US20040192886A1 - Mu-conopeptides - Google Patents

Mu-conopeptides Download PDF

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US20040192886A1
US20040192886A1 US10/828,478 US82847804A US2004192886A1 US 20040192886 A1 US20040192886 A1 US 20040192886A1 US 82847804 A US82847804 A US 82847804A US 2004192886 A1 US2004192886 A1 US 2004192886A1
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Prior art keywords
cys
seq
arg
gly
asp
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Baldomero Olivera
J. McIntosh
James Garrett
Maren Watkins
Lourdes Cruz
Ki-Joon Shon
Richard Jacobsen
Robert Jones
G. Cartier
Gregory Shen
John Wagstaff
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University of Utah Research Foundation UURF
Cognetix Inc
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University of Utah Research Foundation UURF
Cognetix Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • A—HUMAN NECESSITIES
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    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention is to ⁇ -conopeptides, derivatives or pharmaceutically acceptable salts thereof.
  • the present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated sodium channels.
  • the ⁇ -conopeptides or derivatives are useful as neuromuscular blocking agents, local anesthetic agents, analgesic agents and neuroprotective agents.
  • the ⁇ -conopeptides are also useful for treating neuromuscular disorders.
  • the invention is further directed to nucleic acid sequences encoding the ⁇ -conopeptides and encoding propeptides, as well as the propeptides.
  • Conus is a genus of predatory marine gastropods (snails) which envenomate their prey.
  • Venomous cone snails use a highly developed projectile apparatus to deliver their cocktail of toxic conotoxins into their prey.
  • the cone detects the presence of the fish using chemosensors in its siphon and when close enough extends its proboscis and fires a hollow harpoon-like tooth containing venom into the fish. This immobilizes the fish and enables the cone snail to wind it into its mouth via an attached filament.
  • Conus magus the web address grimwade.biochem.unimelb.
  • Conus species venom appears to contain a unique set of 50-200 peptides.
  • the composition of the venom differs greatly between species and between individual snails within each species, each optimally evolved to paralyze its prey.
  • the active components of the venom are small peptides toxins, typically 10-40 amino acid residues in length and are typically highly constrained peptides due to their high density of disulphide bonds.
  • the venoms consist of a large number of different peptide components that when separated exhibit a range of biological activities: when injected into mice they elicit a range of physiological responses from shaking to depression.
  • the paralytic components of the venom that have been the focus of recent investigation are the ⁇ -, ⁇ - and ⁇ -conotoxins. All of these conotoxins act by preventing neuronal communication, but each targets a different aspect of the process to achieve this.
  • the ⁇ -conotoxins target nicotinic ligand gated channels, the ⁇ -conotoxins target the voltage-gated sodium channels and the ⁇ -conotoxins target the voltage-gated calcium channels (Olivera et al., 1985; Olivera et al., 1990).
  • a linkage has been established between ⁇ -, ⁇ A- & ⁇ -conotoxins and the nicotinic ligand-gated ion channel; ⁇ -conotoxins and the voltage-gated calcium channel; ⁇ -conotoxins and the voltage-gated sodium channel; ⁇ -conotoxins and the voltage-gated sodium channel; ⁇ -conotoxins and the voltage-gated potassium channel; conantokins and the ligand-gated glutamate (NMDA) channel.
  • NMDA ligand-gated glutamate
  • Conus peptides which target voltage-gated ion channels include those that delay the inactivation of sodium channels, as well as blockers specific for sodium channels, calcium channels and potassium channels.
  • Peptides that target ligand-gated ion channels include antagonists of NMDA and serotonin receptors, as well as competitive and noncompetitive nicotinic receptor antagonists.
  • Peptides which act on G-protein receptors include neurotensin and vasopressin receptor agonists.
  • the unprecedented pharmaceutical selectivity of conotoxins is at least in part defined by a specific disulfide bond frameworks combined with hypervariable amino acids within disulfide loops (for a review see McIntosh et al., 1998).
  • ⁇ -conotoxin MVIIA ziconotide
  • N-type calcium channel blocker see Heading, C., 1999; U.S. Pat. No. 5,859,186.
