References to Work on Conus Toxins (A-Z, annotated)

Gatto GJ, Bohme GA, Caldwell WS, Letchworth SR, Traina VM, Obinu MC, Laville M, Reibaud M, Pradier L, Dunbar G, Bencherif M. (2004) TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant, neuroprotective and long-lasting cognitive effects.CNS Drug Rev.10(2):147-166.
Preclinical Research, Targacept, Inc. 200 East First Street, Suite 300, Winston-Salem, NC 27101-4165, USA.

Abstract: The development of selective ligands targeting neuronal nicotinic acetylcholine receptors to alleviate symptoms associated with neurodegenerative diseases presents the advantage of affecting multiple deficits that are the hallmarks of these pathologies. TC-1734 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal nicotinic receptors. Microdialysis studies indicate that TC-1734 enhances the release of acetylcholine from the cortex. TC-1734, by either acute or repeated administration, exhibits memory enhancing properties in rats and mice and is neuroprotective following excitotoxic insult in fetal rat brain in cultures and against alterations of synaptic transmission induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal doses, TC-1734 produced additive cognitive effects when used in combination with tacrine or donepezil. Unlike (-)-nicotine, behavioral sensitization does not develop following repeated administration of TC-1734. Its pharmacokinetic (PK) profile (half-life of 2 h) contrasts with the long lasting improvement in working memory (18 h) demonstrating that cognitive improvement extends beyond the lifetime of the compound. The very low acute toxicity of TC-1734 and its receptor activity profile provides additional mechanistic basis for its suggested potential as a clinical candidate. TC-1734 was very well tolerated in acute and chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials demonstrated TC-1734's favorable pharmacokinetic and safety profile by acute oral administration at doses ranging from 2 to 320 mg. The bioavailability, pharmacological, pharmacokinetic, and safety profile of TC-1734 provides an example of a safe, potent and efficacious neuronal nicotinic modulator that holds promise for the management of the hallmark symptomatologies observed in dementia. Publication Types: Review Review, Tutorial

Gibbs, W.W. (1996) A new way to spell relief: V-e-n-o-m, a toxin from killer sea snails promises a better painkiller. Scientific American 274: 20-21.
[Abstract: The only thing worse than a pain- filled life is a painful death. Both are altogether too common. The World Health Organization estimates that on any given day over three million people struggle with chronic pain from cancer alone. In the U.S., a study published last November in the Journal of the American Medical Association revealed that of thousands of terminal patients interviewed at five major hospitals, about half spent their final days in agony. The study's authors laid much of the blame at the feet of a medical culture that chases miracles to the bitter end rather than doing its best to assuage suffering.

But there is another reason that medicine so often fails to offer relief: doctors still have few weapons against pain, and each has major drawbacks. Aspirin and other over-the-counter remedies are far too weak for most chronic conditions. Narcotics such as morphine often work for a while, but many patients quickly become physically dependent and require ever stronger infusions. Eventually, says William G. Brose, director of the Pain Clinic at the Stanford University School of Medicine, "opiatetolerant patients feel no effect even from a dose thousands of times stronger than that needed to kill you or me." As a result, many sufferers can obtain comfort only at the cost of their faculties.

Gonor, J.J. 1966. Escape responses of N. Borneo Strombid gastropods elicited by the predatory prosobranchs Aulica vespertilio & Conus marmoreus . Veliger 8 (4) 226-230.

Gouda, H., Yamazaki, K-i., Hasegawa, J., Kobayashi, Y., Nishiuchi, Y., Sakakibara, S. and Hirono, S. (1997) Solution structure of alpha-conotoxin MI determined by (1)H-NMR spectroscopy and molecular dynamics simulation with the explicit solvent water. BBA - Proteins and Proteomics, 1343: 327-334.

