What's New in 2007

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April 2006 "Pain Relief Drugs from the Sea"
Desley Blanch interviews Dr. Livett about his research and progress with the development of the cone shell analgesic, ACV1, from Conus victoriae. This interview was broadcast on Radio Australia's Innovations program, April 10, 2006. For a printable transcript click here

For further information see Bruce Livett's Research on cone shell venom peptides for treatment of chronic pain conditions at the Department of Biochemistry and Molecular Biology and the Bio21 Institute for Innovation and Entrepreureship at the University of Melbourne.

  • For a free article on theories about pain, click here: Encyclopedia Britannica.

    Analgesic Component of Venom (ACV1) from Cone Snails :
    see Nature Science Update "Snail toxin could ease chronic pain" by Ingrid Holmes


    An "Internet Interview" with Bruce Livett: conducted in February 2001 about his scientific work with cone shells and conotoxins (and his interaction with other malacologists and shell collectors), is now available as a downloadable Adobe pdf file. This extensive Intervista web "interview" conducted by Eduardo Moreira for Callostoma was subsequently published (in condensed form) in American Conchologist Volume 30, Number 1, 2002, pp. 5 & 14.

    For a one-page description of Cone Shells and their Conotoxins click here

    For a video simulation of cone shell envenomaton click here

    Bruce Livett's more recent publications (1998-2006)

    Site Map of Cone Shells and Conotoxins HomePage

       


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    Some recent conopeptide papers: (abstracts to follow)

    1: Peng C, Han Y, Sanders T, Chew G, Liu J, Hawrot E, Chi C, Wang C. (2008) alpha4/7-conotoxin Lp1.1 is a novel antagonist of neuronal nicotinic acetylcholine receptors. Peptides. 2008 Jun 7. [Epub ahead of print]

    2: Gowd KH, Twede V, Watkins M, Krishnan KS, Teichert RW, Bulaj G, Olivera BM.(2008) Conantokin-P, an unusual conantokin with a long disulfide loop. Toxicon. 2008 Jun 3. [Epub ahead of print]

    3: Chen P, Garrett JE, Watkins M, Olivera BM.(2008) Purification and characterization of a novel excitatory peptide from Conus distans venom that defines a novel gene superfamily of conotoxins. Toxicon. 2008 Jun 5. [Epub ahead of print]

    4: Yuan DD, Liu L, Shao XX, Peng C, Chi CW, Guo ZY.(2008) Isolation and cloning of a conotoxin with a novel cysteine pattern from Conus caracteristicus. Peptides. 2008 May 25. [Epub ahead of print]

    5: Teichert RW, Garcia CC, Potian JG, Schmidt JJ, Witzemann V, Olivera BM, McArdle JJ.(2008) Peptide-toxin tools for probing the expression and function of fetal and adult subtypes of the nicotinic acetylcholine receptor. Ann N Y Acad Sci. 2008 Jun;1132:61-70.

    6: Wang L, Pi C, Liu J, Chen S, Peng C, Sun D, Zhou M, Xiang H, Ren Z, Xu A.(2008) Identification and characterization of a novel O-superfamily conotoxin from Conus litteratus. J Pept Sci. 2008 Jun 3. [Epub ahead of print]

    7: Schroeder CI, Ekberg J, Nielsen KJ, Adams D, Loughnan ML, Thomas L, Adams DJ, Alewood PF, Lewis RJ.(2008) Neuronally selective mu -conotoxins from conus striatus utlise an alpha -helical motif to target mammalian sodium channels. J Biol Chem. 2008 Jun 3. [Epub ahead of print]

    8: Williams JA, Day M, Heavner JE.(2008) Ziconotide: an update and review. Expert Opin Pharmacother. 2008 Jun;9(9):1575-83.

    9: Imperial JS, Chen P, Sporning A, Terlau H, Daly NL, Craik DJ, Alewood PF, Olivera BM.(2008) Tyrosine-rich conopeptides affect voltage-gated K+ channels. J Biol Chem. 2008 May 27. [Epub ahead of print]

    10: Duda TF Jr, Remigio EA.(2008) Variation and evolution of toxin gene expression patterns of six closely related venomous marine snails. Mol Ecol. 2008 Jun;17(12):3018-32. Epub 2008 May 16.

    11: Fiedler B, Zhang MM, Buczek O, Azam L, Bulaj G, Norton RS, Olivera BM, Yoshikami D.(2008) Specificity, affinity and efficacy of iota-conotoxin RXIA, an agonist of voltage-gated sodium channels Na(V)1.2, 1.6 and 1.7. Biochem Pharmacol. 2008 Jun 15;75(12):2334-44. Epub 2008 Apr 6.

    12: Doura MB, Gold AB, Keller AB, Perry DC.(2008) Adult and periadolescent rats differ in expression of nicotinic cholinergic receptor subtypes and in the response of these subtypes to chronic nicotine exposure. Brain Res. 2008 Jun 18;1215:40-52. Epub 2008 Apr 4.

