sea anemones (Shinzato et al., 2011). Furthermore, molecular evolutionary assessments indicate that coral SCRiPs have evolved under negative selection as no sites were found that were positively selected based on the Bayes Empirical Bayes approach (Jouiaei et al., 2015a). The role of negative selection in coral toxin evolution is supported by studies on the toxins of Acropora digitifera and Stylophora pistilata (Gacesa et al., 2015; Ben-Ari et al., 2018). Interestingly, this appears to be a general phenomenon for venoms of ancient lineages, whereas toxins from lineages that have evolved more recently appear to evolve under positive selection (Lynch, 2007; Casewell et al., 2011, 2012; Sunagar et al., 2012, 2013, 2014; Brust et al., 2013; Dutertre et al., 2014; Jouiaei et al., 2015a; Sunagar and Moran, 2015).

Given the large number of toxins that appear to be present in coral venom, further molecular characterization is likely to provide further insight into the evolution of this ancient lineage. In particular, characterization of some of the larger toxins might provide insight into origins of a range of toxins, as analysis of the venom from the sea anemone Stichodactyla haddoni showed that some venom peptides have similar sequences to housekeeping proteins involved in regulatory biological functions (Madio et al., 2017). This is a common trend across many venomous taxa because it is suggested that the main ways that toxins are recruited is via gene modification of regulatory proteins, such as sequence duplications (Fry et al., 2009). It has been shown that cnidarian organisms rely on similar structural frameworks of their toxins and then modify these toxins for activity on specific targets (Honma and Shiomi, 2006; Prentis et al., 2018). Because of this evolution from non-toxin related proteins, we see variability in the size of peptides found in nematocyte venom as the evolution of each peptide differs greatly (Table 1).

Despite the similarities between cnidarian organisms, such as coral and sea anemones, it is also likely that significant differences in the evolution of toxins will be found based on analysis of proteins found in the nematocysts of organisms from three different classes of Cnidaria, namely Anthozoa, Scyphozoa, and Hydrozoa (Rachamim et al., 2015). The organisms analyzed from these three classes were the sea anemone Anemonia viridis (Anthozoa), the jellyfish Aurelia aurita (Scyphozoa) and the hydrozoan Hydra magnipapillata (Hydrozoa). Although this analysis led to the identification of hundreds of proteins, only six proteins were common in all three species (Rachamim et al., 2015). Of these, most were structural proteins and only one of the six proteins common to all three species, the dickkopf protein, is predicted to function as a toxin (Rachamim et al., 2015). The A. aurita and H. magnipapillata venom showed the most similarities, mainly composed of cytotoxins and enzymes, while the A. viridis venom proteome composition was predominantly related to peptide neurotoxins (Rachamim et al., 2015). The general lack of conservation across these cnidarians might point to significant evolutionary differences and further cnidarian toxins promises to provide interesting insights into toxin evolution in general.

In the study of venomous creatures, such as spiders and cone snails it can often be quite straightforward to isolate the venom with limited contamination from the environment or other tissues. Indeed, Australian funnel-web spiders (Atracidae) can release microlitres of venom onto their fangs that can be “easily” recovered (Wilson and Alewood, 2004). However, for corals and cnidarian organisms in general this is not always the case, and can complicate the toxin extraction process (Garcia-Arredondo et al., 2016). A range of extraction methods have been used in the analysis of corals and sea anemones, including extraction of the toxins from the nematocyte in the tissue of the coral (Garcia-Arredondo et al., 2016) and homogenization of the whole tentacle of the sea anemone (Prentis et al., 2018). Homogenization of the whole tentacle will clearly yield more than just venom toxins, but even extraction of the toxins from the nematocyst can be complicated, given the small size of the nematocysts. Furthermore, it can be difficult to separate out the calcareous skeleton of the coral from the tissue itself (Garcia-Arredondo et al., 2016). The cellular contents can have implications for interpretation of the results because some components, such as minicollagens share characteristics similar to the cysteine-rich toxins of interest (Madio et al., 2017).

The difficulties in defining the origin of compounds, either from the nematocyst or other tissue, has significant implications for elucidating evolutionary relationships for these toxins. In particular, it is difficult to determine a common ancestor (Kayal et al., 2018). Genome and transcriptomic analyses are likely to provide further insight into the evolution of cnidarian toxins. Using an integrative approach of both genomic and transcriptomic analyses allows for a better understanding of the active toxins found in organisms compared to the potential toxins seen in the genome and will also allow comparison with other toxins from a range of venomous creatures.

Coral venoms are a source of interesting novel bioactive molecules with significant scope for further characterization of novel toxins. Further application of analysis technologies (e.g., genomics, transcriptomics, and proteomics) is likely to significantly enhance the knowledge in this field and identify novel classes of peptides/proteins. The well-characterized coral toxins, SCRiPs, have now been identified as likely neurotoxins, but given the highly microbial environment in which corals exist, further analysis of the nematocyst components of corals is likely to provide a new and unique source of antimicrobial molecules. Studies on coral extracts have indicated that such compounds exist. In addition, determining the composition of peptides that make up the venom from corals may provide insight into the overlap and differences between cnidarian groups.

CS, ND, and DW wrote the manuscript.