Conotoxins: natural product drug leads.

Venomous marine cone snails harbour a variety of small disulfide-rich peptides called conotoxins, which target a broad range of ion channels, membrane receptors, and transporters. More than 700 species of Conus are thought to exist, each expressing a wide array of different peptides. Within this large repertoire of toxins, individual conotoxins are able to discriminate between different subtypes and isoforms of ion channels, making them valuable pharmacological probes or leads for drug design. This review gives a brief background to the discovery of conotoxins and describes their sequences, biological activities, and applications in drug design.

[1]  B. Olivera,et al.  The contryphans, a D-tryptophan-containing family of Conus peptides: interconversion between conformers. , 2009, The journal of peptide research : official journal of the American Peptide Society.

[2]  Alison Haythornthwaite,et al.  Analgesic α-Conotoxins Vc1.1 and Rg1A Inhibit N-Type Calcium Channels in Rat Sensory Neurons via GABAB Receptor Activation , 2008, The Journal of Neuroscience.

[3]  Zhan-Yun Guo,et al.  Isolation and cloning of a conotoxin with a novel cysteine pattern from Conus caracteristicus , 2008, Peptides.

[4]  A. Ganesan.  The impact of natural products upon modern drug discovery. , 2008, Current opinion in chemical biology.

[5]  C. Chi,et al.  Purification and structural characterization of a d‐amino acid‐containing conopeptide, conomarphin, from Conus marmoreus , 2008, The FEBS journal.

[6]  R. Norton,et al.  Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues. , 2008, Journal of molecular biology.

[7]  M. Quik,et al.  Subtype-selective conopeptides targeted to nicotinic receptors:Concerted discovery and biomedical applications , 2008, Channels.

[8]  D. Craik,et al.  The three‐dimensional structure of the analgesic α‐conotoxin, RgIA , 2008, FEBS letters.

[9]  Conan K. L. Wang,et al.  ConoServer, a database for conopeptide sequences and structures , 2008, Bioinform..

[10]  Y. Shai,et al.  Conolysin-Mt: a conus peptide that disrupts cellular membranes. , 2007, Biochemistry.

[11]  D. Craik,et al.  Are α9α10 Nicotinic Acetylcholine Receptors a Pain Target for α-Conotoxins? , 2007, Molecular Pharmacology.

[12]  T. Sixma,et al.  AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity , 2007, The EMBO Journal.

[13]  David J Craik,et al.  Chemical modification of conotoxins to improve stability and activity. , 2007, ACS chemical biology.

[14]  C. Chi,et al.  From the identification of gene organization of α conotoxins to the cloning of novel toxins , 2007 .

[15]  R. Norton,et al.  Conotoxins down under. , 2006, Toxicon : official journal of the International Society on Toxinology.

[16]  D. Keays,et al.  Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor. , 2006, Toxicon : official journal of the International Society on Toxinology.

[17]  J. McIntosh,et al.  Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors , 2006, Proceedings of the National Academy of Sciences.

[18]  Sukanta Mondal,et al.  I‐conotoxin superfamily revisited , 2006, Journal of peptide science : an official publication of the European Peptide Society.

[19]  Lei Xie,et al.  Novel O‐superfamily Conotoxins Identified by cDNA Cloning From Three Vermivorous Conus Species , 2006, Chemical biology & drug design.

[20]  Michelle L Colgrave,et al.  Cyclic MrIA: a stable and potent cyclic conotoxin with a novel topological fold that targets the norepinephrine transporter. , 2006, Journal of medicinal chemistry.

[21]  G. Bulaj,et al.  Structure of conkunitzin-S1, a neurotoxin and Kunitz-fold disulfide variant from cone snail , 2006, Acta crystallographica. Section D, Biological crystallography.

[22]  D. Craik,et al.  The Synthesis, Structural Characterization, and Receptor Specificity of the α-Conotoxin Vc1.1* , 2006, Journal of Biological Chemistry.

[23]  D. Craik,et al.  NMR of conotoxins: structural features and an analysis of chemical shifts of post‐translationally modified amino acids , 2006, Magnetic resonance in chemistry : MRC.

[24]  D. Bertrand,et al.  Structural determinants of selective alpha-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. McIntosh,et al.  α-RgIA: A Novel Conotoxin That Specifically and Potently Blocks the α9α10 nAChR†,‡ , 2006 .

[26]  G. Bulaj,et al.  Conotoxins and the posttranslational modification of secreted gene products , 2005, Cellular and Molecular Life Sciences CMLS.

