Happy festive season to you all - and good coning in 2001 :
30 December 2000
COGNETIX Corporation: new web site:
COGNETIX Corporation, Salt Lake City, Utah, have released their new web site. This excellent and informative resource provides details about this private company whose mission is "to discover new methods to treat human disease or injury in order to improve quality of life". The Company's most advanced product research and development efforts are based on 'conopeptides', peptides derived from the venom of Conus species of predatory sea snails (cone shells). The site provides information about the pharmacological properties of the conopeptides (summarized in a Table)and their potential disease targets (which include Epilepsy, Pain, Local Anesthesia, Neuromuscular Blockade, Neuromuscular Disorders, Demyelinating Disorders (MS, multiple sclerosis; and SCI, spinal cord injury), and Cardiovascular and Cerebrovascular Disorders (Myocardial Ischemia, Arrhythmia, and Stroke). Among the Company's products are CGX 1007 (conantokin-G) for the treatment of epilepsy (reduction of seizures, Stage I Clinical Trials began September 30, 2000); and CGX 1160 (contulakin-G), a neurotensin receptor antagonist, targeted for reduction of short-term post-operative pain. On 5 Feb, 2000 Cognetix, Inc. formed a pain management collaboration with Elan Corporation, plc. by completing a licensing and collaboration agreement to develop and commercialize Cognetix's contulakin-G (CGX-1160) for short-term management of post-operative pain using Elan's proprietary MEDIPAD Drug Delivery System. In addition, CGX-1007 (an NMDA receptor antagonist), has potential for the prevention of neuropathic pain as do a number of mu-conotoxins (sodium channel blockers) shown to be effective in pre-clinical models of pain. At the present time (Dec. 2000) Cognetix had over 20 issued or allowed patents covering the composition of conopeptide sequences from a number of Conus species and methods to treat or diagnose various central and peripheral nervous system disorders and cardiovascular conditions (see List of Conotoxin Patents).
Man and Mollusc Web Resource:
Rated by Ross Mayhew as "the most complete Malacological and Conchological links assemblage on the web":
- Avril's Malacological/Conchological and Internet Resources Page provides excellent links for the on-line Molluscophile community: In agreement with Ross, I heartily recommend everyone check it out and bookmark it for further use.
21 December 2000
Xenome granted $AUD1.6 million:
Medica Holdings Limited, Press Release, 18 December 2000 announced :Xenome granted $1.6 million to further
research and development Extract: Medica is pleased to announce that its most recent investee company, Xenome, has been offered a $1.6 million grant by the Industry Research and Development (IR&D) Board under AusIndustry's R&D Start Program. The grant represents matching funds for a project to develop novel therapeutic compounds for pain and urological disorders. Funds are contingent on certain conditions, such as execution of an Agreement satisfactory to the IR&D Board.
Xenome has licensed a large portfolio of novel venom-based molecules from the University of Queensland and is systematically identifying their pharmacological activity and potential as new therapeutics.
One significant lead compound acts on a key protein in the central nervous system (CNS) which may lead to novel treatment for CNS disorders such as depression and peripheral conditions such as pain and urinary incontinence.
Xenome intends to utilise the grant funds to optimise the pharmacological activity of the molecules and conduct preclinical testing.
13 December 2000
Superior clinical utility suggested for AM336 relative to ziconotide:
At the December meeting of the Australiasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) [Abstract P 1.11, Monday 4 December, 2000], Newcastle, Australia, Dr. M.T. Smith and coworkers presented a poster entitled:
"LACK OF CROSS-TOLERANCE BETWEEN INTRATHECAL AM336 AND INTRAVENOUS MORPHINE IN CONTRAST TO THE MARKED CROSS-TOLERANCE BETWEEN ZICONOTIDE AND MORPHINE".
MT Smith (1), FB Ross (1), R Lewis (2), JB Kurek (3) & PJ Cabot (1), (1) School of Pharmacy, Univ of Qld, Qld,
4072, (2) Centre for Drug Design and Development, Univ of Qld, Qld 4072, (3) AMRAD Operations, Vic 3121
Abstract: The w-conopeptides, AM336 and ziconotide are potent inhibitors of N-type calcium channels and are currently in clinical development as novel analgesic agents for the alleviation of severe pain in patients that have failed to
respond adequately to strong opioids such as morphine. As many of these patients have been treated with morphine, it is important to evaluate whether cross-tolerance occurs between these conopeptides and morphine. Therefore, this study was designed to quantify the extent of cross-tolerance between intrathecal (it) AM336 and intravenous (iv) morphine relative to that for ziconotide (it) and morphine (iv) in adult male Sprague-Dawley rats with chronic inflammatory pain. Hindpaw inflammation was induced by intra-plantar injection of Freund’s Complete Adjuvant (FCA, 0.15 mL) whilst rats were under brief 3% is oflurane: 97% oxygen inhalational anaesthesia. Peptides (or vehicle) were administered via a chronically implanted polyethylene cannula inserted intrathecally between L5 and L6 and exteriorized at the base of the neck. Antinociception was quantified using the paw pressure test (PPT). On day 5 post-FCA, morphine-naďve FCA-treated rats received acute bolus doses of AM336 (0.067 nmol, it) or ziconotide (0.022, 0.059 nmol, it) in a volume of 10 mL followed by a 15 mL saline flush; antinociception was
quantified for 24 h post-dosing. Rats then received a chronic infusion of morphine (10 mg/24 h) via a jugular vein cannula until rats were tolerant to its antinociceptive effects (4 days). Following a 24 h washout infusion of iv saline, rats then received a 2 nd bolus intrathecal dose of the same peptide given initially, to quantify whether the induction of morphine tolerance had altered the antinociceptive potency of subsequently administered AM336 (it) or ziconotide (it). The extent of cross-tolerance between AM336 (it) and morphine (iv) was low and not significantly
different from that observed for intrathecal vehicle (150 mM lactate buffer, pH 4.5) administered before and after a chronic 7-day intrathecal infusion of vehicle. In contrast, marked cross-tolerance was found between intrathecal ziconotide and morphine. This apparently differential effect of morphine tolerance on the antinociceptive effects of subsequently administered intrathecal AM336 and ziconotide, suggests that these two conopeptides interact with different subtypes of the N-type calcium channel in the spinal cord. Furthermore, our findings suggest that AM336 may have superior clinical utility relative to ziconotide. See also Smith et al 2000 Pain. 96:119-127.
3-D Structure of w-Contoxin TxVII:
Kobayashi K, Sasaki T, Sato K, Kohno T.(2000) Three-Dimensional Solution Structure of omega-Conotoxin TxVII, an L-Type Calcium Channel Blocker. Biochemistry 39:14761-14767.
Abstract: We determined the three-dimensional structure of omega-conotoxin TxVII, a 26-residue peptide that is an L-type calcium channel blocker, by (1)H NMR in aqueous solution. Twenty converged structures of this peptide were obtained on the basis of 411 distance constraints obtained from nuclear Overhauser effect connectivities, 20 torsion angle constraints, and 21 constraints associated with hydrogen bonds and disulfide bonds. The root-mean-square deviations about the averaged coordinates of the backbone atoms (N, C(alpha), C, and O) and all heavy atoms were 0.50 +/- 0.09 A and 0.99 +/- 0.13 A, respectively. The structure of omega-conotoxin TxVII is composed of a triple-stranded antiparallel beta-sheet and four turns. The three disulfide bonds in omega-conotoxin TxVII form the classical cystine knot motif of toxic or inhibitory polypeptides. The overall folding of omega-conotoxin TxVII is similar to those of the N-type calcium channel blockers, omega-conotoxin GVIA and MVIIA, despite the low amino acid sequence homology among them. omega-Conotoxin TxVII exposes many hydrophobic residues to a certain surface area. In contrast, omega-conotoxin GVIA and MVIIA expose basic residues in the same way as omega-conotoxin TxVII. The channel binding site of omega-conotoxin TxVII is different from those of omega-conotoxin GVIA and MVIIA, although the overall folding of these three peptides is similar. The gathered hydrophobic residues of omega-conotoxin TxVII probably interact with the hydrophobic cluster of the alpha(1) subunit of the L-type calcium channel, which consists of 13 residues located in segments 5 and 6 in domain III and in segment 6 in domain IV.
w-Contoxins MVIIA and CVID in conscious rabbits:
Wright, C.E., Robertson, A.D., Whorlow, S.L. and Angus, J.A. (2000) Cardiovascular and autonomic effects of omega-conotoxins MVIIA and CVID in conscious rabbits and isolated tissue assays. Br J Pharmacol. 131: 1325-1336.
