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Conus Venom Peptide Pharmacology 1521-0081/12/6402-259–298$25.00 PHARMACOLOGICAL REVIEWS Vol. 64, No. 2 Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics 5322/3751766 Pharmacol Rev 64:259–298, 2012 ASSOCIATE EDITOR: ANNETTE C. DOLPHIN Conus Venom Peptide Pharmacology Richard J. Lewis, Se´bastien Dutertre, Irina Vetter, and MacDonald J. Christie Institute for Molecular Bioscience, the University of Queensland in St. Lucia, Brisbane, Queensland, Australia (R.J.L., S.D., I.V.); and Discipline of Pharmacology, the University of Sydney, Sydney, New South Wales, Australia (M.J.C.) Abstract ................................................................................ 260 I. Introduction............................................................................. 260 II. ␻-Conotoxin inhibitors of voltage-gated calcium channels .................................... 263 A. Subtype selectivity ................................................................... 264 B. Structure-activity relationships ........................................................ 266 C. Calcium channel inhibition by conotoxins in pain management ........................... 267 II. Conotoxins interacting with voltage-gated sodium channels .................................. 269 Downloaded from A. ␮-Conotoxin inhibitors of voltage-gated sodium channels ................................. 271 B. ␮O-Conotoxin inhibitors of voltage-gated sodium channels................................ 272 C. Other conotoxin inhibitors of voltage-gated sodium channels.............................. 273 D. ␦-Conotoxin activators of voltage-gated sodium channels ................................. 273 E. ␫-Conotoxin activators of voltage-gated sodium channels.................................. 273 F. Sodium channel inhibition in pain management ......................................... 274 by guest on September 7, 2017 III. ␬-Conotoxins interacting with potassium channels .......................................... 277 A. ␬A-Conotoxins ....................................................................... 277 B. ␬O-Conotoxins ....................................................................... 277 C. ␬M-Conotoxins ....................................................................... 278 D. ␬J-Conotoxins........................................................................ 278 E. ␬I(2)-Conotoxins...................................................................... 279 F. Contryphan-Vn ...................................................................... 279 G. Conkunitzin-S1 ...................................................................... 279 IV. Conotoxins interacting with ligand-gated ion channels ...................................... 279 A. Conotoxin inhibitors of nicotinic acetylcholine receptors .................................. 279 ␴ B. -Conotoxin inhibitors of serotonin 5-hT3 receptors ...................................... 283 C. Ikot-Ikot conopeptide enhancers of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors ............................................................................ 283 D. Conantokin inhibitors of N-methyl-D-aspartate receptors ................................. 284 E. Ligand-gated ion channels inhibitors in pain management ............................... 285 V. Conotoxins Interacting with G protein-coupled receptors and neurotransmitter transporters .......... 287 A. ␳-Conopeptide inhibitors of ␣1-adrenoceptors............................................ 287 B. ␹-Conopeptide inhibitors of the noradrenaline transporter ................................ 288 C. Conopeptides modulating vasopressin/oxytocin receptors ................................. 289 D. Neurotensin receptor agonists ......................................................... 289 Address correspondence to: Richard J. Lewis, Institute for Molecular Bioscience, the University of Queensland, Q4072, Australia. E-mail: [email protected] This work was supported by a National Health and Medical Research Council of Australia (NHMRC) Research Fellowship (to R.J.L., M.J.C.); an NHMRC Trainee Fellowship (to I.V.), a University of Queensland Postdoctoral Fellowship (to S.D.), and an NHMRC Program Grant (to R.J.L., M.J.C.). This article is available online at http://pharmrev.aspetjournals.org. http://dx.doi.org/10.1124/pr.111.005322. 259 260 LEWIS ET AL. VI. Conclusions and outlook.................................................................. 289 Acknowledgments ....................................................................... 290 References .............................................................................. 