[27]  R. Lewis,et al.  Anti-allodynic efficacy of the χ-conopeptide, Xen2174, in rats with neuropathic pain , 2005, Pain.

[28]  W. Gilly,et al.  Piscivorous Behavior of a Temperate Cone Snail, Conus californicus , 2005, The Biological Bulletin.

[29]  Norelle L Daly,et al.  Engineering stable peptide toxins by means of backbone cyclization: stabilization of the alpha-conotoxin MII. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Lewis,et al.  β2 Subunit Contribution to 4/7 α-Conotoxin Binding to the Nicotinic Acetylcholine Receptor* , 2005, Journal of Biological Chemistry.

[31]  D. Yoshikami,et al.  Characterization of D‐amino‐acid‐containing excitatory conotoxins and redefinition of the I‐conotoxin superfamily , 2005, The FEBS journal.

[32]  D. Bertrand,et al.  Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an α-conotoxin PnIA variant , 2005, Nature Structural &Molecular Biology.

[33]  Peter Roepstorff,et al.  Precursors of novel Gla-containing conotoxins contain a carboxy-terminal recognition site that directs gamma-carboxylation. , 2005, Biochemistry.

[34]  G. Fields,et al.  Polypeptide chains containing D-gamma-hydroxyvaline. , 2005, Journal of the American Chemical Society.

[35]  Miljanich Gp,et al.  Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. , 2004, Current medicinal chemistry.

[36]  Jean-Christophe Gelly,et al.  Squash inhibitors: from structural motifs to macrocyclic knottins. , 2004, Current protein & peptide science.

[37]  K. Gayler,et al.  Drugs from the sea: conopeptides as potential therapeutics. , 2004, Current medicinal chemistry.

[38]  Todd T. Talley,et al.  Structural and Ligand Recognition Characteristics of an Acetylcholine-binding Protein from Aplysia californica* , 2004, Journal of Biological Chemistry.

[39]  David J. Craik,et al.  Structure-activity relationships of alpha-conotoxins targeting neuronal nicotinic acetylcholine receptors. , 2004, European journal of biochemistry.

[40]  D. Craik,et al.  Structures of muO-conotoxins from Conus marmoreus. I nhibitors of tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels in mammalian sensory neurons. , 2004, The Journal of biological chemistry.

[41]  T. Sixma,et al.  Nicotine and Carbamylcholine Binding to Nicotinic Acetylcholine Receptors as Studied in AChBP Crystal Structures , 2004, Neuron.

[42]  R. Firn,et al.  Natural products--a simple model to explain chemical diversity. , 2003, Natural product reports.

[43]  M. Rowbotham,et al.  Oral opioid therapy for chronic peripheral and central neuropathic pain. , 2003, The New England journal of medicine.

[44]  D. Gailani,et al.  The Factor IX γ-Carboxyglutamic Acid (Gla) Domain Is Involved in Interactions between Factor IX and Factor XIa* , 2003, The Journal of Biological Chemistry.

[45]  Richard B Greenwald,et al.  Effective drug delivery by PEGylated drug conjugates. , 2003, Advanced drug delivery reviews.

[46]  D. Craik,et al.  Isolation, Structure, and Activity of GID, a Novel α4/7-Conotoxin with an Extended N-terminal Sequence* , 2003, The Journal of Biological Chemistry.

[47]  J. McIntosh,et al.  α-Conotoxins ImI and ImII , 2003, The Journal of Biological Chemistry.

[48]  B. Olivera.  Conus Venom Peptides: Reflections from the Biology of Clades and Species , 2002 .

[49]  I. Rubio-Aliaga,et al.  Mammalian peptide transporters as targets for drug delivery. , 2002, Trends in pharmacological sciences.

[50]  G. Bulaj,et al.  Conorfamide, a Conus venom peptide belonging to the RFamide family of neuropeptides. , 2002, Toxicon : official journal of the International Society on Toxinology.

[51]  Reshma P Shetty,et al.  gamma -Glutamyl carboxylation: An extracellular posttranslational modification that antedates the divergence of molluscs, arthropods, and chordates. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[52]  D. Craik.  Plant cyclotides: circular, knotted peptide toxins. , 2001, Toxicon : official journal of the International Society on Toxinology.

[53]  T. Sixma,et al.  A glia-derived acetylcholine-binding protein that modulates synaptic transmission , 2001, Nature.