Abstract: The effects of a novel N-type voltage-operated calcium channel antagonist, omega-conotoxin CVID, were compared with omega-conotoxin MVIIA on sympathetic-evoked activation of right atria (RA), small mesenteric arteries (MA) and vasa deferentia (VD) isolated from the rat. Their effects were also compared on blood pressure and cardiovascular reflexes in conscious rabbits. The pIC(50) values for MVIIA and CVID, respectively, for inhibiting sympathetic-evoked responses were equivalent in RA (8.7 and 8.7) and VD (9.0 and 8.7); however, in MA the values were 8.4 and 7.7. The cardiac to vascular (RA/MA) potency ratios, antilog (plog RA - plog MA), for MVIIA and CVID were 2 and 10. The offset rates for CVID and MVIIA were rapid, and peptide reapplication caused rapid onset of blockade, suggesting limited desensitization. In the conscious rabbit, CVID and MVIIA (100 mug kg(-1) i.v.) caused a similar fall in blood pressure and a tachycardia that rapidly reached maximum. Both peptides decreased the vagal- and sympathetic-mediated components of the baroreflex, but had no effect on the vagal nasopharyngeal reflex. The orthostatic reflex to 90 degrees tilt was blocked by MVIIA with sustained postural hypotension for >/=90 min after administration. In contrast, CVID caused postural hypotension at 30 min which recovered rapidly. Neither CVID nor MVIIA (3 mug kg(-1) i.t.) significantly altered cardiovascular variables or autonomic reflexes. In conclusion, CVID appears to be relatively weak at inhibiting the reflex response to tilt consistent with its weaker inhibition of rat mesenteric artery constriction to perivascular nerve stimulation. This may point to subtype N-type calcium channel selectivity.
Peptide toxins and small-cell lung carcinoma :
Sher, E., Giovannini, F., Boot, J. and Lang, B. (2000) Peptide neurotoxins, small-cell lung carcinoma and neurological paraneoplastic syndromes. Biochimie 82: 927-936.
Abstract:
Peptide neurotoxins isolated from the venom of snakes, spiders and snails have represented invaluable tools for the identification and characterisation of membrane ion channels and receptors in vertebrate cells, including human neurons. We here report on the use of these toxins for the characterisation of membrane ion channels and receptors expressed by one of the most aggressive human cancers, small-cell lung carcinoma. This tumour shares many properties with other neuro-endocrine cell types, including the ability of firing action potentials and release hormones in a calcium-dependent manner. Toxins such as alpha-bungarotoxin and omega-conotoxins, among others, have been successfully used to characterise neuronal nicotinic receptors and voltage-dependent calcium channels, respectively, in human small-cell lung carcinoma cells. These receptors and ion channels are not only crucial for the growth of this specific tumour, but also represent autoantigens against which cancer patients build an autoimmune response. Although the aim of this autoimmune response is eventually the destruction of the cancer cells, the circulating antibodies cross-react with similar ion channels and receptors present in normal neurons or other cells, causing a number of different paraneoplastic diseases, the best characterised of which is the Lambert-Eaton myasthenic syndrome. Conotoxin-based radioimmunoassays have become an invaluable tool for the diagnosis and follow up of these paraneoplastic disorders and could represent a step forward in the early diagnosis of small-cell lung carcinoma itself.
Ziconotide - evaluation for chronic pain:
Jain, K.K.(2000) An evaluation of intrathecal ziconotide for the treatment of chronic pain.
Expert Opin Investig Drugs 9:2403-2410.
Abstract:
Ziconotide, the synthetic form of cone snail peptide varpi-conotoxin MVIIA, is a neurone-specific N-type calcium channel blocker with an analgesic and neuroprotective effect. Intrathecal ziconotide has been recommended for approval by the FDA for the management of chronic pain. Spinally administered ziconotide produces analgesia by blocking neurotransmitter release from primary nociceptive afferents and prevents the propagation of pain signals to the brain. It has an advantage over intrathecal morphine in that there is no development of tolerance after prolonged use. Systemic toxicity is considerably reduced by administration of smaller doses intrathecally and selective delivery to the site of action in the nervous system. Nevertheless, there are neurological adverse effects due to delay in clearance of ziconotide from the neural tissues. Overall, ziconotide has a favourable risk/benefit ratio with advantages over several currently available intrathecal therapies for pain.
See also:
Wang, Y.X., Gao, D., Pettus, M., Phillips, C. and Bowersox, S.S. (2000) Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats. Pain 84:271-281.
Atanassoff, P.G., Hartmannsgruber, M.W., Thrasher, J., Wermeling, D., Longton, W., Gaeta, R., Singh, T., Mayo, M., McGuire, D. and Luther, R.R. (2000) Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain.Reg Anesth Pain Med. 25:274-278
Wang, Y.X., Pettus, M., Gao, D., Phillips, C. and Scott Bowersox S. (2000) Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain.Pain 84: 151-158.
Abstract:This review focuses on the advances in the development of N-type calcium channel blockers as analgesic agents over the last 2 years. Firstly, it highlights the clinical progress with SNX-111 (Ziconotide; Elan Pharmaceuticals, Smithfield, RI) and then secondly, it outlines the various approaches being taken by researchers to design orally active, selective, small molecule modulators without the perceived disadvantages associated with SNX-111.
Venoms to Drugs 2 - Scientific Meeting The 2nd Venoms to Drugs meeting on Heron Island on Queensland's Great Barrier Reef will NOW be held 14th - 19th of July 2002 (see entry for March 8, 2001).
Venue: Heron Island is an idyllic coral cay 60km from the Australian mainland on the Great Barrier Reef. A conference in "Heron time" offers the Great Barrier Reef at its best, sunsets on the terrace, sub-tropical ambience and casual friendliness for conference delegates.
A web site is under development for registration for this meeting and should be available at the end of 2000. In the meantime, a downloadable pdf announcement is available and information is available from the Conference Manager, Mrs Ruth Drinkwater). To be included on the emailing list for this conference,please contact the Conference Manager, r.drinkwater@imb.uq.edu.au
26 November 2000
Glory of India Cone:
The Glory of India Cone: Conus Milneedwardsi, Jousseaume, 1894 is featured among the past images on the Man and Mollusc website "This is one of the "Four Glories" of the Cone world - the other three being the famous Glory of the Seas, and the Glories of Bengal and the Atlantic... It has four forms, which are found in deep water a) from Sri Lanka to Kuwait, b) From the Red Sea to Madagascar, c) around the Mauritius and Reunion Islands, and (surprise!) d) from Ryuku Is., south of Japan. The latter three forms remain extremely rare, but trawlers are regularly dredging up the W. Indian form by the hundreds: a small specimen can be had for $10 wholesale!! Like all cones, it is a carnivore, and spears fishes for its its prey with a tiny harpoon-like projectile (a specialized form of "radula" or Gastropod-tooth) and which it uses to inject its prey with a nerve toxin. The intended victim is quickly paralyzed, after which it is swallowed whole and digested at liesure. It is not known exactly what it eats, but it probably dines on Polychaete worms, or perhaps shrimp. Cones are amoungst the fastest known hunters in the animal world, and an attack can take place in only a few milliseconds! (A milli-second is one thousanth of a second, and a cone attack can take place in 10 or less of them)".