R.E.W. Hatley. (2002) Marine mollusks and the skin. Dermatologic Therapy 15: 38-43.
Abstract: Human contact with marine mollusks such as shellfish, marine snails, octopuses, and squids may result in human illness including dermatologic disorders. These range from minor traumatic injury of the skin to more serious systemic illnesses that include dermatologic manifestations. Notable among these are dermatologic manifestations of illness caused by toxins from ingested mollusks, stings of the cone snail, and envenomation by the bite of the blue-ringed octopus. Cone snail and blue-ringed octopus envenomations, although rare, can be deadly due to neuromuscular paralysis. Management of dermatologic illnesses caused by marine mollusks depends upon the nature of the exposure. Attention to local measures is usually sufficient for minor cuts and abrasions. Conversely, cone snail and blue-ringed octopus envenomations require immediate attention, possibly including cardiopulmonary resuscitation.

Haubrich, C., Frielingsdorf, V., Herzig, S., Schroder, H., Schwarting, R., Sturm, V. and Voges, J. (2000) N-type calcium channel blockers - tools for modulation of cerebral functional units ?. Brain Res. 855: 225 - 234

Hawdon GM, Winkel KD. (1997) Venomous marine creatures.Aust Fam Physician. 26: 1369-1374.
Australian Venom Research Unit, Cabrini Private Hospital.
BACKGROUND: Many venomous marine creatures inhabit Australian waters, causing significant morbidity and occasional fatalities. No antivenom is available for most of these creatures. Little is known about the venom or syndromes produced by many of these creatures. OBJECTIVE: This article discusses the features of envenomation by some of the more commonly encountered venomous marine creatures, and the recommended first aid and medical management of such envenomations. DISCUSSION: The information contained within this article is intended to provide the reader with an overview of some of the more common marine envenomations, and hopefully with the knowledge to effectively manage such problems.
Comment in: Aust Fam Physician. 1998 May;27(5):343-4. Aust Fam Physician. 1998 May;27(5):344.

Heading, C.E., 1999. Ziconotide, Neurex Corp. Current Opinion in CPNS Investigational Drugs 1, 153-166.

Heading, C.E., 2001. Ziconotide (Elan Pharmaceuticals). IDrugs 4, 339-350.

Heading, C.E., 2002. Conus peptides and neuroprotection. Curr Opin Investig Drugs 3, 915-920.

Heiman, E.L.., ( 2002) Shells of East Sinai, an illustrated list. Conidae. Triton, 5: 19-23.

Heiman, E.L., (2002) Shells of East Sinai an illustrated list. Conidae. Triton, Supplement 1: 1-10.

Hill, J.M., Atkins, A.R., Loughnan, M.L., Jones, A., Adams, D.A., Martin, R.C., Lewis, R.J., Craik, D.J. and Alewood, P.F. (2000)Conotoxin TVIIA, a novel peptide from the venom of Conus tulipa: 1. Isolation, characterization and chemical synthesis. Europ. J. Biochem. 267: 4642-4649..
Abstract: A novel conotoxin belonging to the `four-loop' structural class has been isolated from the venom of the piscivorous cone snail Conus tulipa. It was identified using a chemical-directed strategy based largely on mass spectrometric techniques. The new toxin, conotoxin TVIIA, consists of 30 amino-acid residues and contains three disulfide bonds. The amino-acid sequence was determined by Edman analysis as SCSGRDSRCOOVCCMGLMCSRGKCVSIYGE where O = 4-transl-hydroxyproline. Two under-hydroxylated analogues, Pro10TVIIA and Pro10,11TVIIA, were also identified in the venom of C. tulipa. The sequences of TVIIA and Pro10TVIIA were further verified by chemical synthesis and coelution studies with native material. Conotoxin TVIIA has a six cysteine four-loop structural framework common to many peptides from Conus venoms including the omega-, delta- and kappa-conotoxins. However, TVIIA displays little sequence homology with these well-characterized pharmacological classes of peptides, but displays striking sequence homology with conotoxin GS, a peptide from Conus geographus that blocks skeletal muscle sodium channels. These new toxins and GS share several biochemical features and represent a distinct subgroup of the four-loop conotoxins.