291 Abstract——Conopeptides are a diverse group of re- and therapeutic potential of cone snail venom peptide cently evolved venom peptides used for prey capture families acting at voltage-gated ion channels (␻-, ␮-, and/or defense. Each species of cone snails produces in ␮O-, ␦-, ␫-, and ␬-conotoxins), ligand-gated ion channels excess of 1000 conopeptides, with those pharmacolog- (␣-conotoxins, ␴-conotoxin, ikot-ikot, and conan- ically characterized (ϳ0.1%) targeting a diverse range tokins), G-protein-coupled receptors (␳-conopeptides, of membrane proteins typically with high potency and conopressins, and contulakins), and neurotransmitter specificity. The majority of conopeptides inhibit volt- transporters (␹-conopeptides), with expanded discus- age- or ligand-gated ion channels, providing valuable sion on the clinical potential of sodium and calcium research tools for the dissection of the role played by channel inhibitors and ␣-conotoxins. Expanding the specific ion channels in excitable cells. It is notewor- discovery of new bioactives using proteomic/tran- thy that many of these targets are found to be ex- scriptomic approaches combined with high-through- pressed in pain pathways, with several conopeptides put platforms and better defining conopeptide struc- having entered the clinic as potential treatments for ture-activity relationships using relevant membrane pain [e.g., pyroglutamate1-MrIA (Xen2174)] and one protein crystal structures are expected to grow the now marketed for intrathecal treatment of severe pain already significant impact conopeptides have had as [ziconotide (Prialt)]. This review discusses the diver- both research probes and leads to new therapies. sity, pharmacology, structure-activity relationships, I. Introduction tation, venom peptides have coevolved with sophisti- cated and specialized envenomation machinery com- The interrogation of chemical diversity with therapeuti- prising fangs, barbs, modified teeth, harpoons, cally relevant screens remains the dominant discovery en- nematocysts, spines, or sprays. Not surprisingly, gine for the pharmaceutical industry. Although most suc- cess with this approach has been achieved by exploring given that most venoms are delivered intravenously, natural product extracts composed mostly of smaller or- there are multiple examples of convergent evolution of ganic molecules, there is a growing realization that pep- a relatively small number of structural scaffolds that tides are an underused source of leads for new therapeu- possess the requisite stability to remain intact, both tics. This realization is now gaining momentum following within the venom and in plasma after envenomation. the disappointments of combinatorial chemistry, increas- These “privileged” structural frameworks have pro- ing failure rates of small molecules in clinical development, vided the scaffolds for an explosion in sequence diver- and the limitations of small-molecule–based approaches sity that explains much of the chemical diversity for many druggable targets. Sources of peptides include found in present-day venoms. plant cyclotides (Henriques and Craik, 2010), phage dis- Among the venomous species, cone snails within the play libraries (Pande et al., 2010), and venom peptides family Conidae are unique for their ability to use a diverse (Lewis and Garcia, 2003). Among these sources, venom array of small disulfide-bridged peptides (conopeptides or peptides provide arguably the largest source of chemical conotoxins) for prey capture (Fig. 1). Conopeptides have diversity, being driven by evolutionary pressure for im- evolved across all phylogenetic clades and feeding strate- proved prey capture and/or defense. This diversity has gies of cone snails from at least 16 genetically distinct arisen multiple times in nature in animals as diverse as superfamilies, many of which are subject to extensive post- sea anemones, jellyfish, centipedes, spiders, scorpi- translational modifications (Table 1). This highly evolved ons, cone snails, cephalopods, echinoderms, snakes, hunting strategy, developed in parallel with the deploy- lizards, fish, platypus and arguably even fleas, mos- ment of a hollow, barbed harpoon, allows normally herbiv- quitoes, kissing bugs, leeches, ticks, and vampire bats orous molluscs to prey on animals as diverse as worms (Fry et al., 2009). Ensuring their successful implemen- (vermivorous species), fish (piscivorous species), and other molluscs (molluscivorous species). Successful implementa- 1Abbreviations: 5-HT , 5-hydroxytryptamine ; ACh, acetylcho- 3 3 tion of this strategy has allowed this single genus of widely line; AChBP, acetylcholine binding protein; Am2766, CKQAG- ␣ distributed marine molluscs to evolve into more than 500 ESCDIFSQNCCVGTCAFICIE-NH2; AMPA, -amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid; AR, adrenergic receptor; Cav, Conus species. Cone snails hunt prey mostly
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