Dangerous Cones:
Collection of poisonous cones", courtesy of Paul Monfils. Featured are Conus geographus, Conus striatus, Conus textile and Conus tulipa
Cone database:
An interesting biligual Japanese/English shell site featuring microshells. A model for database usage on the web. The site includes a List of common names for Cones and numerous images which when clicked on shows three views of the shell together with a length scale marker in mm. In the Shells Database enter CONIDAE. Includes among others,
Conus anemone, Lamarck 1810 from Littoral in Cape York, South Australia;
Conus dictator from Sri Lanka;
Conus monachus, Linnaeus 1758 from Darwin, Australia
Conus neptunus, Reeve 1843 from the Philippines; Conus teramachii, Kuroda 1956 off Maputo, Mozambique, and
Conus vicweei, OLD 1973 from Indonesia.
25 November 2000
Mediterranean Cone species:
In answer to a question on CONCH-L by Bill Fenzan asking for some recent literature concerning Conus vayssierei in the Mediterranean Sea, Henk K. Mienis
(E-mail: mienis@netzer.org.il & mienis@hotmail.com) replied (22 Nov 2000) that he had so far looked in vain in the well known Italian journals "La Conchiglia" and "Bollettino Malacologica", although remembers having seen some pictures in one of the journals. However, in an issue of "La Conchiglia", 23 (263): 10-15 (1992), he found an interesting article by Gabriella Raybaudi Massilia dealing with the possible presence of Conus desidiosus A. Adams, 1854 near Lampedusa Island, south of Italy. Also Geiger (2000 in Boll. Malac.) referred recently to Conus desidiosus in his treatise concerning the distribution of the living Haliotis species, because in the same area in the central Mediterranean a second Haliotis species seems to occur. Henk was forced to conclude that "the number of Conus species known to be present in the Mediterranean is still far from fixed".
Have your say : - I invite comment on this and the related question of nomenclature of Mediterranean Conus species. To have your say, join the Cone Shells Club! on Yahoo (This club is for anyone who likes to collect cone shells), or leave a note on the Cone Shells and Conotoxins Discussion List (see link to ListBot at top of this page).
Card Catalogue of World-wide Shells by S. D. Kaicher - Index of species
:
For information on the number of packs and an
index to the species covered
go to http://coa.acnatsci.org/conchnet/kaicher.txt. This compilation was created by Paul Callomon, Elle Scientific Publications Osaka-fu, Yao-shi, Suehiro-cho 5-2-1 581-0001 Japan, in December 1999
The European Register of Marine Species is a research consortium funded by the European Union under the MAST(Marine Science and Technology) programme. The area covered by the project is all the continental shelf seas of Europe, from the Canaries and Azores to Greenland and north west Russia, including the Mediterranean shelf and Baltic Seas.
"The foundation of biodiversity research and management is correctly identifying and naming species. This Concerted Action proposal will in 24 months produce a register of marine species in Europe, linked with a bibliography of identification guides, register of taxonomic experts and locations of collections of reference specimens, and an Information Pack on European marine biodiversity (based on this project`s results). The species register is novel in its geographic extent, range of taxa covered, and that it will use the state-of-the-art World Wide Web software for publication and networking. It is anticipated that the register will become a standard reference (and technological tool) for marine biodiversity training, research and management in Europe".
On Thursday October 26, 2000, DRAXIS Announced that Ziconotide is to Receive Priority Review from the Canadian Drug Regulators, the Therapeutic Products Programme (TPP) of Health Canada. TPP's Priority Review Process allows for a faster review to make available promising drug products for life-threatening or severely debilitating conditions for which there are few effective therapies already on the market. Dr. Martin Barkin, President and CEO of DRAXIS Health stated, ``We are very encouraged that Ziconotide has been deemed eligible for priority review by the TPP. This process is very selectively used as evidenced by the fact that in 1999 only eight NDS submissions were selected for priority review out of a total of 84. Under the Priority Review Process the approval time for Ziconotide is expected to approximate six months, far less than the standard, which can average 18 months or more.''
20 October 2000
Conantokins may be useful in treating Parkinson's disease.:
Amy Adams and colleagues from the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112-5820, USA. report that two conantokins (conantokin-G, conantokin-T(G)) potentiate L-DOPA-induced contralateral rotation in 6-hydroxydopamine-treated rats. These NMDA receptor antagonists "may be useful adjuncts in the treatment of Parkinson's disease, both in prolonging the effects of L-DOPA and reducing the side effects associated with prolonged usage and high dosing."
Adams, A. C., Layer, R. T., Tyler McCabe,R. and Keefe, K. A. (2000) Effects of conantokins on l-3,4-dihydroxyphenylalanine-induced behavior and immediate early gene expression. European Journal of Pharmacology 404:303-313.
Abstract: Conantokins, peptides from Conus snails, are N-methyl-d-aspartate (NMDA) receptor antagonists. NMDA receptor antagonists potentiate l-3,4-dihydroxyphenylalanine (l-DOPA)-induced rotation in 6-hydroxydopamine-treated rodents, an index of anti-Parkinsonian potential. This study examined. the effects of conantokin-G, conantokin-T(G), CGS 19755, and ifenprodil on L-DOPA-induced contralateral rotation and immediate early gene (IEG) expression in 6-hydroxydopamine-treated rats. Rats received unilateral infusions of 6-hydroxydopamine into the medial forebrain bundle. Three weeks later, rats were treated with an NMDA receptor antagonist, followed by an injection of L-DOPA. Contralateral rotations were recorded for 2 h. In addition, the expression of zif268 and c-fos were examined. Conantokin-G, conantokin-T(G), and CGS 19755 potentiated L-DOPA-induced rotation. Conantokin-G and ifenprodil had no effect on L-DOPA-induced IEG expression, whereas conantokin-T(G) and CGS 19755 attenuated expression. These data suggest that conantokins may be useful in treating Parkinson's disease. Furthermore, different NMDA receptor antagonists have distinct effects on striatal gene expression.
Subunit interface selective toxins as probes of nicotinic acetylcholine receptor structure:
Palmer Taylor and colleagues from the Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA. report on the use of subunit-selective toxins (conotoxins, waglerins, and the alpha-neurotoxin from N. mossambica mossambica) to provide insight into the nature of the binding sites at the interface of nicotinic acetylcholine receptor subunits.
Taylor, P., Malanz, S., Molles, B.E., Osaka, H. and Tsigelny, I. (2000) Subunit interface selective toxins as probes of nicotinic acetylcholine receptor structure. Pflugers Arch 440 (5 Suppl) R115-R117
Abstract:The pentametric assembly of the nicotinic acetylcholine receptor with two of the five subunit interfaces serving as a ligand binding sites offers an opportunity to distinguish features on the surfaces of the subunits, and their ligand specificity characteristics. The receptor from mammalian muscle, with its circular order of homologous subunits (alphagamma alphadelta beta), assembles in a unique arrangement. The residues governing assembly can be ascertained through mutagenesis. Selectivity of certain natural toxins is sufficient to distinguish between sites at the alphagamma and alphadelta subunit interfaces. By interchanging residues on the gamma and delta subunits through mutagenesis, and ascertaining how they interact with the alpha subunit, determinants forming the binding sites can be delineated. The alpha-conotoxins show a 10,000-fold preference for the alphadelta over alphagamma subunit interface with alphaepsilon falling in between. The waglerins show a 2,000-fold preference for alphaepsilon over the alphagamma and alphadelta interfaces. Finally, the alpha-neurotoxin from N. mossambica mossambica shows a 10,000-fold preference for the alphagamma and alphadelta interfaces over alphaepsilon. Identification of interactive residues through mutagenesis, when coupled with homology modeling of domains and site-directed residue modification, has revealed important elements of receptor structure.