    13: Wang Y, Shao X, Li M, Wang S, Chi C, Wang C.(2008) mr1e, a conotoxin from Conus marmoreus with a novel disulfide pattern. Acta Biochim Biophys Sin (Shanghai). 2008 May;40(5):391-6.

    14: Dwoskin LP, Wooters TE, Sumithran SP, Siripurapu KB, Joyce BM, Lockman PR, Manda VK, Ayers JT, Zhang Z, Deaciuc AG, McIntosh JM, Crooks PA, Bardo MT.(2008) N,N'-Alkane-diyl-bis-3-picoliniums as Nicotinic Receptor Antagonists: Inhibition of Nicotine-induced Dopamine Release and Hyperactivity. J Pharmacol Exp Ther. 2008 May 6. [Epub ahead of print]

    15: Arredondo J, Chernyavsky AI, Jolkovsky DL, Pinkerton KE, Grando SA.(2008) Receptor-mediated tobacco toxicity: acceleration of sequential expression of alpha5 and alpha7 nicotinic receptor subunits in oral keratinocytes exposed to cigarette smoke. FASEB J. 2008 May;22(5):1356-68.

    16: Papke RL, Dwoskin LP, Crooks PA, Zheng G, Zhang Z, McIntosh JM, Stokes C.(2008) Extending the analysis of nicotinic receptor antagonists with the study of alpha6 nicotinic receptor subunit chimeras. Neuropharmacology. 2008 Jun;54(8):1189-200. Epub 2008 Mar 28.

    6 April 2008

      Conotoxins and receptors

      Olivera, BM (2008) Using Conus venom peptides to understand nervous systems and discover drugs. FASEB J. 22:252.1 [Meeting Abstract]

      Miller MT, Hansen,SB, McIntosh JM, Olivera BM and Taylor P (2006) Structural insights into competitive and non-competitive nicotinic antagonists. FASEB J. 20:A244 [Meeting Abstract]

    25 March 2008

      alpha conotoxin Vc1.1 receives US patent

      US Patent NumberUS Patent Number 7,348,400 B2 “a-Conotoxin Peptides with Analgesic Properties”, Bruce Livett, Zeinab Khalil, Ken Gayler, John Down, David Sandall, David Keays.  Date of Patent : March 25, 2008

    27 February, 2008

      US patent win for unlisted Xenome

      Nick Evans BioTechnologyNews.Net Tuesday, 25 March 2008

      UNLISTED Brisbane peptide company Xenome has won a US patent battle over the company’s novel class of norepinephrine transporter (NET) inhibitors. The patent was reissued this week following a ruling on a patent interference process between Xenome and an unnamed US company.

      Abstract: Xen2174 is derived from the venom of the cone snail. The ruling sees Xenome granted the patent for the class of drugs, originally assigned to the company by the University of Queensland, and means the company’s lead pain compound, Xen2174, is cleared for development without the risk of patent infringement claims in the US.
      Xen2174 is already covered by broadly granted patents in other major markets, including Europe.
      New Xenome chief executive Ian Nisbet told BTN that the ruling was significant for the company. “There was an interference around that patent application, and our position was deemed to be the predominant one, which meant that our patent was ultimately issued. That’s clearly a major win for the company,” he said. Nisbet said that Xenome has recently completed enrolment of a Phase 1/2 trial of the drug in cancer pain patients.

      “We recruited 37 patients into that study and we’re in the process of analysing data, and those results will be available in about the middle of the year,” he said.
      Nisbet said the company hoped that positive results from the Xen2174 clinical trial would generate interest in the company as it considered an initial public offering later this year.
      Xenome is one of a number of Australian biotechs waiting on a recovery in the broader market before considering a stock market listing. Nisbet said the company planned to list within the next 12 months, depending on the state of the market.

        Background notes

      Under the US patent system, “interference” is declared if two patent applications are filed which set forth claims covering the same subject matter. Under those circumstances the patent office can require that each of the parties appear to determine who was the earliest to discover the claimed invention.

      Xen2174 is a synthetic drug modelled on a peptide isolated from the venom of a cone shell found on Australia's Great Barrier Reef.
      Xen2174 selectively targets the norepinephrine transporter (NET), a well-established pharmaceutical target for a number of conditions. Inhibition of this transporter elevates the levels of norepinephrine in the spinal cord, preventing pain signals from reaching the brain.
      Xen2174 successfully completed a Phase 1 human safety trial in healthy volunteers in 2005, where it was tested in systemic circulation, via intravenous administration.

      Xen2174 is currently being tested in a Phase 1/2 clinical trial targeting chronic intractable pain in cancer patients via single dose intrathecal injection. This study again focuses on safety under this type of administration as well as pharmacokinetics and signs of efficacy at various doses.

    18 February, 2008

      Disulfide-rich peptide toxins from Gemmula species

      Heralde FM 3rd, Imperial J, Bandyopadhyay PK, Olivera BM, Concepcion GP, Santos AD (2007) A rapidly diverging superfamily of peptide toxins in venomous Gemmula species.Toxicon. 2007 Dec 28; [Epub ahead of print] doi:10.1016/j.toxicon.2007.12.022
      National Institute of Molecular Biology and Biotechnology, University of the Philippines, Diliman, Quezon City 1001, Philippines; Marine Science Institute, University of the Philippines, Diliman, Quezon City 1001, Philippines.