[54]  T. Sixma,et al.  Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors , 2001, Nature.

[55]  G. S. Begley,et al.  A Conserved Motif within the Vitamin K-dependent Carboxylase Gene Is Widely Distributed across Animal Phyla* , 2000, The Journal of Biological Chemistry.

[56]  P. Andrews,et al.  Novel ω-Conotoxins from Conus catus Discriminate among Neuronal Calcium Channel Subtypes* , 2000, The Journal of Biological Chemistry.

[57]  J. Lefèvre,et al.  Structural and dynamic characterization of omega-conotoxin MVIIA: the binding loop exhibits slow conformational exchange. , 2000, Biochemistry.

[58]  G. Bulaj,et al.  Conus peptides - combinatorial chemistry at a cone snail's pace. , 2000, Current opinion in drug discovery & development.

[59]  D. Craik,et al.  Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. , 1999, Journal of molecular biology.

[60]  D. Craik.  Applications of NMR in Drug Design: Structure-Activity Relationships in Disulfide-Rich Peptides , 1999, Protein & Peptide Letters.

[61]  B. Olivera,et al.  Post-translationally modified neuropeptides from Conus venoms. , 1999, European journal of biochemistry.

[62]  F. Marí,et al.  Three-dimensional structure of α-conotoxin EI determined by1H NMR spectroscopy , 1999, Letters in Peptide Science.

[63]  B. Olivera,et al.  Contulakin-G, an O-Glycosylated Invertebrate Neurotensin* , 1999, The Journal of Biological Chemistry.

[64]  B. Olivera,et al.  Speciation of Cone Snails and Interspecific Hyperdivergence of Their Venom Peptides: Potential Evolutionary Significance of Introns a , 1999, Annals of the New York Academy of Sciences.

[65]  David J. Craik,et al.  Conotoxins and their potential pharmaceutical applications , 1999 .

[66]  D. Yoshikami,et al.  α-Conotoxin AuIB Selectively Blocks α3β4 Nicotinic Acetylcholine Receptors and Nicotine-Evoked Norepinephrine Release , 1998, The Journal of Neuroscience.

[67]  C M Weeks,et al.  The 1.1 A resolution crystal structure of [Tyr15]EpI, a novel alpha-conotoxin from Conus episcopatus, solved by direct methods. , 1998, Biochemistry.

[68]  David John Adams,et al.  α-Conotoxin EpI, a Novel Sulfated Peptide from Conus episcopatus That Selectively Targets Neuronal Nicotinic Acetylcholine Receptors* , 1998, The Journal of Biological Chemistry.

[69]  D. Craik,et al.  Structure determination of the three disulfide bond isomers of alpha-conotoxin GI: a model for the role of disulfide bonds in structural stability. , 1998, Journal of molecular biology.

[70]  B. Olivera,et al.  Conantokin-G Precursor and Its Role in γ-Carboxylation by a Vitamin K-dependent Carboxylase from a ConusSnail* , 1998, The Journal of Biological Chemistry.

[71]  J. Rivier,et al.  Three-Dimensional Solution Structure of α-Conotoxin MII, an α3β2 Neuronal Nicotinic Acetylcholine Receptor-Targeted Ligand†,‡ , 1997 .

[72]  B. Olivera,et al.  E.E. Just Lecture, 1996. Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology. , 1997, Molecular biology of the cell.

[73]  D. Craik,et al.  Crystal structure at 1.1 A resolution of alpha-conotoxin PnIB: comparison with alpha-conotoxins PnIA and GI. , 1997, Biochemistry.

[74]  T. Stanley,et al.  Identification of a vitamin K‐dependent carboxylase in the venom duct of a Conus snail , 1997, FEBS letters.

[75]  D. Craik,et al.  Determination of the Solution Structures of Conantokin-G and Conantokin-T by CD and NMR Spectroscopy* , 1997, The Journal of Biological Chemistry.

[76]  W R Gray,et al.  Three-dimensional structure of the alpha-conotoxin GI at 1.2 A resolution. , 1996, Biochemistry.

[77]  G. Amidon,et al.  The intestinal peptide carrier: A potential transport system for small peptide derived drugs , 1996 .

[78]  D. Craik,et al.  Three-dimensional solution structure of mu-conotoxin GIIIB, a specific blocker of skeletal muscle sodium channels. , 1996, Biochemistry.

[79]  Walter Stühmer,et al.  Strategy for rapid immobilization of prey by a fish-hunting marine snail , 1996, Nature.