16 October 2000
Conotoxin from Conus californicus targets sodium channels:
Jon-Paul Bingham, Al Burlingame, Ed Moczydlowski and Wil Gilly from Yale, UCSF and Stanford report on a new class of sodium channel conotoxin, with new selectivity, new cys frame work, and with novel
post-translational modifications. This novel conotoxin, which was isolated from the milked venom of Conus californicus, is also comparatively big. Bingham, J.-P., Burlingame, A., Moczydlowski, E., Gilly, W.F. (2000) A new highly selective conotoxin from Conus californicus that targets voltage-gated neuronal Na+
channels of squid. Journal of General Physiology116:12a-13a.
Abstract: Venoms from Conus, a carnivorous marine gastropod, are a rich source of peptide toxins that target various ion channels with highly selective subtype specificity. For example, Conus snails have provided omega-conotoxins which differentiate the various isoforms of voltage-gated calcium channels, alpha-conotoxins which differentiate between various penatameric isoforms of nicotinic acetylcholine receptor channels, and mu-conotoxins which differentiate muscle, neuronal and cardiac isoforms of voltage-gated sodium channels. In our study of the endemic Conus species, Conus californicus that is found in cooler waters of the mid coastal of region of California, we demonstrated the presence of a new highly selective sodiium channel toxin present in both the crude duct venom extract and the captive milked venom. Thus far, this novel peptide toxin was found to selectively differentiate between various species isoforms of sodium channels. It blocked the voltage-gated sodium channel in giant fiber lobe (GFL) of Pacific squid, with an absence of effect on squid calcium and potassium currents and the glutamate-activated response in GFL. The lack of an effect on sodium currents of the mollusc Aplysia californica also demonstrated its selectivity at a phylogenetic level. By analysis of the captive milked venom by reverse-phase high performance liquid chromatography (RP-HPLC), and electrospray mass spectrometry (ESMS), we observed that the active peptide was a major constituent in the hydrophobic region of the HPLC profile. However, its concentration in the crude duct venom was relatively minor. Sequential isolation and Edman characterization demonstrated a high number of post-translational modifications, a high percentage of hydrophobic amino acids, and an unusual disulfide framework distinct from other previously reported conotoxins directed against voltage-gated sodium channels (mu-, delta-, and GS-conotoxins). These features provide evidence that this toxin represents a new class of sodium channel conotoxins.
9 October 2000
Christine Soares articles for Discovery Health - the Cutting Edge:
Christine Soares has written a series of articles highlighting Bioprospecting (drugs from the sea) including Ziconotide.
Collection of beautiful, rare cone shell images:
Check out this image for a beautiful collection of cone shells on the Conidae page at The Shell Store.
Cognetix studying peptide sodium channel blockers for chronic pain:
Source: Drug Discovery Online 9/22/2000 Cognetix Inc. (Salt Lake City, UT) has received a $98,900 Phase I Small Business Innovation Research (SBIR) grant from the National Institute of Neurological Disorders and Stroke to support the company's development of conopeptides for treating chronic pain.
Earlier this year, Cognetix and Elan Corp. (Dublin) announced a licensing and collaborative agreement to develop and commercialize Cognetix' contulakin-G (CGX-1160) for short-term management of post-operative pain.
Isolated from the venom of predatory marine snails, conopeptides block discrete sodium channels involved in chronic pain. Conopeptides that interact with these sodium channels should do so without inducing side effects associated with prototypical sodium channel blocking drugs.
Chronic pain afflicts approximately 34 million people in the United States, with an annual economic impact of approximately $40 billion. The causes of chronic pain syndromes are diverse; symptoms are difficult to treat using conventional analgesics and anti-inflammatory drugs.
In addition to pain treatments, Cognetix has research and development efforts underway in epilepsy, neuromuscular blockade, regional anesthesia, neuromuscular disorders, and cardiovascular diseases.
For more information: Cognetix Inc., 421 Wakara Way, Suite 201, Salt Lake City, UT 84108. Tel: 801-581-0400. Fax: 801-581-9555. Edited by Angelo DePalma
Managing Editor, Drug Discovery Online
Tueurs sublimes dans le Pacifique [Killers of the Pacific]
: This popular science article about venomous cone shells and their potential medical applications is by science writer Stephane Deligeorges and was published in the journal la Recherche (No 314, November 1998) Link here for an english translation using Babelfish (http://babelfish.altavista.com/translate.dyn).
14 September 2000
mu-Conotoxin actions on muscle
: Added the following reference on mu-contoxin action in rat muscle.
Li, R.A., Ennis, I.L., Velez, P., Tomaselli, G.F. and Marban, E. (2000) Novel Structural Determinants of mu-Conotoxin (GIIIB) Block in Rat Skeletal Muscle mu1 Na Channels. J Biol Chem 275(36):27551-27558
Institute of Molecular Cardiobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
mu-Conotoxin (mu-CTX) specifically occludes the pore of voltage-dependent Na+ channels. In the rat skeletal muscle Na+ channel (mu1), we examined the contribution of charged residues between the P loops and S6 in all four domains to mu-CTX block. Conversion of the negatively charged domain II (DII) residues Asp-762 and Glu-765 to cysteine increased the IC(50) for mu-CTX block by approximately 100-fold (wild-type = 22.3 7.0 nm; D762C = 2558 250 nm; E765C = 2020 379 nm). Restoration or reversal of charge by external modification of the cysteine-substituted channels with methanethiosulfonate reagents (methanethiosulfonate ethylsulfonate (MTSES) and methanethiosulfonate ethylammonium (MTSEA)) did not affect mu-CTX block (D762C: IC(50, MTSEA) = 2165.1 250 nm; IC(50, MTSES-) = 2753.5 456.9 nm; E765C: IC(50, MTSEA) = 2200.1 550.3 nm; IC(50, MTSES-) = 3248.1 2011.9 nm) compared with their unmodified counterparts. In contrast, the charge-conserving mutations D762E (IC(50) = 21.9 4.3 nm) and E765D (IC(50) = 22.0 7.0 nm) preserved wild-type blocking behavior, whereas the charge reversal mutants D762K (IC(50) = 4139.9 687.9 nm) and E765K (IC(50) = 4202.7 1088.0 nm) destabilized mu-CTX block even further, suggesting a prominent electrostatic component of the interactions between these DII residues and mu-CTX. Kinetic analysis of mu-CTX block reveals that the changes in toxin sensitivity are largely due to accelerated toxin dissociation (k(off)) rates with little changes in association (k(on)) rates. We conclude that the acidic residues at positions 762 and 765 are key determinants of mu-CTX block, primarily by virtue of their negative charge. The inability of the bulky MTSES or MTSEA side chain to modify mu-CTX sensitivity places steric constraints on the sites of toxin interaction.
PMID: 10859326
12 September 2000
Cone Snail Venom May Help People with Epilepsy
: (Reported by Mari N. Jensen on
BioMedNet)
Investigators H. Steve White and Baldomero Olivera at the ASBMB/APET conference (June 4-8, 2000) reported that a new drug in the early stages of development for particularly intractable cases of epilepsy is the conotoxin called conantokin-G.