      Abstract: The gem turrids (genus Gemmula Weinkauff, 1875) are venomous snails in the family Turridae. A gene superfamily of disulfide-rich peptides expressed in Gemmula venom ducts was characterized. Gemmula speciosa (Reeve, 1843) venom duct cDNA clones revealed two different conotoxin-like prepropeptide precursors, with identical signal sequences, a largely conserved pro region, and a cysteine-rich C-terminal mature peptide region. The conserved signal sequence was used to successfully amplify homologous genes from three other Gemmula species; all had the same pattern of Cys residues in the predicted mature venom peptide. Although the signal sequence and propeptide regions were highly conserved, the mature toxin regions diverged greatly in sequence, except that the Cys residues were conserved. We designate this as the Pg-gene superfamily (Pg-superfamily) of Gemmula venom peptides. Purification of two members of the family directly from G. speciosa venom was achieved; amino acid sequence analysis revealed that these peptides are highly posttranslationally modified. With at least 10-fold as many species of turrids as cone snails, identification of rapidly diversifying gene superfamilies such as the Pg-superfamily of Gemmula is essential before the facile and systematic discovery and characterization of peptide toxins from turrid venoms can be achieved.

    15 February, 2008

      Venom peptides from Conus ventricosus

      Romeo C, Di Francesco L, Oliverio M, Palazzo P, Massilia GR, Ascenzi P, Polticelli F and Schininà ME (2008) Conus ventricosus venom peptides profiling by HPLC-MS: A new insight in the intraspecific variation. J Sep Sci. 31:488-498 [Epub ahead of print]
      Consorzio Interuniversitario “Istituto Nazionale Biostrutture e Biosistemi”, Roma, Italy.

      Abstract: Conus is a genus of predatory marine gastropods that poison the prey with a complex mixture of compounds active on muscle and nerve cells. An individual cone snail's venom contains a mixture of pharmacological agents, mostly short, structurally constrained peptides. This study is focused on the composition of the venom employed by Conus ventricosus Gmelin, 1791, a worm-hunting cone snail living in the Mediterranean Sea. For this purpose, LC coupled to MS techniques has been successfully used to establish qualitative and quantitative differences in conopeptides from minute amounts of venom ducts. We were able to prove variability in the venom conopeptide complement, possibly related to different trophic habits of the species in the Mediterranean Sea. Moreover, the information-rich MS techniques enabled us to identify two novel C. ventricosus peptides, here named Conotoxin-Vn and alpha-Conotoxin-Vn. On the basis of the structural data collected so far, we suggest that Conotoxin-Vn is a conopeptide belonging to the omega-family that recognizes calcium channels through a specific pharmacophore. Similarly, molecular modeling data suggest that alpha-Conotoxin-Vn should represent a competitive antagonist of neuronal nicotinic acetylcholine receptors (nAChRs).

    7 February, 2008

      Biogeographical patterns in Cape Verde Conus

      Cunha RL*†, Tenorio MJ, Afonso C, Castilho R and Zardoya R*. (2008) Replaying the tape: recurring biogeographical patterns in Cape Verde Conus after 12 million years. Molecular Ecology 17: 885–901
      *Departamento de Biodiversidad y Biología Evolutiva, Museo Nacional de Ciencias Naturales-CSIC, José Gutiérrez Abascal, 2, 28006 Madrid, Spain, †CCMAR, Campus de Gambelas-Universidade do Algarve, 8005-139 Faro, Portugal, ‡Facultad de Ciencias, Universidad de Cadiz, 11510 Puerto Real, Cádiz, Spain

      Abstract: Isolated oceanic islands are excellent natural laboratories to test the relative role of historical contingency and determinism in evolutionary diversification. Endemics of the marine venomous snail Conus in the Cape Verde archipelago were originated from at least two independent colonizations of ‘small’ and ‘large’ shelled species separated by 12 million years. In this study, we have reconstructed phylogenetic relationships within large-shelled Conus (C. ateralbus, C. pseudonivifer, C. trochulus, and C. venulatus) based on mitochondrial cox1 and nad4 haplotype sequences. The reconstructed molecular phylogeny revealed three well-supported and relatively divergent clades (A, B, and C) that do not correspond to current species classification based on shell colour and banding patterns. Clade A grouped specimens assigned either to C. pseudonivifer or C. trochulus, clade B is composed of specimens assigned to C. venulatus, and clade C comprises specimens assigned either to C. venulatus or C. ateralbus. Geometric morphometric analyses found significant differences between the radular teeth shape of C. pseudonivifer/C. trochulus and C. venulatus/C. ateralbus. In clades A and B, northwestern Boavista and Maio specimens cluster together to the exclusion of eastern Boavista samples. In Sal, populations form a monophyletic island assemblage(clade C). The large-shelled Conus have remarkably replicated biogeographical patterns of diversification of small-shelled Conus. Similar selective forces (i.e. nonplanktonic lecithotrophy with limited larval dispersal and allopatric diversification) together with repeated instances of low sea level stands during glacial maxima that allowed connection between islands, have overcome the effect of historical contingency, and explain the observed recurring biogeographical patterns.