  • ⁇ -Conotoxin MVIIA isolated from Conus magus , is approximately 1000 times more potent than morphine, yet does not produce the tolerance or addictive properties of opiates.
  • ⁇ -Conotoxin MVIIA has completed Phase III (final stages) of human clinical trials and has been approved as a therapeutic agent.
  • ⁇ -Conotoxin MVIIA is introduced into human patients by means of an implantable, programmable pump with a catheter threaded into the intrathecal space.
  • Preclinical testing for use in post-surgical pain is being carried out on another Conus peptide, Contulakin-G, isolated from Conus geographus (Craig et al. 1999).
  • Contulakin-G is a 16 amino acid 0-linked glycopeptide whose C-terminus resembles neurotensin. It is an agonist of neurotensin receptors, but appears significantly more potent than neurotensin in inhibiting pain in in vivo assays.
  • the present invention is to ⁇ -conopeptides, derivatives or pharmaceutically acceptable salts thereof.
  • the present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated sodium channels.
  • the ⁇ -conopeptides or derivatives are useful as neuromuscular blocking agents, local anesthetic agents, analgesic agents and neuroprotective agents.
  • the ⁇ -conopeptides are also useful for treating neuromuscular disorders.
  • the invention is further directed to nucleic acid sequences encoding the ⁇ -conopeptides and encoding propeptides, as well as the propeptides.
  • the present invention is directed to ⁇ -conopeptides, having the amino acid sequences set forth in Tables 1 and 2 below.
  • the present invention is also directed to derivatives or pharmaceutically acceptable salts of the ⁇ -conopeptides or the derivatives.
  • derivatives include peptides in which the Arg residues may be substituted by Lys, omithine, homoargine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any synthetic basic amino acid; the Lys residues may be substituted by Arg, ornithine, homoargine, nor-Lys, or any synthetic basic amino acid; the Tyr residues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic hydroxy containing amino acid; the Ser residues may be substituted with Thr or any synthetic hydroxylated amino acid; the Thr residues may be substituted
  • the halogen may be iodo, chloro, fluoro or bromo; preferably iodo for halogen substituted-Tyr and bromo for halogen-substituted Trp.
  • the Tyr residues may also be substituted with the 3-hydroxyl or 2-hydroxyl isomers (meta-Tyr or ortho-Tyr, respectively) and corresponding O-sulpho- and O-phospho-derivatives.
  • the acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g., tetrazolyl derivatives of Gly and Ala.
  • the Met residues may be substituted by norleucine (Nle).
  • the Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L).
  • Examples of synthetic aromatic amino acid include, but are not lirnited to, nitro-Phe, 4-substituted-Phe wherein the substituent is C 1 -C 3 alkyl, carboxyl, hyrdroxymethyl, sulphomethyl, halo, phenyl, —CHO, —CN, —SO 3 H and —NHAc.
  • Examples of synthetic hydroxy containing amino acid include, but are not limited to, such as 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr.
  • Examples of synthetic basic amino acids include, but are not limited to, N-1-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4-piperinyl)-Ala, 2-[3-(2S)pyrrolininyl)-Gly and 2-[3-(2S)pyrrolininyl)-Ala.
  • These and other synthetic basic amino acids, synthetic hydroxy containing amino acids or synthetic aromatic amino acids are described in Building Block Index, Version 3.0 (1999 Catalog, pages 4-47 for hydroxy containing amino acids and aromatic amino acids and pages 66-87 for basic amino acids; see also web address amino-acids.
  • the Asn residues may be modified to contain an N-glycan and the Ser, Thr and Hyp residues may be modified to contain an O-glycan (e.g., g-N, g-S, g-T and g-Hyp).
  • a glycan shall mean any N-, S- or O-linked mono-, di-, tri-, poly- or oligosaccharide that can be attached to any hydroxy, amino or thiol group of natural or modified amino acids by synthetic or enzymatic methodologies known in the art.
  • the monosaccharides making up the glycan can include D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose, D-galactosamine, D-glucosamine, D-N-acetyl-glucosamine (GlcNAc), D-N-acetyl-galactosamine (GalNAc), D-fucose or D-arabinose.
  • These saccharides may be structurally modified, e.g., with one or more O-sulfate, O-phosphate, O-acetyl or acidic groups, such as sialic acid, including combinations thereof.