Conantokin-G, a 17-amino-acid peptide isolated from the venom of Conus geographus, is a selective N-methyl-D-aspartate (NMDA) antagonist that acts on NMDA-NR2b, one of the six known NMDA receptors. NMDA receptors are glutamate receptors, excitatory receptors in the vertebrate central nervous system. Drug therapy directed at such receptors may counteract the recurrent seizures that characterize epilepsy, a disease of the central nervous system that affects more than two million Americans. One-quarter of epileptic patients worldwide are resistant to the current available therapies, which include pharmaceuticals, surgery and vagal nerve stimulation.
The NMDA receptor is thought have an important role in acute seizures, as well as the process of epileptogenesis, the development of the disorder. So an NMDA antagonist could used treat patients at risk for developing epilepsy, in addition to those who have epilepsy, says Olivera’s colleague H. Steve White, Associate Professor of Pharmacology and Toxicology at the University of Utah.
Other NMDA antagonists have been tried as epilepsy drugs, but the attempts were abandoned due to toxic effects. White wondered whether using a selective NMDA antagonist such as conantokin-G would control seizures without the negative effects seen in more generic NMDA antagonists.
He’s now tested various types of rats and mice using intracerebrovascular injections of conantokin-G. Unlike other NMDA antagonists, the toxin is a broad-spectrum anticonvulsant and is effective in doses that don't produce severe side effects, he says. The companies Cognetix and Medtronics are now starting work to develop the drug, he adds.
Michel Lazdunski, Director of the Institut de Pharmacologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique in Valbonne, France, says such a drug may cause memory problems, because glutamate is a neurotransmitter that is involved in learning and memory. Nevertheless, “I think this drug might be useful for a small subset of patients that have epileptic seizures that come all the time and who cannot accept surgery.” He adds, “I think it’s fascinating that this toxin might be used for some people.”
9 September 2000
Tom Eichhorst's Shell Related Sites
:
Tom Eichhorst's Shell Related Internet Sites on the "Of Sea and Shore" webpage are a wonderful up-to-date resource. http://www.ofseaandshore.com/tomlinks.htm
Of Sea and Shore
:
Tom Rice's Of Sea and Shore site provides information about mollusks and other marine invertebrates for shell collectors and professionals. http://www.ofseaandshore.com/
8 September 2000
Conus nobilis victor Broderip, 1842
:
Rich Goldberg has some very nice images on his Worldwide Conchology page of Conus nobilis victor from Indonesia. Conus nobilis victor Broderip, 1842 "There are many species of cone shells that exhibit considerable color and pattern variation. One of our favorites is Conus nobilis victor from eastern Flores Island, Nusa Tenggara, Indonesia. What can variability tell us about a molluscan species? A variable series of shells from one population, or a widely distributed sampling can illustrate a possible relationship between similar species, or forms. In this case, extreme forms of Conus nobilis victor from one population show how similar in appearance the subspecies comes to typical forms of Conus nobilis. Many still consider Conus victor to be a full species. Based on these preliminary observations, there is little doubt about the close relationship between Conus nobilis and Conus victor, thus the trend toward subspecific ranking for the shells from Indonesia."
Tony Swann of Wheldon & Wesley offers a summary of a talk he gave at the British Museum on Shell Books to coincide with the uploading to abebooks.com of a major collection of shell books he has just purchased. This collection can be viewed by going to the Wheldon & Wesley catalogs and clicking on FINE & RARE, or, MOLLUSCA. (included are for example Book # NTID745H24 HINTON, Alan. GUIDE TO AUSTRALIAN SHELLS. Robert Brown & Associates. Port Moresby. No Date. 77 Colour Plates Illustrating over 1,600 Individual Shells Representing 1060 Distinct Species. index; fully illustrated in col. on gloss art paper; hardcover in d/w; fine condition. Considered the most authoritative work on the subject; Book # 9036 Kohn, A.J. A CHRONOLOGICAL TAXONOMY OF CONUS, 1758-1840 Smithsonian 1992 Fine Cloth; 315p., 26 plates & color frontis Book; # 1449 Kohn, A.J. Type specimens and identity of the described species of Conus, 1758-1810 229 pp., 21 plates, 6 parts, J. Linn. Soc. Zool., 1963-81 with 4 other papers on Conus, in 1 vol., roy. 8vo, half cloth (unlettered), 1959-81 Includes the first six (of eight) parts of the series of articles on type specimens of the genus Conus published in J. Linn. Soc. Zool. In 1992 the author published a revised version of the series in book form; Book # 1582 Luther R. and Chung, N. Cowries and Cones of Hong Kong, 1975 pp. 128, sm. 8vo, wrappers, Hong Kong ; Book # 1651 Marsh, J.A. and Rippingale, O.H. Cone Shells of the World, 1964 pp. 166, with 22 coloured plates, 4to, cloth (endpapers marked), Brisbane - (also Book #5792 ; and 1st edition. Book # 000952) ; Book # 20901 Rolan Mosquera, E. Aportaciones al conoscimiento de Conus ermineus Born, 1778 (Gastropoda Conidae) estudio de los estadios juveniles. 1986 In 8 , bross., pp. 8 con 6 figs. .
Evolutionary diversity among cone shell toxin families:
Tom Duda and Steven Palumbi from Harvard have published another interesting paper on evolutionary diversity in predatory cone snails. This time, a comparison of the conotoxin multigene families among two closely related vermivorous Conus species, Conus ebreus and Conus abbreviatus.
Duda, T.F. Jr, Palumbi, S.R. (2000) Evolutionary Diversification of Multigene Families: Allelic Selection of Toxins in Predatory Cone Snails. Mol. Biol. Evol. 17(9):1286–1293 Department of Organismic and Evolutionary Biology, Biological Laboratories, Harvard University. Abstract:
In order to investigate the evolution of conotoxin multigene families among two closely related vermivorous Conus: species, we sequenced 104 four-loop conotoxin mRNAs from two individuals of Conus: ebraeus and compared these with sequences already obtained from Conus: abbreviatus. In contrast to the diversity of conotoxin sequences obtained from C. abbreviatus, only two common sequence variants were recovered from C. ebraeus. Segregation patterns of the variants in these two individuals and restriction digests of four-loop conotoxin amplification products from nine additional individuals suggest that the common variants are alleles from a single locus. These two putative alleles differ at nine positions that occur nonrandomly in the toxin-coding region of the sequences. Moreover, all substitutions are at nonsynonymous sites and are responsible for seven amino acid differences among the predicted amino acid sequences of the alleles. These results imply that conotoxin diversity is driven by strong diversifying selection and some form of frequency-dependent or overdominant selection at conotoxin loci, and they suggest that diverse conotoxin multigene families can originate from duplications at polymorphic loci. Furthermore, none of the sequences recovered from C. ebraeus appeared to be orthologs of loci from C. abbreviatus, and attempts to amplify orthologous sequences with locus-specific primers were unsuccessful among these species. These patterns suggest that venoms of closely related Conus: species may differ due to the differential expression of conotoxin loci. [PMID: 10958845]
"In conclusion, venom diversity among Conus species is facilitated by four factors: (1) diversifying selection among loci, as revealed by the rapid evolution of conotoxin loci in C. abbreviatus (Duda and Palumbi 1999a); (2) diversifying selection within loci, as shown by the concentration of substitutions within the toxin-coding region among two alleles from C. ebraeus; (3) gene duplications, possibly of already polymorphic loci, that create a genetic architecture that can maintain a diverse set of loci; and (4) differential expression of conotoxins, as implied from the absence of identifiable expressed orthologous sequences from two closely related Conus species, C. abbreviatus and C. ebraeus."
