Sea Anemones: Quiet Achievers in the Field of Peptide Toxins
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toxins Review Sea Anemones: Quiet Achievers in the Field of Peptide Toxins Peter J. Prentis 1,2 ID , Ana Pavasovic 1,3 and Raymond S. Norton 4,* ID 1 School of Earth, Environmental and Biological Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4001, Australia; [email protected] (P.J.P.); [email protected] (A.P.) 2 Institute of Future Environments, Queensland University of Technology (QUT), Brisbane, QLD 4001, Australia 3 Faculty of Health, Queensland University of Technology (QUT), Brisbane, QLD 4001, Australia 4 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia * Correspondence: [email protected]; Tel.: +61-3-9903-9167 Received: 18 December 2017; Accepted: 4 January 2018; Published: 8 January 2018 Abstract: Sea anemones have been understudied as a source of peptide and protein toxins, with relatively few examined as a source of new pharmacological tools or therapeutic leads. This is surprising given the success of some anemone peptides that have been tested, such as the potassium channel blocker from Stichodactyla helianthus known as ShK. An analogue of this peptide, ShK-186, which is now known as dalazatide, has successfully completed Phase 1 clinical trials and is about to enter Phase 2 trials for the treatment of autoimmune diseases. One of the impediments to the exploitation of sea anemone toxins in the pharmaceutical industry has been the difficulty associated with their high-throughput discovery and isolation. Recent developments in multiple ‘omic’ technologies, including genomics, transcriptomics and proteomics, coupled with advanced bioinformatics, have opened the way for large-scale discovery of novel sea anemone toxins from a range of species. Many of these toxins will be useful pharmacological tools and some will hopefully prove to be valuable therapeutic leads. Keywords: sea anemone; peptide; ShK; potassium channel; autoimmune disease; genomics; transcriptomics; proteomics; evolution Key Contribution: The sea anemone peptide ShK highlights the potential of these venomous animals to produce valuable therapeutic leads, and the abundance in nature of peptides related to ShK suggests that this scaffold can support a range of functions. Current genomic, transcriptomic and proteomic studies of sea anemones promise to greatly expand the number of ShK analogues and to identify a range of novel peptide families. 1. Introduction Sea anemones are members of the phylum Cnidaria, class Anthozoa, subclass Hexacorallia and order Actiniaria, one of the oldest extant orders of venomous animals. In common with many other venomous animals, they produce venom that is a complex mixture of small molecules, peptides and proteins [1–7]. Unlike some of the better known groups of venomous animals such as snakes and spiders, however, or even their fellow cnidarians the Australian box jellyfish or Irukandji, which (quite appropriately) attract considerable public attention [8,9], the potentially harmful consequences of contact with sea anemones are relatively unknown. Indeed, many members of the public are not even aware that they are animals rather than plants, let alone venomous ones (Figure1). Toxins 2018, 10, 36; doi:10.3390/toxins10010036 www.mdpi.com/journal/toxins Toxins 2018, 10, 36 2 of 15 Toxins 2018, 10, 36 2 of 14 While most most injuries injuries caused caused by by sea sea anemones anemones are areassociated associated with with skin skinrashes rashes and oedema, and oedema, more moreextreme extreme reactions reactions have have been been reported reported for forseveral several species, species, including including ActinodendronActinodendron plumosum plumosum and other species from the family Actinodendronidae (species from this family are collectively known as thethe hell’shell’s fire fire anemones), anemones),Telmatactis Telmatactisspecies, species,Phyllodiscus Phyllodiscus semoni semoni(night (night or wasp or wasp anemone), anemone),Actinia Actinia equina (beadletequina (beadlet anemone) anemone) and Anemonia and Anemonia sulcata (thesulcata snakelocks (the snakelocks anemone, anemone, synonomy synonomyAnemonia Anemonia viridis)[ viridis10,11].) For[10,11]. example, For example, a swimmer a swimmer lost consciousness lost consciousness and underwent and underwent cardiopulmonary cardiopulmonary arrest after beingarrest stung after bybeing the stung sea anemone, by the seaActinia anemone, equina Actinia, although equina this, although may have this been may a consequencehave been a ofconsequence an anaphylactic of an reactionanaphylactic following reaction prior following exposure prior to unknownexposure to sea unknown anemones sea [ 12anemones]. Sea anemones [12]. Sea fromanemones the family from