    6 February, 2008

      Structure and function of α-conotoxin RgIA and analogues

      Ellison M1, Feng Z-P2, Park AJ1, Zhang X2, Olivera BM1, McIntosh JM1 and Norton RS2 (2008) α-RgIA, a novel α-conotoxin that blocks the α9α10 nAChR: Structure and identification of key receptor binding residues. Journal of Molecular Biology, In Press, Accepted Manuscript, Available online 4 February 2008
      1Department of Biology, University of Utah, Salt Lake City, Utah, 84112, USA. 2The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050 Australia

      Abstract: α-Conotoxins are small disulfide-constrained peptides from cone snails which act as antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). The 13-residue peptide α-RgIA is a member of the α-4,3 family of α-conotoxins and selectively blocks the α9α10 nAChR subtype, in contrast to another well characterized member of this family, α-ImI, which is a potent inhibitor of the α7 and α3α2 nAChR subtypes. In this study, we have altered side chains in both the 4-residue and 3-residue loops of α-RgIA, and have modified its C-terminus. The effects of these changes on activity against α9α10 and α7 nAChRs were measured, the solution structures of α-RgIA and its Y10W, D5E and P6V analogues were determined from NMR data, and resonance assignments made for α-RgIA[R9A]. The structures for α-RgIA and its three analogues were well-defined except at the chain termini. Comparison of these structures with reported structures of α-ImI reveals a common two-loop backbone architecture within the α-4,3 family, but with variations in side chain solvent accessibility and orientation. Asp5, Pro6 and Arg7 in loop 1 are critical for blockade of both the α9α10 and α7 subtypes. In loop 2, α-RgIA[Y10W] had activity near that of wild-type α-RgIA, with high potency for α9α10 and low potency for α7, and had a similar structure to wild-type. By contrast, Arg9, in loop 2, is critical for specific binding to the α9α10 subtype, probably because it is larger and more solvent accessible than Ala9 in α-ImI. Our findings contribute to a better understanding of the molecular basis for antagonism of the α9α10 nAChR subtype, which is a target for the development of analgesics for treatment of chronic neuropathic pain.
      Keywords: conotoxin; structure; peptide; NMR; nicotinic acetylcholine receptor; pain

      Conotoxin presentations at Society for Neuroscience meeting November 2007

      At the Society for Neuroscience meeting in SanDiego, CA, November 2007 there were a number of presentations on contoxins. A selection of these Abstracts is available here.

    4 February, 2008

      Structure of alpha-conotoxin RgIA: Comparison with ImI and Vc1.1

      Clark RJ1, Daly NL1, Halai R1, Nevin ST2, Adams DJ2, Craik DJ1 (2008). The three-dimensional structure of the analgesic α-conotoxin, RgIA. FEBS Letters (DOI: 10.1016/j.febslet.2008.01.027):Received 10 January 2008; accepted 17 January 2008. published online 31 January 2008
      1Institute for Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia; 2School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia

      Abstract: The α-conotoxin RgIA is a selective antagonist of the α9α10 nicotinic acetylcholine receptor and has been shown to be a potent analgesic and reduces nerve injury associated inflammation. RgIA was chemically synthesized and found to fold into two disulfide isomers, globular and ribbon. The native globular isomer inhibited ACh-evoked currents reversibly in oocytes expressing rat α9α10 nAChRs but the ribbon isomer was inactive. We determined the three-dimensional structure of RgIA using NMR methods to assist in elucidating the molecular role of RgIA in analgesia and inflammation.
      Keywords: Conotoxin, Nuclear magnetic resonance, Analgesic, Oxidative folding, Disulfide isomers

    31 January, 2008

      From Cone Snail to Drugs: Olivera's UP Centenial Address

      On January 16, 2008, Prof. Baldomero M. Olivera PhD received an honorary degree and presented this Centenial address to assembled staff and graduates at the University of the Philippines: From Cone Snails to Drugs: The Scientific Odyssey of a UP Graduate. In 2007, Prof Olivera was named by the Harvard Foundation as "2007 Scientist of the Year". You can read more about his career and award here.
      The Centennial lecture was beamed live via video-conferencing from the UP Film Center to the UP Mindanao , Mintal Campus College of Humanities and Social Sciences Audio-Visual Room and the adjacent Theater Hall.