Link to current Peptide and Venom Research, specifically Studies on bioactive molecules from Australia’s venomous creatures including cone shell peptides (conotoxins), spider venoms, jumper ant venoms, and snake and scorpion venoms. This research is being conducted at the Centre for Drug Design and Development (CDDD), University of Queensland, (3-D Centre, Director Prof. Peter Andrews) under the direction of Dr. Paul Alewood, and at Xenome Ltd. by Drs. Richard Lewis and Roger Drinkwater. XENOME, a company within MEDICA HOLDINGS (Medica is a Pooled Development Fund specialising in investments in the biotechnology sector) is focused on the discovery of new drugs to treat disorders of the nervous system by exploiting Australia's diversity of naturally occurring venoms and toxins. Xenome, a new venture formed in January 2000 as a spin-off from the University of Queensland's Institute for Molecular Biosciences, is currently evaluating a large number of toxins and related molecules and hopes to discover novel pharmacological activities, particularly those acting on the central nervous system. It is also targeting conditions such as acute pain and stroke (See Media Press Releases for 3 July 2000 "Medica has lifted stake in Xenome to 42%" and 6 March 2000 "NEW PAIN DRUG CLINICAL TRIAL APPROVED").
Complementary NMR studies are carried out by Prof. David Craik, CDDD.
Link here to the Australian research laboratories of Drs. Ray Norton, at the Biomolecular Research Institute, CSIRO, Melbourne; Prof. Jim Angus and Dr. Christine Wright, Pharmacology, Univ. Melbourne; Prof David Adams, Physiology, Univ. of Queensland; and Drs. Bruce Livett, John Down and Ken Gayler, Biochemistry and Molecular Biology, Univ. Melbourne, Australia, who are working on various aspects of conotoxin structure and function.
26 August 2000
First account of a fatal cone shell envenomation:
Alerted by 'Toto' Olivera of the book by Rumphius (1705), I went looking for it in the library and was delighted to find that THE AMBONESE CURIOSITY CABINET by GEORGIUS EVERHARDUS RUMPHIUS has recently been translated, edited, and annotated with an introduction by E.M. BEEKMAN and is published (1999) by Yale Univeristy Press. This provides the first recorded account of a fatal cone shell envenomation. The following excerpt is from Book 2, HARD SHELLFISH, pp 148-154.
"X. Voluta pennata, these are oblong like a Roll, the head is not flat, but it protrudes like that of a Turbo, with a small red point on top, having two forms, yellow and brown; The yellow kind are called Partridges (attagenes)47 or Gold Cloth, because their entire body is painted with yellow feathers, that have black edges, almost like the feathers of that Bird: The second kind (note 48) is somewhat smaller and narrower, straight like a Roll, painted brown and white like feathers and it is called Silver Cloth; both have a narrow mouth and can stick out a little tongue, that is white, edged with red and in it is a small bone, or thorn, which will hurt you , if stung by it: The third or brown kind is different, larger and also painted brown and white, but the feathers are not arranged as orderly; they have a deathly color and are finely ribbed along the whorls: Although the Attagenata are caught and eaten daily, they are not innocent of poison, which was experienced by a slave woman on Banda, who knew that she had only held this little Whelk in her hand, which she had picked up out of the Sea, while they were pulling in a Seine net; and while she was walking to the beach, she felt a slight itching in her hand, which gradually crept up her arm and through her entire body; and so she died from it instantaneously".
Guy BOLTZ has an interactive CD-Rom available"Seashells of the French West Indies" containing 330 species of shells including the following 19 species of Cone Shells. A shareware version of the program can be downloaded free for evaluation from his French Caribbean Islands Seashells homepage. The full program "Coquillages des Antilles Francaises" can be ordered from Mr. BOLTZ Guy, 7 rue de Zimmerbach, 68000 COLMAR, for 120 Frs. Included are: Conus attenuatus, boni, burryae, centurio, citrinus, columba, daucus, ermineus, granulatus, jaspideus, magellanicus, mindanus, mus, norai, puncticulatus, pusillus, rgius, riosi, and spurius.
Guido Poppe has a very extensive list (500+) of CONIDAE (Cone Shells), over 110 with images, at his recently revised Conchology web page.
Lewis, R.J., Nielsen, K.J., Craik, D.J., Loughnan, M.L., Adams, D.A., Sharpe, I.A., Luchian, T., Adams, D.J., Bond, T., Thomas, L., Jones, A., Matheson, J.L., Drinkwater, R., Andrews, P.R., and Alewood, P.F. (2000) Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. J. Biol. Chem. 275: 35335-35344.
Abstract: omega-Conotoxins selective for N-type calcium channels are useful in the management of severe pain. In an attempt to expand the therapeutic potential of this class, four new omega-conotoxins (CVIA-D) have been discovered in the venom of the piscivorous cone snail, Conus catus, using assay-guided fractionation and gene cloning. Compared to other omega-conotoxins, CVID has a novel loop 4 sequence and the highest selectivity for N-type over P/Q-type calcium channels in radioligand binding assays. CVIA-D also inhibited contractions of electrically stimulated rat vas deferens. In electrophysiological studies, CVID and MVIIA had similar potencies to inhibit current through central ({alpa}(1B-d)) and peripheral (alpha(1B-b)) splice variants of the rat N-type calcium channels when coexpressed with rat beta3 in Xenopus oocytes. However, the potency of CVID and MVIIA increased when {alpa}(1B-d) and {alpa}(1B-b) were expressed in the absence of rat b3, an effect most pronounced for CVID at {alpa}(1B-d) (540-fold), and least pronounced for MVIIA at {alpa}(1B-d) (3-fold). The novel selectivity of CVID may have therapeutic implications. (1)H NMR studies reveal that CVID possess a combination of unique structural features, including two hydrogen bonds which stabilise loop 2 and places loop 2 proximal to loop 4, creating a globular surface that is rigid and well-defined.
Sequences and selectivity of Conotoxins CVIA-D for voltage-dependent calcium channels is shown below.
CVIACKSTGASCRRTSYDCCTGSCRS--GRC* N-TYPE CALCIUM CHANNEL BLOCKER CVIBCKGKGASCRKTMYDCCRGSCRS--GRC* N/P/Q TYPE CALCIUM CHANNELS CVICCKGKGQSCSKLMYDCCTGSCSRR-GKC* N/P/Q TYPE CALCIUM CHANNELS CVIDCKSKGAKCSKLMYDCCSGSCSGTVGRC* N-TYPE CALCIUM CHANNEL
12 August 2000
Conformational studies on contoxins:
Belva, H. and Lange, C. (2000) Conformational studies of omega-conotoxins using electrospray mass spectrometry. Rapid Commun Mass Spectrom14: 1433-1439. (Spectrometrie de Masse Bio-Organique, CNRS-UMR 6014, FR11, INSERM-IFR23, UFR des sciences, Universite de Rouen, 76821 Mont Saint Aignan-Cedex, France.) Abstract: Omega-conotoxins MVIIA and MVIIB from Conus magus were investigated for the effect of experimental conditions on their conformations, because of the presence of three disulfide bridges in these toxins. There were no significant effects of ion-source temperature, cone voltage, pH and percentage of cosolvent. We show that charge state distributions (CSDs) observed in their electrospray mass spectra are not a true reflection of the behaviour in the bulk solution because of electrostatic effects during the ion-evaporation process in the ion source. As a result it is not possible to deduce from the observed CSDs that some basic amino acids are hidden in the core of the peptide structure. This is important in view of the complementary finding that nearly all labile hydrogens are rapidly exchanged in deuterated solvents. The mass spectrometry results can be reconciled with results of NMR experiments and molecular calculations from the literature.