Aliciideaethe family are Aliciideae known to are be particularlyknown to be dangerous particularly to humans, dangerous with severeto humans, reactions with observed severe followingreactions contactobserved with following both Triactis contact producta with [both13] and TriactisP. semoni producta[10]. [13] In fact, andP. P. semoni semoniis responsible[10]. In fact, for P. one semoni of the is fewresponsible fatalities for to one result of fromthe few sea fatalities anemone to envenomation result from sea [14 anemone]. The venom envenomation from P. semoni [14]. Thehas causedvenom acutefrom P. renal semoni failure has in caused humans, acute with renal a protein failure toxin in humans, (PsTX-115) with from a protein this venom toxin causing (PsTX-115) severe from kidney this damagevenom causing in rat models severe [kidney15]. damage in rat models [15]. Figure 1. Sea anemone species that are locally abundant in the waters off south-eastern Queensland, Figure 1. Sea anemone species that are locally abundant in the waters off south-eastern Queensland, Australia; these species have been largely unexplored for their toxin contents and are currently under Australia; these species have been largely unexplored for their toxin contents and are currently under investigationinvestigation in our labs to identify new peptide an andd protein toxins with pote potentiallyntially novel functions. ((AA)) AulactiniaAulactinia veratra veratra(B )( undescribedB) undescribed species species of Anthopleura of Anthopleura(C) Calliactis (C) polypusCalliactis(D polypus) Actinia australiensis(D) Actinia. Photoaustraliensis credit:. Photo Ana Pavasovic. credit: Ana Pavasovic. 2. Venom Apparatus 2. Venom Apparatus Sea anemones, in common with other members of the phylum Cnidaria, possess numerous Sea anemones, in common with other members of the phylum Cnidaria, possess numerous specialized stinging cells (cnidocytes) that are widely distributed throughout the body [16]. These specialized stinging cells (cnidocytes) that are widely distributed throughout the body [16]. stinging cells are equipped with organelles known as nematocysts (cnidae), which contain small These stinging cells are equipped with organelles known as nematocysts (cnidae), which contain small threads that are forcefully everted when stimulated mechanically or chemically [17]. These threads that are forcefully everted when stimulated mechanically or chemically [17]. These nematocysts nematocysts contain a complex cocktail of toxins that is used to envenomate predatory and prey contain a complex cocktail of toxins that is used to envenomate predatory and prey species upon species upon discharge [1,3,6]. Nematocysts show significant heterogeneity in their density and discharge [1,3,6]. Nematocysts show significant heterogeneity in their density and morphology across morphology across different structures within sea anemones [18]. For example, in Actinia tenebrosa (or its northern hemisphere relatives Actinia equina and Actinia fragacea), acrorhagi (which are used in aggressive intra-specific combat (Figure 2)) contain holotrichs and basitrichs [19] (Figure 3), while the Toxins 2018, 10, 36 3 of 15 different structures within sea anemones [18]. For example, in Actinia tenebrosa (or its northern hemisphere relatives Actinia equina and Actinia fragacea), acrorhagi (which are used in aggressive Toxins 2018, 10, 36 3 of 14 intra-specific combat (Figure2)) contain holotrichs and basitrichs [ 19] (Figure3), while the tentacles (whichtentacles are (which used in are prey used capture in prey and capture defence) and contain defence) basitrichs contain and basitrichs spirocysts; and basitrichs spirocysts; are alsobasitrichs found inare the also mesenteric found in the filaments, mesenteric column, filaments, pedal column disc and, pedal actinopharynx disc and actinopharynx [19] (Figure3 [19]). The (Figure differences 3). The indifferences cnidae composition in cnidae composition are related to are differences related to in differences the functional in the specialization functional ofspecialization morphological of structures,morphological i.e., thestructures, capture ofi.e., prey the (crustaceans,capture of prey small (crustaceans, fish), defence small against fish), predators defence against and intraspecific predators aggressionand intraspecific [19–22 aggression]. [19–22]. Figure 2. ThisThis photograph photograph shows shows the the bright bright blue blue acrorh acrorhagiagi used used in intraspecific in intraspecific combat combat [20] [20and] andred redtentacles tentacles used used in prey in preycapture capture and defence and defence against against predators predators of the ofAustralian the Australian sea anemone, sea anemone, Actinia Actiniatenebrosa tenebrosa. Both structures. Both structures