      Ziconotide (omega-conotoxin MVIIA): non-clinical safety

      Skov MJ, Beck JC, de Kater AW, Shopp GM. (2007) Nonclinical safety of ziconotide: an intrathecal analgesic of a new pharmaceutical class. Int J Toxicol. 26: 411-421.
      Elan Pharmaceuticals, Inc., South San Francisco, California 94080, USA. michael.skov@elan.com

      Abstract: Ziconotide, a potent, selective, reversible blocker of neuronal N-type voltage-sensitive calcium channels, is approved in the United States for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. In the European Union, ziconotide is indicated for the treatment of severe chronic pain in patients who require intrathecal analgesia. Nonclinical investigations of ziconotide included a comprehensive characterization of its toxicology, incorporating acute and subchronic toxicity studies in rats, dogs, and monkeys; reproductive toxicity assessments in rats and rabbits; and mutagenic, carcinogenic evaluations performed in vivo and in vitro. Additional investigations assessed the potential for cardiotoxicity (rats) and immunogenicity (mice, rats, and guinea pigs), and the presence or absence of intraspinal granuloma formation and local cell proliferation and apoptosis (dogs). The resulting nonclinical toxicology profile was predictive of human adverse events reported in clinical trials and consistent with ziconotide's pharmacological activity. Frequently observed nonclinical behavioral effects included tremoring, shaking, ataxia, and hyperreactivity. Occurrences were generally transient and reversible upon cessation of treatment, and intolerable effects occurred at doses more than 45 times the maximum recommended clinical dose. Ziconotide was not associated with target organ toxicity, teratogenicity, or treatment-related gross or histopathological changes; it displayed no mutagenic or carcinogenic potential and no propensity to induce local cell proliferation or apoptosis. Although guinea pigs developed systemic anaphylaxis, antibodies to ziconotide were not detected in mice, rats, or guinea pigs, indicating low immunogenic potential. No evidence of granuloma formation was observed with intrathecal ziconotide treatment. In summary, the results from these nonclinical safety assessments revealed no significant toxicological risk to humans treated with ziconotide as recommended.

    29 January, 2008

      Conotoxin transcripts in Conus leopardus

      Remigio, EA and Duda TF Jr (2008) Evolution of ecological specialization and venom of a predatory marine gastropod Molecular Ecology, OnlineEarly ArticlesPublished article online: 23-Jan-2008 doi: 10.1111/j.1365-294X.2007.03627.x
      Department of Ecology and Evolutionary Biology/Museum of Zoology, University of Michigan, 1109 Geddes Avenue, Ann Arbor, MI 48109, USA, †Smithsonian Tropical Research Institute, Apartado 0843-03092, Balboa, Ancón, Panama. Correspondence: T. F. Duda Jr, Fax: 734-763-4080;
      E-mail: tfduda@umich.edu
      Keywords: conotoxins, Conus, ecological specialization, gene expression

      Abstract: Understanding the evolution of ecological specialization is important for making inferences about the origins of biodiversity. Members of the predatory, marine gastropod genus Conus exhibit a variety of diets and the ability to capture prey is linked to a venom comprised of peptide neurotoxins, termed conotoxins. We identified conotoxin transcripts from Conus leopardus, a species of Conus that uniquely preys exclusively on hemichordates, and compared its venom duct transcriptome to that of four other Conus species to determine whether a shift to a specialized diet is associated with changes in the venom composition of this species. We also examined the secondary structure of predicted amino acid sequences of conotoxin transcripts of C. leopardus to identify substitutions that may be linked to specialization on hemichordates. We identified seven distinct conotoxin sequences from C. leopardus that appear to represent transcripts of seven distinct loci. Expression levels and the diversity of conotoxins expressed by C. leopardus are considerably less than those of other Conus. Moreover, gene products of two transcripts exhibited unique secondary structures that have not been previously observed from other Conus. These results suggest that transition to a specialist diet is associated with reduction in the number of components expressed in venoms of Conus and that diverse venoms of Conus are maintained in species with a broad dietary width.

    25 January, 2008

      Conotoxins from Conus austini

      Zugasti-Cruz A, Aguilar MB, Falcón A, Olivera BM, Heimer de la Cotera EP (2008). Two new 4-Cys conotoxins (framework 14) of the vermivorous snail Conus austini from the Gulf of Mexico with activity in the central nervous system of mice. Peptides. 2007 Dec 5; [Epub ahead of print]
      Posgrado en Ciencias del Mar y Limnología, Universidad Nacional Autónoma de México, Ciudad Universitaria, México 04510, D.F., Mexico; Laboratorio de Neurofarmacología Marina, Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Querétaro 76230, Mexico.

      Abstract: As part of continuing studies of the venom components present in Conus austini (syn.: Conus cancellatus), a vermivorous cone snail collected in the western Gulf of Mexico, Mexico, two major peptides, as14a and as14b, were purified and characterized. Their amino acid sequences were determined by automatic Edman sequencing after reduction and alkylation. Their molecular masses, established by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, confirmed the chemical analyses and indicated that as14a and as14b have free C-termini. Each peptide contains 4-Cys residues arranged in a pattern (C-C-C-C, framework 14). The primary structure of as14a is GGVGRCIYNCMNSGGGLNFIQCKTMCY (experimental monoisotopic mass 2883.92Da; calculated monoisotopic mass 2884.20Da), whereas that of as14b is RWDVDQCIYYCLNGVVGYSYTECQTMCT (experimental monoisotopic mass 3308.63Da; calculated monoisotopic mass 3308.34Da). Both purified peptides elicited scratching and grooming activity in mice, and as14b also caused body and rear limb extension and tail curling immediately upon injection. The high sequence similarity of peptide as14a with peptide vil14a from the vermivorous C. villepinii suggests that the former might block K(+) channels.