Cone snails as a source of new pharmaceuticals:
Alan Harvey's much awaited review "Strategies for discovering drugs from previously unexplored natural products" [Research focus] has been published in Drug Discovery Today, 2000, 5: 294-300
Here is what he has to say about Cone snails: "Another rather inaccessible source of novel chemicals is the Conus genus of marine snails. However, cone snail venoms are a particularly rich source of pharmacologically active peptides, acting on a variety of receptors and ion channels [39] . One particular conopeptide, omega-conotoxin MVIIA from Conus magus, is in Phase III clinical trials for the treatment of intractable pain; it acts as a specific blocker of N-type calcium channels in the pain fibres of the spinal cord [40] . With this successful example of a use for a conopeptide, Conus venoms can be expected to be actively searched for novel lead structures [41] . Moreover, of the 500 known species of Conus, only about a dozen have been examined in any detail, and new groups of biologically active peptide continue to be found [42]. Difficulties in collecting the snails and worries about conservation will require a molecular engineering approach to expand access to the peptide constituents of most Conus venoms. This is a challenging assignment because many of the more interesting components contain several post-translational modifications [43]".
39. Olivera, B.M. et al. (1999) Speciation of cone snails and interspecific hyperdivergence of their venom peptides potential – evolutionary significance of introns. Ann. New York Acad. Sci. 870, 223–237
40. Penn, R.D. and Paice, J.A. (2000) Adverse effects associated with intrathecal administration of ziconotide. Pain 85, 291–296
41. Shen, G.S. et al. (2000) Conopeptides: from deadly venoms to novel therapeutics. Drug Discovery Today 5, 98–106
42. Walker, C.S. et al. (1999 The T-superfamily of conotoxins. J. Biol. Chem. 274, 30664–30671
43. Craig, A.G. et al. (1999) Post-translationally modified neuropeptides from Conus venoms. Eur. J. Biochem. 264, 271–275
5 August 2000
Cone Shells in the Florida Museum:
Search the Florida Museum Malacology Master Database for Cone Shells. When asked enter for CLASS=G, Subclass=Prosobranchia, Family=CONIDAE, Genus=Conus. To begin with, search for 10 entries in Table format. To avoid timeout, searches for larger numbers (eg. 200) are best requested as Exact Search in either Table or Report format. eg. a search for the above with Species=californicus revealed 32 entries and for Species=purpurascens, 41 entries. You can do country searches too. eg. Try entering just Genus=Conus, Country=Somalia. Compile your own list eg. Australian Cones.
4 August 2000
References on conotoxins - added the following :
McIntosh, J.M., Corpuz, G.O., Layer, R.T., Garrett, J.E., Wagstaff, J.D., Bulaj, G., Vyazovkina, A., Yoshikami, D., Cruz, L.J. and Olivera, B.M. (2000) Isolation and characterization of a novel Conus peptide with apparent antinociceptive activity. J Biol Chem. 275:32391-32397. [from Conus marmoreus]
Benie, A.J., Whitford, D., Hargittai, B., Barany, G. and Janes, R.W. (2000) Solution structure of alpha-conotoxin SI. FEBS Lett. 476(3):287-295. Link here for the solution structure, pdb=1QMW, of alpha-conotoxin S. [from Conus striatus].
Jacobsen, R.B., Koch, E.D., Lange-Malecki, B., Stocker, M., Verhey, J., Van Wagoner, R.M., Vyazovkina, A., Olivera, B.M. and Terlau, H. (2000) Single amino acid substitutions in {kappa}-Conotoxin PVIIA disrupt interaction with the Shaker K{super+} channel.
J Biol Chem. 2000 May 18 [epub ahead of print]
[from Conus purpurascens]
McIntosh, J.M., Gardner, S., Luo, S., Garrett, J.E. and Yoshikami, D. (2000)
Conus peptides: novel probes for nicotinic acetylcholine receptor structure and function.
Eur J Pharmacol. 393: 205-208.. [subpopulations of alpha3beta2beta3-containing nicotinic receptors appear to be differentially sensitive to the beta3 neuronal nicotinic receptor blocker, alpha-conotoxin MII from Conus magus]
Lirazan, M.B., Hooper, D., Corpuz, G.P., Ramilo, C.A., Bandyopadhyay, P., Cruz, L.J. and Olivera BM.(2000)
The spasmodic peptide defines a new conotoxin superfamily. Biochemistry 39: 1583-1588. {from Conus textile. The spasmodic peptide has a novel disulfide framework and distinct signal sequence which together define a new P-superfamily of conopeptides. A cDNA encoding another member of the P-superfamily was identified from a different species, Conus gloriamaris. See entry for 12 February 2000].
Reference on neuronal nicotinic receptor and use of alpha-conotoxins-ImI and alpha-conotoxin-MII:
Kaiser, S. and Wonnacott, S. (2000) alpha-Bungarotoxin-sensitive nicotinic receptors indirectly modulate [(3)H]dopamine release in rat striatal slices via glutamate release.
Mol Pharmacol. 2000 Aug;58(2):312-318.
Posted a list of 28 articles on Cone Shells available from A.N. (Bram) van der Bijl, Burgemeester van Bruggenstraat 41, 1165 NV Halfweg, Nederland. Phone +31-20-4977772 e-mail anvdbijl@xs4all.nl
[updated 3 August 2000]
24 July 2000
References on conotoxins and analogues - added the following :
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.Eur J Biochem.267:4649-4657.
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. .Eur J Biochem. 267: 4642-4648.
Tisa, L,S. (2000) Interaction of omega-conotoxin and the membrane calcium transport system of escherichia coli.
FEMS Microbiol Lett. 188: 97-101.
References on contryphans - added the following:
(The contryphan family of peptides is widely distributed in venoms of the fish-hunting cone snails. Contryphan-R from Conus radiatus, contryphan-Sm from Conus stercusmuscarum and contryphan-P from Conus purpurascens venom are disulfide-constrained octapeptides containing a D-tryptophan. Contryphan-R from Conus radiatus produces the "stiff-tail" syndrome in mice).
Pallaghy, P.K. and Norton, R.S. (2000) The cyclic contryphan motif CPxXPXC, a robust scaffold potentially useful as an omega-conotoxin mimic. Biopolymers 54 :173-179.
References on conantokins - added the following:
Williams, A.J., Dave, J.R., Phillips, J.B., Lin, Y., McCabe, R.T. and Tortella, F.C. (2000) Neuroprotective efficacy and therapeutic window of the high-affinity N-methyl-D-aspartate antagonist conantokin-G: In vitro (Primary cerebellar neurons) and In vivo (Rat model of transient focal brain ischemia) studies. J Pharmacol Exp Ther. 294: 378-386.
22 July 2000
Cone shells on postage stamps:
Updated information about cone shells on postage stamps on my page Collection of Coneshell Stamps containing images of stamps in our own collection of "Cone shells from around the world" (with thanks to John Down).
Converted a list of Cone Shells on Stamps provided by Tom Walker for viewing on the web. For the moment I have linked images of the following cone shells to postage stamps featuring that particular species :
Conus episcopatus Penhryn Cook Is $2;
Conus vexillum vexillum Samoa $13;
Conus textile Samoa $24;
Conus textile Australia 45c;
Conus litteratus Samoa $26;
Conus tessulatus Samoa $50;
Conus bandanus nigrescens Samoa $1;
Conus gloriamaris Gilbert and Ellis Islands 10c. Tom is currently preparing a comprehensive catalogue with illustrations of every stamp. New images will be linked to this table as they become available. Tom is always happy for new collectors to contact him.