Hill, J.M., Alewood, P.F. and Craik, D.J.(2000) Conotoxin TVIIA, a novel peptide from the venom of Conus tulipa : 2. Three-dimensional solution structure. Europ J Biochem. 267: 4649-4658. .
Abstract: The three-dimensional solution structure of conotoxin TVIIA, a 30-residue polypeptide from the venom of the piscivorous cone snail Conus tulipa, has been determined using 2D 1H NMR spectroscopy.TVIIA contains six cysteine residues which form a `four-loop' structural framework common to many peptides from Conus venoms including the omega-, delta-, kappa-, and O-conotoxins. However, TVIIA does not belong to these well-characterized pharmacological classes of conotoxins, but displays high sequence identity with conotoxin GS, a muscle sodium channel blocker from Conus geographus. Structure calculations were based on 562 interproton distance restraints inferred from NOE data, together with 18 backbone and nine side-chain torsion angle restraints derived from spin-spin coupling constants. The final family of 20 structures had mean pairwise rms differences over residues 2-27 of 0.18 +- 0.05 A for the backbone atoms and 1.39 +- 0.33 A for all heavy atoms. The structure consists of a triple-stranded, antiparallel beta sheet with +2x, 1 topology (residues 7-9, 16-20 and 23-27) and several beta turns. The core of the molecule is formed by three disulfide bonds which form a cystine knot motif common to many toxic and inhibitory polypeptides. The global fold, molecular shape and distribution of amino-acid sidechains in TVIIA is similar to that previously reported for conotoxin GS, and comparison with other four-loop conotoxin structures provides further indication that TVIIA and GS represent a new and distinct subgroup of this structural family. The structure of TVIIA determined in this study provides the basis for determining a structure-activity relationship for these molecules and their interaction with target receptors.

Hill, J.M., Oomen, C.J., Miranda, L.P., Bingham, J.-P., Alewood, P.F. and Craik, D.J. (1998) Three-Dimensional Solution Structure of a-Conotoxin MII by NMR Spectroscopy: Effects of Solution Environment on Helicity. Biochemistry 37 15621-15630.

Hinegardner, R.T. (1958) The venom apparatus of the cone shell. Hawaii Medical Journal 17: 533-563.

Hogg, R.C. and Bertrand, D. (2004) Nicotinic acetylcholine receptors as drug targets. Curr Drug Targets CNS Neurol Disord. 3:123-130.
Department of Physiology, CMU, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland. hogg1@etu.unige.ch

Abstract: While it has long been documented that nicotine contained in tobacco leaves gives rise to major public health problems it has also been observed that this alkaloid can have beneficial effects. However, it is only with the identification of a family of genes coding for the neuronal nicotinic acetylcholine receptors and increased knowledge of their expression and function in the central nervous system that these receptors have received attention concerning their potential as drug targets. In light of the latest findings about nicotinic acetylcholine receptors and their involvement in disease states we review the possibility to design new drugs targeted to these ligand-gated channels. Beneficial and possible undesirable actions of agonists, antagonists and allosteric modulators are discussed and placed in perspective of our most recent knowledge.

Hopkins, C., Grilley, M., Miller, C., Shon, K.-J., Cruz, L.J., Gray, W.R., Dykert, J., Rivier, J., Yoshikami, D. and Olivera, B.M. (1995) A new family of Conus peptides targeted to the nicotinic acetylcholine receptor. J. Biol. Chem. 270: 22361-22367.

[Conus purpurascens, the purple cone, alphaA-conotoxin PIVA, Gulf of California - eastern Pacific]

Abstract

In this work, a new family of Conus peptides, the alpha A-conotoxins, which target the nicotinic acetylcholine receptor, is defined. The first members of this family have been characterized from the eastern Pacific species, Conus purpurascens (the purple cone)., three peptides that cause paralysis in fish were purified and characterized from milked venom. The sequence and disulfide bonding pattern of one of these, alpha A-conotoxin PIVA, is as follows: [formula: see text] where O represents trans-4-hydroxyproline. The two other peptides purified from C. purpurascens venom are the under-hydroxylated derivatives, [Pro13]alpha A-conotoxin PIVA and [Pro7,13]alpha A-conotoxin PIVA. The peptides have been chemically synthesized in a biologically active form. Both electrophysiological experiments and competition binding with alpha-bungarotoxin demonstrate that alpha A-PIVA acts as an antagonist of the nicotinic acetylcholine receptor at the postsynaptic membrane.