      3-D structure of conotoxin tx3a from Conus textile

      McDougal OM, Turner MW, Ormond AJ, Poulter CD (2008). Three-Dimensional Structure of Conotoxin tx3a: An m-1 Branch Peptide of the M-Superfamily. Biochemistry. 2008 Jan 19; [Epub ahead of print]
      Department of Chemistry and Biochemistry, Boise State University, Boise, Idaho 83725, and Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 .

      Abstract: The M-superfamily, one of eight major conotoxin superfamilies found in the venom of the cone snail, contains a Cys framework with disulfide-linked loops labeled 1, 2, and 3 (-CC (1) C (2) C (3) CC-). M-Superfamily conotoxins can be divided into the m-1, -2, -3, and -4 branches, based upon the number of residues located in the third Cys loop between the fourth and fifth Cys residues. Here we provide a three-dimensional solution structure for the m-1 conotoxin tx3a found in the venom of Conus textile. The 15-amino acid peptide, CCSWDVCDHPSCTCC, has disulfide bonds between Cys (1) and Cys (14), Cys (2) and Cys (12), and Cys (7) and Cys (15) typical of the C1-C5, C2-C4, and C3-C6 connectivity pattern seen in m-1 branch peptides. The tertiary structure of tx3a was determined by two-dimensional (1)H NMR in combination with the combined assignment and dynamics algorithm for nuclear magnetic resonance (NMR) applications CYANA program. Input for structure calculations consisted of 62 inter- and intraproton, five phi angle, and four hydrogen bond constraints. The root-mean-square deviation values for the 20 final structures are 0.32 +/- 0.07 and 0.84 +/- 0.11 A for the backbone and heavy atoms, respectively. Surprisingly, the structure of tx3a has a "triple-turn" motif seen in the m-2 branch conotoxin mr3a, which is absent in mr3e, the only other member of the m-1 branch of the M-superfamily whose structure is known. Interestingly, injection of tx3a into mice elicits an excitatory response similar to that of the m-2 branch peptide mr3a, even though the conotoxins have different disulfide connectivity patterns.

    20 January, 2008

      Conorfamide-Sr2 from Conus spurius

      Aguilar MB, Luna-Ramírez KS, Echeverría D, Falcón A, Olivera BM, Heimer de la Cotera EP, Maillo M. (2008) Conorfamide-Sr2, a gamma-carboxyglutamate-containing FMRFamide-related peptide from the venom of Conus spurius with activity in mice and mollusks. Peptides. 2007 Dec 5; [Epub ahead of print]
      Laboratorio de Neurofarmacología Marina, Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Querétaro 76230, Mexico.

      Abstract: A novel peptide, conorfamide-Sr2 (CNF-Sr2), was purified from the venom extract of Conus spurius, collected in the Caribbean Sea off the Yucatan Peninsula. Its primary structure was determined by automated Edman degradation and amino acid analysis, and confirmed by electrospray ionization mass spectrometry. Conorfamide-Sr2 contains 12 amino acids and no Cys residues, and it is only the second FMRFamide-related peptide isolated from a venom. Its primary structure PMgammaDPLgammaIIRI-nh(2), (gamma, gamma-carboxyglutamate; -nh(2), amidated C-terminus; calculated monoisotopic mass, 1468.72Da; experimental monoisotopic mass, 1468.70Da) shows two features that are unusual among FMRFamide-related peptides (FaRPs, also known as RFamide peptides), namely the novel presence of gamma-carboxyglutamate, and a rather uncommon C-terminal residue, Ile. CNF-Sr2 exhibits paralytic activity in the limpet Patella opea and causes hyperactivity in the freshwater snail Pomacea paludosa and in the mouse. The sequence similarities of CNF-Sr2 with FaRPs from marine and freshwater mollusks and mice might explain its biological effects in these organisms. It also resembles FaRPs from polychaetes (the prey of C. spurius), which suggests a natural biological role. Based on these similarities, CNF-Sr2 might interact with receptors of these three distinct types of FaRPs, G-protein-coupled receptors, Na(+) channels activated by FMRFamide (FaNaCs), and acid-sensing ion channels (ASICs). The biological activities of CNF-Sr2 in mollusks and mice make it a potential tool to study molecular targets in these and other organisms.

    17 January, 2008

      Do hydroxyprolines determine the folding and activity of conotoxins ?



