10.2 Peptide and Protein Toxins 10.2.1 Fish Integument Toxins
Integumentary secretions of soapfishs, another teleost family, contain hemolytic peptides called grammistins (Hashimoto and Oshima 1972; Hashimoto 1979; Sugiyama et al., 2005). These are linear peptides of 12-28 residues that contain many basic amino acids and possess alpha-helical secondary structures. These peptides display antimicrobial activities against a wide variety of bacteria. Several grammistins were recently cloned (Kaji et al. 2006). Pardaxins (named after the genus Pardachirus) are surface-active anti-microbial and hemolytic peptides that are secreted from the skin of the Red Sea sole when it is stressed; these were purified and shown to form pores in liposomes (Lazarovici et al. 1986; Thompson et al. 1986 also, see Chap. 6).
Quite a few families of fish have members that possess poisonous spines. Perhaps the most well known are the scorpion fish including the Pacific stonefishs and lion-fish. During the past 15 years the proteinaceous toxins isolated from three stone-fish, Synanceja horrida (stonustoxin), S. trachynis (trachnilysin) and S. verrucosa (verrucotoxin and neoverrucotoxin) have been purified and extensively characterized (Poh et al. 1991; Ueda et al. 2006; Ghadessy et al. 1996). They are large (~150 kDa) but relatively stable proteins, containing two subunits of similar size. The cloned a- and P-subunits (71 and 79 kDa, respectively) of stonustoxin display ~50% sequence homology. There are 7 and 8 cysteine residues, respectively, in these subunits, and 10 of the 15 residues participate in intrachain disulfide linkages. The remaining five cysteines are uncombined. The stonefish toxins are pore-forming proteins, explaining their ability to lyse erythrocytes (Chen et al. 1997; Khoo 2002). The synaptic effects of trachnilysin will be described further in Chap. 6.
Many other fish contain poisonous spines that inflict painful wounds in fisherman and bathers. Oriental catfish (Plotosus lineatus) spine venom contains hemolytic, edema-forming and lethal proteins. The hemolytic protein fraction is of large size (~180 kDa) compared with the lethal proteins (~12 kDa). One lethal protein has been purified and partially characterized (Shiomi et al. 1986). Sting rays also possess poisonous spines and broken spines are often embedded in the surfaces of their predators; their proteinaceous toxins have yet to be purified and characterized.
Investigations of marine toxins during the past few decades have provided a remarkable diversity of molecules new to science. Besides stimulating chemical interest in unique structures posing many synthetic challenges, these substances often possess such unique targets that they can serve not only as useful research tools, but in some cases can either be useful drug candidates in their naturally occurring forms or as leads for designing analogs that possess even more selective actions. Traditionally, small, non-peptide molecules (MW < ~500) have served as lead compounds for drug design, due to their superior bioavailability and ease of synthesis, but this approach is rapidly being enlarged to include much larger molecules including peptides and nucleic acids. Who would have thought that an extremely lethal, large bacterial protein like botulinum toxin would become a very useful drug for treating various muscle spasms (Cooper 2007). Similarly a sea anemone peptide of 35 residues (ShK, Fig. 1) that blocks an important K+ channel (Kv1.3) in T-lymphocytes has reasonable pharmacokinetic properties and has become a drug candidate for treating host-graft (transplantation) immune rejection and certain autoimmune diseases (Beeton et al. 2006).
Regardless of whether a natural product or its analogue is to be used as a molecular probe or as a drug, target selectivity will generally be of the utmost importance. If the toxin is to be used as a probe in an in vitro system, where additional sites of action are not present, the degree of selectivity is much less stringent. On the other hand, for use as in vivo probe or as a drug administered to the whole organism, the natural product may require considerable structural manipulation (engineering) to improve target selectivity, reduce toxicity and improve pharmacokinetic properties. Natural products including toxins often preferentially interact with one or a few receptor subtypes, but it would be rare for a toxin to affect only a single receptor subtype, as this would limit its ability in nature to neutralize a wide variety of prey or predators.
Historically, marine natural products research has lagged behind the investigation of terrestrial natural products, due to the limited accessibility of most marine organisms. However, the chemical diversity of natural toxins among marine animals is likely to be much higher than for terrestrial animal toxins, as the phyletic diversity of marine animals is greater. Since the chemical diversity of marine organisms is only beginning to be appreciated, it can be anticipated that future studies will reveal a plethora of new compounds of scientific and potential therapeutic interest.
Acknowledgments We thank Professor Ben Dunn, Department of Biochemistry and Molecular Biology, University of Florida for preparing the ribbon structures (Figs. 1-4) from Brookhaven Protein Data Bank structures.