Hori, S., Okutani, T. (1996). A New Pyramidellid Gastropod Ectoparasitic on Conus. Venus, Japanese J. Malacology 55(1):7-14. {Coneodostomia okamurai, Boonea okamurai n.spp., RhizoConus, VirroConus}

HÖRNES & al., 1851. Die fossilen Mollusken Des Tertiaer-Beckens von Wien. - No 1. Conus. 42pp., 5pls.,

Hovda, D.A., Fu, K., Badie, H., Samii, A., Pinanong, P. and Becker, D.P. (1994) Administration of an omega-conopeptide one hour following traumatic brain injury reduces 45calcium accumulation. Acta Neurochir Suppl (Wien) 60: 521-523. [SNX-111, NIH 95067173]

Huang, C.-C., Lyu, P.-C., Lin, C.-H. and Hsu, K.-S. (1997) Conantokin-T selectively antagonizes N-methyl-d-aspartate-evoked responses in rat hippocampal slice.Toxicon, 35: 355-364. .
Abstract: This study investigated the mode of action of conantokin-T, a 21 amino acid peptide toxin isolated from the venom of the fish-hunting cone snail Conus tulipa, on excitatory synaptic transmission in rat hippocampal slices using intracellular recording techniques. Superfusion of conantokin-T (1-500 nM) specifically and irreversibly decreased the pharmacologically isolated N-methyl-d-aspartate receptor (NMDA)-mediated excitatory postsynaptic potential (EPSPNMDA) in a concentration-dependent manner but had no effect on normal excitatory synaptic transmission (EPSP). The sensitivity of postsynaptic neurons to NMDA but not to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid was also antagonized by conantokin-T pretreatment. In addition, the conantokin-T-induced depression of EPSPNMDA could be antagonized by prior treatment of hippocampal slices with eitherdl-2-amino-5-phosphonovaleate (10 muM) or ifenprodil (20 muM). However, 7-chlorokynurenic acid (1 muM) had no effect on the action of conantokin-T. These findings indicated that conantokin-T modulates the NMDA receptor by an interaction with its glutamate binding site and polyamine recognition site.

Humblet, C., Narasimhan, L. and Singh, J. (1995)Snail and spider toxins share similar tertiary structure and 'cystine motif'Toxicon, 33: 270. .
Abstract: The multi-disulphide bridged peptide toxins, omega-conotoxin GVIA from the venom of the cone snail, Conus geographus, and omega-agatoxins IVA and IVB from the venom of the funnel-web spider Agelenopsis aperta, have become-valuable tools for studying the physiology, pharmacology and anatomical distribution of neuronal voltage-sensitive calcium channels. A comparison of the structures of omega-conotoxin GVIA and omega-agatoxin IVB will be presented with particular focus on the structural role of their disulphides. Despite the difference in size, these toxins have a similar location and disulphide connectivity of half-cystines. The tertiary structures of the two toxins show remarkable similarity. Both toxins fold into a triple-stranded beta-sheet with a +2x, - 1 topology. A sequence alignment indicates a 27% sequence identity, most of which (23%) is accounted for by the half-cystines. The low level of identity between residues other than half-cystines suggests that the structural similarity observed is prominently dictated by the relationship between their cystine motifs. Toxins from snail venoms have been shown to present a common cystine pattern despite very low primary sequence homology. Interestingly, the example presented here shows that similar cystine motifs are found in toxins that originate from different animal species. The structural similarity, in relation to the similar cystine motifs, might imply a common tertiary structure for toxins that share this core. On that basis, the present observation provides a rationale for model-building of toxins which possess a similar cystine motif.

Ibanez-Tallon I, Wen H, Miwa JM, Xing J, Tekinay AB, Ono F, Brehm P, Heintz N. (2004) Tethering naturally occurring Peptide toxins for cell-autonomous modulation of ion channels and receptors in vivo. Neuron. 43:305-311.
Howard Hughes Medical Institute, Laboratory of Molecular Biology, The Rockefeller University, New York, NY 10021 USA.
Abstract: The physiologies of cells depend on electrochemical signals carried by ion channels and receptors. Venomous animals produce an enormous variety of peptide toxins with high affinity for specific ion channels and receptors. The mammalian prototoxin lynx1 shares with alpha-bungarotoxin the ability to bind and modulate nicotin