      Lopez-Vera E, Walewska A, Skalicky JJ, Olivera BM, Bulaj G. (2008) Role of Hydroxyprolines in the in Vitro Oxidative Folding and Biological Activity of Conotoxins. Biochemistry. 2008 Jan 12; [Epub ahead of print]
      Department of Biology, Department of Medicinal Chemistry, and Department of Biochemistry, University of Utah, Salt Lake City, Utah 84108, and Faculty of Chemistry, University of Gdansk, 80-952 Gdansk, Poland.

      Abstract: Hydroxylation of proline residue occurs in specific peptides and proteins derived from plants and animals, but the functional role of this modification has been characterized primarily in collagen. Marine cone snails produce disulfide-rich peptides that have undergone a plethora of posttranslational modifications, including proline hydroxylation. Although Conus snails extensively utilize proline hydroxylation, the consequences of this modification remain largely unexplored. In this work, we investigated the function of 4-hydroxyproline (Hyp) in conotoxins from three distinct gene families: mu-, omega-, and alpha-conotoxins. Analogues of mu-GIIIA, omega-MVIIC, alpha-GI, and alpha-ImI were synthesized with either Pro or Hyp, and their in vitro oxidative folding and biological activity were characterized. For GIIIA, which naturally contains three Hyp residues, the modifications improved the ability to block NaV1.4 sodium channels but did not affect folding. In contrast, the presence of Hyp in MVIIC had a significant impact on the oxidative folding but not on the biological activity. The folding yields for the MVIIC[Pro7Hyp] analogue were approximately 2-fold higher than for MVIIC under a variety of optimized oxidation conditions. For alpha-conotoxins ImI and GI, the hydroxylation of the conserved Pro residue improved their folding but impaired their activities against target receptors. Since prolyl-4-hydroxylase and protein disulfide isomerase coexist as a heterotetramer in the ER, we discuss the effects of Hyp on the folding of conotoxins in the context of cis-trans isomerization of Pro and Hyp. Taken together, our data suggest that proline hydroxylation is important for both in vitro oxidative folding and the bioactivity of conotoxins.

      [The following hydroxyproline-containing conotoxins are included: mu-conotoxins GIIA, GIIIB, GIIIC, PIIIA; kM-conotoxin RIIK; psi-conotoxin PIIIE; alpha-conotoxin (4/7) EI; alpha-conotoxin (4/3) Reg1b; delta-conotoxin PVIA, SVIE; alphaA-conotoxins PIVA, EIVA; omega-conotoxin GVIA; chi-conotoxin MrIA, MrIB; and contryphans R, and Tx]

      Two Cone Shell Articles
      (from "Man and Mollusc" by Ross Mayhew of Schooner Specimen Shells)

    • The "Glory of" Gang of Cones
      Conus gloriamaris Chemnitz 1777 (Glory of the Seas Cone); Conus bengalensis Okutani 1968 (Glory of Bengal Cone); Conus milneedwardsi Jousseaume 1894 (Glory of India Cone) and Conus granulatus Linneus 1758 (Glory of the Atlantic Cone)
    • Killer Conesnails
      Conus geographus Linne 1758 (Geography cone) and Conus textile Linne 1758 (Textile cone)
    16 January, 2008

      New Species of Cone Shells

      One new species: Conus beatrix Tenorio, Poppe & Tagaro, 2007, collected on Aliguay Is., P.I. by Manuel J. Tenorio and Paul Kersten, and one new subspecies Conus recluzianus simanoki Tenorio, Poppe & Tagaro, 2007 collected at the Burma / Thailand border by Philippe Quisquandon, were published in Visaya, vol. 2, No. 2 (November, 2007).

      The Cone Collector Volume 5 January 2008



      Click here to download The Cone Collector #5 (PDF - 1.9 MB).
      [Earlier issues, #0 - #4, are available for download at www.seashell-collector.com]

      Edited by António Monteiro, with layout by André Poremski.
      Contributions include:

    • Who's Who in Cones : by Gabriella Raybaudi Massilia
    • Live Taken Specimen of Rare Species (Conus darkini Röckel, Korn & Richard) , 1992), by Richard Goldberg
    • Special Population of Conus fuvus Reeve, 1843, by António Monteiro
      Reference: BEN-SAÂD, AÏCHA, JANSSENS, ADRIAAN & NOLF, FRANK 2007. Another population variant of Conus furvus Reeve, 1843 (Mollusca: Gastropoda: Conoidea: Conidae) from the Cuyo Islands (Palawan, Philippines).Neptunea, Vol. 6 No. 1
    • Two Exceptional Specimens (Conus vexillum Gmelin, 1791 and Conus ammiralis Linnaeus, 1758) by Philippe Quiquandon
    • Distribution of Conus kohni Mclean & Nybakken, 1979 by John K. Tucker
    • The Most Variable Cone? by António Monteiro and by Paul Kersten
      Is it Conus mercator Linnaeus, 1758, C. venulatus Hwass, 1792, or C. generalis Linnaeus, 1767, or C. magus Linnaeus, 1758 and its different forms such as assimilis Adams, 1854, borneensis Sowerby, 1866, carinatus Swainson, 1822, cernohorskyi da Motta, 1983, circae Sowerby, 1858, consul Boivin, 1864, fr auenfeldi Crosse, 1865, fulvobullatus da Motta, 1982, metcalfi i Reeve, 1843, raphanus Hwass, 1792, signifer Crosse, 1865 and ustulatus Reeve, 1843.
    • Australis or Anonymous? by Jon Singleton
      C. australis vs. C. cebuganus Reference: DA MOTTA, A. J. 1982. C. cebuganus sp. nov. Carfel Shell News 4(3) 2007; For images of these species SEARCH on Eurasiashells. de Suduiraut, E. G. www.eurasiashells.net.
    • About Conus aurantius, Hwass 1792 by Frits Fontein
    • Caribbean Corner: Notes on Conus stearnsii Conrad, 1869 by André Poremski
    • Scuba Diving For Shells Part 1: Night Snorkeling In The Grenadines - A Blessing by David Touitou
      Conus dominicanus
    • Conus queketti E.A. Smith, 1906. What is it? by R. M. (Mike) Filmer
      Mike concludes that C. queketti is only a form of C. imperialis. Other species discussed are C. pennaceus Born, 1778 and C. biliosus Röding, 1798, C. lohri Kilburn, 1972 and C. meyeri Walls, 1979).
    • Why Are Some Cone Shells So Often Eroded? by António Monteiro and Carlos Afonso
      Conus miruchae
    • Australian Corner: Cone News from Australia
      - 12 Any Votes for blainvillii ?
      by John Singleton
      Included in the discussion are Conus pseudocedonulli Blainville, 1818, C. ammiralis Linneaus, 1758, C. archithalassus Hwass, 1792, C. da Motta 1987
    • Cone News from Australia
      - 13. Just White or Albino?
      by Jon Singleton
      Included in the discussion are C. cloveri and ateralbus, C. trigonus, C. rufi maculosus and C. pertusus, C. victoriae and C. anemone, C. amadis, magus, furvus and spectrum; C. araneosus, lynceus, malaccanus and nobilis. The Atlantic cones, C. mindanus and spurius. C. puncticulatus form columba, C. mappa granarius , C. cloveri and ateralbus
    • Conus cordigera vs C. nobilis by António Monteiro
      Conus cordigera Sowerby II in 1866, C. nobilis Linnaeus, 1758
    • The Golden Nocturnus by Jon Singleton
      Conus nocturnus Hwass, 1792; C. marmoreus Linneaus, 1758
    • Fossil Conus from Castell’Arquato (Piacenza) by Giancarlo Paganelli
      Fossil cones discussed include Conus antidiluvianus Bruguière, 1792, Conus brocchii Bronn, 1828, Conus canaliculatus Brocchi, 1814, Conus pelagicus Brocchi, 1814, Conus ponderosus Brocchi, 1814, Conus pyrula Brocchi, 1814, Conus striatulus Brocchi, 1814, and Conus virginalis Brocchi, 1814
    • Conus kawamurai Habe, 1962 An Extinct Species? by António Monteiro
      Conus kawamurai Habe, 1962; Conus granulatus , Conus ochroleucus tmetus Tomlin, 1937 and Conus ochroleucus tmetus Tomlin, 1937

    5 January, 2008

      Folding of conotoxins

      Bulaj G, Olivera BM. (2008) Folding of conotoxins: formation of the native disulfide bridges during chemical synthesis and biosynthesis of Conus peptides. Antioxid Redox Signal. 10:141-56.
      Department of Medicinal Chemistry, College of Pharmacy, Salt Lake City, Utah., Department of Biology University of Utah, Salt Lake City, Utah.

      Abstract: Conopeptides from >700 species of predatory marine Conus snails provide an impressive molecular diversity of cysteine-rich peptides. Most of the estimated 50,000-100,000 distinct conopeptides range in size from 10 to 50 amino acid residues, often with multiple posttranslational modifications. The great majority contain from two to four disulfide bridges. As the biosynthetic and chemical production of this impressive repertoire of disulfide-rich peptides has been investigated, particularly the formation of native disulfide bridges, differences between in vivo and in vitro oxidative folding have become increasingly evident. In this article, we provide an overview of the molecular diversity of conotoxins with an emphasis on the cysteine patterns and disulfide frameworks. The conotoxin folding studies reviewed include regioselective and direct oxidation strategies, recombinant expression, optimization of folding methods, mechanisms of in vitro folding, and preliminary data on the biosynthesis of conotoxins in venom ducts. Despite these studies, how the cone snails efficiently produce properly folded conotoxins remains unanswered. As chemists continue to master oxidative folding techniques, insights gleaned from how conotoxins are folded in vivo will likely lead to the development of the new folding methods, as well as shed some light on fundamental mechanisms relevant to the protein folding problem.

    1 January, 2008

      Welcome to 2008




    Continued in What's new in 2007
    See also : What's new in 2006, What's new in 2005, What's new in 2004, What's new in 2003, What's new in 2002, What's new in 2001, What's new in 2000, What's new in 1999, What's new in 1998, What's New in 1997 and What's New in 1996

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