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Conotoxins: Molecular and Therapeutic Targets
Richard J. Lewis
1 Introduction 46
2 Calcium Channel Inhibitors 47
2.1 Calcium Channels 47
2.2 ra-Conotoxins 50
3 Sodium Channel Modulators 51
3.1 Voltage-gated Sodium Channels (VGSCs) 51
3.2 ^-Conotoxins 53
3.3 |lO-Conotoxins 53
3.4 S-Conotoxins 55
4 Potassium Channel Inhibitors 56
4.1 K-Conotoxins 56
4.2 kA- and KM-Conotoxins 56
5 Antagonists of Nicotinic Acetylcholine Receptors 56
5.1 a-Conotoxins 56
6 Norepinephrine Transporter Inhibitors 57
6.1 %-Conotoxins 57
7 a1-Adrenoceptor Antagonists 58
7.1 p-Conotoxins 58
8 NMDA Receptor Antagonists 60
8.1 Conantokins 60
9 Vasopressin Receptor Modulators 60
9.1 Conopressins 60
10 Neurotensin Receptor Agonists 61
10.1 Contulakin-G 61
11 Conclusions 61
Abstract Marine molluscs known as cone snails produce beautiful shells and a complex array of over 50,000 venom peptides evolved for prey capture and defence. Many of these peptides selectively modulate ion channels and transporters, making them a valuable source of new ligands for studying the role these targets
Institute for Molecular Biosciences, The University of Queensland, Brisbane 4072, Australia
Institute for Molecular Bioscie e-mail: [email protected]
N. Fusetani and W. Kem (eds.), Marine Toxins as Research Tools,
Progress in Molecular and Subcellular Biology, Marine Molecular Biotechnology 46,
DOI: 10.1007/978-3-540-87895-7, © Springer-Verlag Berlin Heidelberg 2009
play in normal and disease physiology. A number of conopeptides reduce pain in animal models, and several are now in pre-clinical and clinical development for the treatment of severe pain often associated with diseases such as cancer. Less than 1% of cone snail venom peptides are pharmacologically characterised.
Cone snails are a large group (500+ species) of recently evolved, widely distributed marine molluscs of the family Conidae. They hunt prey using a highly developed envenomation apparatus that can paralyse prey within seconds ensuring its capture and reducing exposure to predation by larger fishes. Each species of cone snail produces a rich cocktail of mostly small, disulfide-bonded peptides evolved to rapidly immobilise their prey of either fish (piscivorous species), molluscs (mol-luscivorous species) or worms (vermivorous species). The venom peptides of cone snails are expressed in a venom duct and injected through a hollow-tipped and barbed harpoon-like structure (modified radula) into the soft tissue of animals, using a muscular proboscis (Fig. 1). Depending on their lethality to animals, individual venom peptides are referred to as either conotoxins (lethal) or conopeptides (non-lethal). Each venom contains a unique array of over 100 different peptides (Fig. 2). The defensive, attractant or prey tranquilizing effects of specific conopeptides are less clearly defined. This broadly evolved bioactivity provides a unique source of new research tools and potential therapeutic agents, with ra-MVIIA (Prialt or Ziconitide) already having reached the clinic (Lewis and Garcia 2003).
Conotoxins are genetically encoded as propeptides which following expression are cleaved by specialised venom endoproteases (e.g., Tex31) to produce the final mature venom peptide (Milne et al. 2003). Their small size (typically <5 kDa), relative ease of synthesis, structural stability and target specificity make them ideal pharmacological probes (Adams et al. 1999). Somewhat surprisingly, many of these classes of conotoxins act on pain targets, allowing the specific dissection of key ion channels and receptors underlying pain, and providing new ligands with potential as pain therapeutics (Lewis and Garcia 2003). It is estimated that in excess of 50,000 conopeptides have evolved, with only ~0.1% characterised pharmacologically. The use of high throughput and more recent multiplexed high content screens should accelerate target discovery, although many conotoxins are expected to be selective for the prey species over related mammalian targets and may be missed in most screens.
This chapter focuses on the families of conotoxins and conopeptides acting at calcium (ra-conotoxins), sodium (|-, |O- and 5-conotoxins) and potassium channels (K-conotoxins), the norepinephrine transporter (%-conopeptides), nicotinic acetylcholine receptor (a-conotoxins), at-adrenoceptor (p-conopeptides), NMDA receptor (conantokins), vasopressin receptor (conopressins) and neurotensin receptor (contulakins). The therapeutic potential of selected members of these classes are highlighted in Table 1.
2 Calcium Channel Inhibitors
2.1 Calcium Channels ra-Conotoxins produced by fish hunting cone snails (Table 2) are amongst the most potent ichthyotoxins. Their selectivity for specific calcium channel subtypes found in nerves provide unique tools with which to identify and determine the
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