  • the gylcan may also include similar polyhydroxy groups, such as D-penicillamine 2,5 and halogenated derivatives thereof or polypropylene glycol derivatives.
  • the glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3.
  • the linkage between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-.
  • Core O-glycans have been described by Van de Steen et al. (1998), incorporated herein by reference. Mucin type O-linked oligosaccharides are attached to Ser or Thr (or other hydroxylated residues of the present peptides) by a GalNAc residue. The monosaccharide building blocks and the linkage attached to this first GalNAc residue define the “core glycans,” of which eight have been identified. The type of glycosidic linkage (orientation and connectivities) are defined for each core glycan. Suitable glycans and glycan analogs are described further in U.S. Ser. No. 09/420,797 filed 19 Oct. 1999 (now U.S. Pat. No.
  • a preferred glycan is Gal( ⁇ 1 ⁇ 3)GalNAc( ⁇ 1 ⁇ ).
  • pairs of Cys residues may be replaced pairwise with isoteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/Ala combinations.
  • isoteric lactam or ester-thioether replacements such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/Ala combinations.
  • Sequential coupling by known methods (Barnay et al., 2000; Hruby et al., 1994; Bitan et al., 1997) allows replacement of native Cys bridges with lactam bridges.
  • Thioether analogs may be readily synthesized using halo-Ala residues commercially available from RSP Amino Acid Analogues.
  • the present invention is further directed to derivatives of the above peptides and peptide derivatives which are acylic permutations in which the cyclic permutants retain the native bridging pattern of native toxin. See, for example, Craik et al. (2001).
  • the present invention is further directed to a method of treating disorders associated with voltage gated ion channel disorders in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a ⁇ -conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention is also directed to a pharmaceutical composition comprising a therapeutically effective amount of a ⁇ -conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
  • the present invention is further directed to uses of these peptides or nucleic acids as described herein as neuromuscular blocking agents, local anesthetic agents, analgesic agents and neuroprotective agents.
  • the ⁇ -conopeptides are also useful for treating neuromuscular disorders.
  • the present invention is directed to the use of ⁇ -conopeptides as a local anesthetic for treating pain.
  • the ⁇ -conopeptides have long lasting anesthetic activity and are particularly useful for spinal anesthesia, either administered acutely for post-operative pain or via an intrathecal pump for severe chronic pain situations.
  • the ⁇ -conopeptides are also useful as analgesics in chronic and neuropathic pain states, such as trigeminal neuralgia, diabetic neuropathy, post-herpetic neuralgia, neuroma pain and phantom limb pain.
  • the ⁇ -conopeptides are also useful for treating burn pain and as ocular anesthetics.
  • the present invention is directed to the use of ⁇ -conopeptides as neuroprotectants.
  • the ⁇ -conopeptides are useful for the treatment and alleviation of epilepsy and as a general anticonvulsant agent.
  • the ⁇ -conopeptides are also useful for treating neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS).
  • ALS Amyotrophic Lateral Sclerosis
  • the ⁇ -conopeptides are further useful as cerebroprotectants, such as for reducing neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia which typically follows stroke, cerebrovascular accident, brain or spinal cord trauma, myocardial infarct, physical trauma, drowning, suffocation, perinatal asphyxia, or hypoglycemic events.
  • the present invention is directed to the use of ⁇ -conopeptides as neuromuscular blockers and for treating neuromuscular disorders.
  • the ⁇ -conopeptides are useful for providing relaxation of muscle, for treating benign essential blepharospasm and other forms of focal dystonia and for anti-wrinkle use.
  • the present invention is also directed to nucleic acids which encode ⁇ -conopeptides of the present invention or which encodes precursor peptides for these ⁇ -conopeptides, as well as the precursor peptide.
  • the nucleic acid sequences encoding the precursor peptides of other ⁇ -conopeptides of the present invention are set forth in Table 1. Table 1 also sets forth the amino acid sequences of these precursor peptides.
  • the present invention is further directed to the use of selectively radioiodinated or radiotritiated ⁇ -conopeptides for characterizing pore occlusion sites on different sodium channel subtypes or for use in screening assays.