[80]  D. Craik,et al.  The 1.1 A crystal structure of the neuronal acetylcholine receptor antagonist, alpha-conotoxin PnIA from Conus pennaceus. , 1996, Structure.

[81]  M Ptak,et al.  Refined three-dimensional solution structure of insect defensin A. , 1995, Structure.

[82]  E. Méndez,et al.  Solution structure of gamma 1-H and gamma 1-P thionins from barley and wheat endosperm determined by 1H-NMR: a structural motif common to toxic arthropod proteins. , 1993, Biochemistry.

[83]  X. Gallet,et al.  Two-dimensional1H NMR study of recombinant insect defensin A in water: Resonance assignments, secondary structure and global folding , 1992, Journal of biomolecular NMR.

[84]  G. Snyder,et al.  Factors governing selective formation of specific disulfides in synthetic variants of alpha-conotoxin. , 1991, Biochemistry.

[85]  C. Roumestand,et al.  Three-dimensional structure of natural charybdotoxin in aqueous solution by 1H-NMR. Charybdotoxin possesses a structural motif found in other scorpion toxins. , 1991, European journal of biochemistry.

[86]  J. Rivier,et al.  Conantokin-G: A novel peptide antagonist to the N-methyl-d-aspartic acid (NMDA) receptor , 1990, Neuroscience Letters.

[87]  S. Woodward,et al.  Diversity of Conus neuropeptides. , 1990, Science.

[88]  S. Woodward,et al.  Constant and hypervariable regions in conotoxin propeptides. , 1990, The EMBO journal.

[89]  S. Woodward,et al.  A molluscivorous Conus toxin: conserved frameworks in conotoxins. , 1989, Biochemistry.

[90]  B. Olivera,et al.  Invertebrate vasopressin/oxytocin homologs. Characterization of peptides from Conus geographus and Conus straitus venoms. , 1987, The Journal of biological chemistry.

[91]  W R Gray,et al.  Peptide neurotoxins from fish-hunting cone snails. , 1985, Science.

[92]  D. Yoshikami,et al.  Conus geographus toxins that discriminate between neuronal and muscle sodium channels. , 1985, The Journal of biological chemistry.

[93]  J. McIntosh,et al.  Gamma-carboxyglutamate in a neuroactive toxin. , 1984, The Journal of biological chemistry.

[94]  R. Quinn,et al.  Characterization of the neurotoxic constituents of Conus geographus (L) venom. , 1977, Life sciences.

[95]  R. Endean,et al.  Pharmacology of the venom of the gastropod Conus magus. , 1974, Toxicon : official journal of the International Society on Toxinology.

[96]  A. Kohn.  Food Specialization in Conus in Hawaii and California , 1966 .

[97]  A. Kohn,et al.  PRELIMINARY STUDIES ON THE VENOM OF THE MARINE SNAIL CONUS * , 1960, Annals of the New York Academy of Sciences.

[98]  A. Kohn.  The Ecology of Conus in Hawaii , 1959 .

[99]  G. Bulaj.  Formation of disulfide bonds in proteins and peptides. , 2005, Biotechnology advances.

[100]  B. Olivera,et al.  Conus venoms: a rich source of novel ion channel-targeted peptides. , 2004, Physiological reviews.

[101]  A. Schmidt,et al.  Structure-function relationships in factor IX and factor IXa. , 2003, Trends in cardiovascular medicine.

[102]  G. Fields,et al.  Conopeptides: Unique pharmacological agents that challenge current peptide methodologies , 2003 .

[103]  James K Simpson.  Chronic neuropathic pain. , 2003, The New England journal of medicine.

[104]  D. Craik,et al.  alpha-Conotoxins: nicotinic acetylcholine receptor antagonists as pharmacological tools and potential drug leads. , 2001, Current medicinal chemistry.

[105]  J. McIntosh,et al.  Conus peptides targeted to specific nicotinic acetylcholine receptor subtypes. , 1999, Annual review of biochemistry.

[106]  P. Sargent,et al.  The diversity of neuronal nicotinic acetylcholine receptors. , 1993, Annual review of neuroscience.

[107]  Lourdes J. Cruz,et al.  Conus venoms: a rich source of neuroactive peptides , 1985 .

[108]  R. Endean,et al.  The effects of crude venoms of Conus magus and Conus striatus on the contractile response and electrical activity of guinea-pig cardiac musculature. , 1979, Toxicon : official journal of the International Society on Toxinology.