15 July 2000
Images of the following Western Atlantic cone shells are available on the Jacksonville Shell Club site.
This is by no means the entire complement of Atlantic cones. Others listed in the checklist of Marine Shells from North-East Florida include
Conus anabathrum Crosse, 1865 Florida Cone;
Conus daucus Hwass, 1792 Carrot Cone ;
Conus flavescens G. B. Sowerby II, 1834 Flame Cone;
Conus largilliertii Kiener, 1845 Philippi’s Cone;
Conus spurius atlanticus Clench, 1942 Alphabet Cone; and
Conus stearnsii Conrad, 1869 Dusky Cone.
Rare cones :
In 1969, S. Peter Dance published his book "Rare Shells" in which he illustrated and discussed fifty shells which had an interesting and often exciting history. At one time during the past, each of those species was considered "rare" and virtually unobtainable no matter what assets that one had available. While many of the species are now common and easily obtainable for a pittance compared to their former cost, assembling a collection of all fifty, even today, poses a formidable challenge. Jacksonville Shell Club member Harry G. Lee was presented Mr. Dance's book as a gift in 1976. Now, some 22-plus years later, the Club has published his labours - 50Rare Shells (1969) (8 of them Conus) on the web - no small task considering that even today some of the species are known to science from about a dozen specimens.
Included are the following 8 cones -Conus thomae Gmelin, 1791 - St. Thomas Cone; Conus cervus Lamarck, 1822 - Deer Cone; Conus crocatus Lamarck, 1810 - Saffron Cone; Conus gloriamaris Chemnitz, 1777 - Glory-of-the-seas Cone; Conus milneedwardsi Jousseaume, 1894 - Gloria-of-India Cone; Conus excelsus G. B.Sowerby III, 1908 - Illustrious Cone; Conus adamsonii Broderip, 1836 - Rhododendron Cone; and Conus dusaveli H. Adams, 1872 - Du Savel's Cone. [Mr. George Sangiouloglou (Athens, Greece) provided the images and Mr. Tom Eichhorst (Rio Rancho, New Mexico) assisted in scanning some of the species].
Eduardo Marban and colleagues from the Institute of Molecular Cardiobiology, at Johns Hopkins University School of Medicine, Baltimore, reported (in the JBC on June 19, 2000) that negatively-charged residues in the sodium channel from rat skeletal muscle (specifically P-S6 residues D762 and E765 in domain II of the µ1-2 Na channels) are critical for high-affinity binding of µ-conotoxin GIIIB from Conus geographus. The precise localization of these residues within the pore is also crucial for optimal interactions between µ-CTX and the Na channel. "These P-S6 residues exert their effects by stabilizing the bound toxin-channel complex via electrostatic interactions with the toxin. Furthermore, the toxin may interact with the pore in certain preferred orientations, highlighting the highly asymmetrical nature of the Na+ channel pore".
Li, R.A., Ennis, I.L., Vélez, P., Tomaselli, G.F. and Marban, E. (2000) "Novel structural determinants of µ-conotoxin (GIIIB) block in rat skeletal muscle (µ1) Na+ channels" Journal of Biological Chemistry June 19, 2000 (M909719199) Abstract: mu-Conotoxin (µ-CTX) specifically occludes the pore of voltage-dependent Na+ channels. In the rat skeletal muscle Na+ channel (1), we examined the contribution of charged residues between the P loops and S6 in all four domains to µ-CTX block. Conversion of the negatively-charged domain II (DII) residues D762 and E765 to cysteine increased the IC50 for µ-CTX block by ~100-fold. Restoration or reversal of charge by external modification of the cysteine-substituted channels with methanethiosulfonate (MTS) reagents did not affect µ-CTX block relative to their unmodified counterparts. In contrast, the charge-conserving mutations D762E and E765D preserved wild-type blocking behavior while the charge-reversal mutants D762K and E765K destabilized µ-CTX block even further, suggesting a prominent electrostatic component of the interactions between these DII residues and µ-CTX. Kinetic analysis of µ-CTX block reveals that the changes in toxin sensitivity are largely due to accelerated toxin dissociation (koff) rates with little changes in association (kon) rates. We conclude that the acidic residues at positions 762 and 765 are key determinants of µ-CTX block, primarily by virtue of their negative charge. The inability of the bulky MTSES or MTSEA side chain to modify µ-CTX sensitivity places steric constraints on the site of toxin interaction.
Ziconotide "approved" : [http://www.elancorp.com/news/display.asp?id=151] On the 28 June 2000, Elan Corporation (see also Elan Pharmaceuticals) announced receipt of an approvable letter from the U.S. Food and Drug Administration ('FDA') for Ziconotide, a novel N-type neuronal calcium channel blocker, for the treatment of severe chronic pain via the intrathecal route. This follows their submission of a New Drug Application ("NDA") 6 months ago (29 December 1999) for ziconotide as "a potential innovative new therapy for the treatment of intractable pain". For a fascinating account of the development of this novel medication see two articles in Worth On-Line magazine by Craig Canine : Pain, Profit, and Sweet Relief(Part 1) and Part 2 and 98/03-Follow-Up by Nick Pachetti entitled Neurex's Pretty Poison.
Ziconotide, formerly known as SNX-111 was developed by Neurex Corp. in Menlo Park, California and is an N-type calcium channel blocker based on a natural component of the venom from a fish-hunting cone snail, Conus magus. The natural compound is a small peptide, an omega-conotoxin (omega-conotoxin MVIIA).
4 July 2000
Ever since seeing the etching of a Conus marmoreus by Rembrant that was clearly sinistral (rather than the normal dextral configuration), I have been interested to know to what extent sinistral forms of Conus occur in nature. The question "does anyone know how frequent sinistral cones are in modern-day oceans?" was posed recently to the Conchologists of America List, CONCH-L by Ross Mayhew and elicited the following responses:
From Guido T. Poppe
My experience in Conidae C. ventricosus (mediterraneus) is rare when left handed but not impossible to obtain. We had about 6 over the latest decade. Apart from this, I've seen only two left handed Conus furvus. The sinistral Conus gloriamaris are all fakes of course.
From Harry G. Lee
To the references made earlier on abnormally-reversed Conus species, let me
add that I have sinistral specimens of the following cones in my collection:
Conus anabathrum Crosse, 1865; Conus baccatus Sowerby, 1877; Conus furvus Reeve, 1843; Conus infrenatus Reeve, 1848; Conus tinianus Hwass, 1792; and Conus ventricosus Gmelin, 1791.
I hasten to add, splitting or lumping notwithstanding, Contraconus seems to be a monophyletic enterprise, and, regardless of how many trivial taxa derived, it was a lineage which prospered but lived only a few million years - a trice geologically.
The 2nd Venoms to Drugs meeting on Heron Island on Queensland's Great Barrier Reef will NOW be held 14th - 19th of July 2002 (see entry for March 8, 2001).
Conus nobilis victor Broderip, 1842 "There are many species of cone shells that exhibit considerable color and pattern variation. One of our favorites is Conus nobilis victor from eastern Flores Island, Nusa Tenggara, Indonesia. What can variability tell us about a molluscan species? A variable series of shells from one population, or a widely distributed sampling can illustrate a possible relationship between similar species, or forms. In this case, extreme forms of Conus nobilis victor from one population show how similar in appearance the subspecies comes to typical forms of Conus nobilis. Many still consider Conus victor to be a full species. Based on these preliminary observations, there is little doubt about the close relationship between Conus nobilis and Conus victor, thus the trend toward subspecific ranking for the shells from Indonesia."
Also make sure to visit the 
Tony Swann of Wheldon & Wesley offers a 
Link to current 
Conus genuanus
Conus guinaicus
Conus pulcher