  • the present invention is also directed to the use of ⁇ -conopeptides for screening small molecule libraries to identify small molecules that are selective blocking agents at specific sodium channel subtypes expressed in mammalian systems.
  • the blocking activity of a small molecule at a particular sodium channel subtype is compared to the blocking activity of a ⁇ -conopeptide at the same sodium channel subtype.
  • the ability of a small molecule to displace a ⁇ -conopeptide from a sodium channel subtype is determined.
  • the binding affinity of a small molecule for a sodium channel subtype is compared to the binding affinity of a ⁇ -conopeptide for the same sodium channel subtype.
  • the present invention is to ⁇ -conopeptides, derivatives or pharmaceutically acceptable salts thereof.
  • the present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated sodium channels.
  • the ⁇ -conopeptides or derivatives are useful as neuromuscular blocking agents, local anesthetic agents, analgesic agents and neuroprotective agents.
  • the ⁇ -conopeptides are also useful for treating neuromuscular disorders.
  • the invention is further directed to nucleic acid sequences encoding the ⁇ -conopeptides and encoding propeptides, as well as the propeptides.
  • the present invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of an ⁇ -conopeptides, a mutein thereof, an analog thereof, an active fragment thereof or pharmaceutically acceptable salts or solvates.
  • Such a pharmaceutical composition has the capability of acting at voltage gated ion channels, and are thus useful for treating a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to the partial or complete blockade of voltage gated ion channels of the central nervous system comprising the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention.
  • the present invention is directed to the use of ⁇ -conopeptides as neuromuscular blockers and for treating neuromuscular disorders.
  • the ⁇ -conopeptides are useful for providing relaxation of muscle, for treating benign essential blepharospasm and other forms of focal dystonia and for anti-wrinkle use.
  • the ⁇ -conopeptides are useful as neurmuscular blocking agents in conjunction with surgery or for intubation of the trachea by conventional parenteral administration e.g., intramuscular or intravenous administration in solution.
  • the ⁇ -conopeptides are useful as agents for treating neuromuscular disorders such as myofacial pain syndrome, chronic muscle spasm, dystonias and spasticity.
  • the primary factor detrimental to neurons in neurological disorders associated with deficient oxygen supply or mitochondrial dysfunction is insufficient ATP production relative to their requirement.
  • As a large part of the energy consumed by brain cells is used for maintenance of the Na + gradient across the cellular membrane, reduction of energy demand by down-modulation of voltage-gated Na(+)-channels is one strategy for neuroprotection.
  • preservation of the inward Na + gradient may be beneficial because it is an essential driving force for vital ion exchanges and transport mechanisms such as Ca 2+ homeostasis and neurotransmitter uptake.
  • the ⁇ -conopeptides of the present invention are useful as neuroprotectants.
  • the pharmaceutical compositions of the present invention are useful as neuroprotectants, especially cerebroprotectants, neuromuscular blockers, analgesics (both as a local anesthetic and for general analgesia use) or adjuvants to general anesthetics.
  • a “neurological disorder or disease” is a disorder or disease of the nervous system including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage as in cardiac arrest or neonatal distress or epilepsy.
  • a “neurological disorder or disease” is a disease state and condition in which a neuroprotectant, anticonvulsant, analgesic and/or as an adjunct in general anesthesia may be indicated, useful, recommended or prescribed.
  • the present invention is directed to the use of these compounds for reducing neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia which typically follows stroke, cerebrovascular accident, brain or spinal cord trauma, myocardial infarct, physical trauma, drowning, suffocation, perinatal asphyxia, or hypoglycemic events.
  • the present invention is further directed to the use of these compounds for treating pain, including acute and chronic pain, such migraine, nociceptive and neuropathic pain.
  • a “neuroprotectant” is a compound capable of preventing the neuronal death associated with a neurological disorder or disease.
  • An “analgesic” is a compound capable of relieving pain by altering perception of nociceptive stimuli without producing anesthesia or loss of consciousness.
  • a “muscle relaxant” is a compound that reduces muscular tension.
  • An “adjunct in general anesthesia” is a compound useful in conjunction with anesthetic agents in producing the loss of ability to perceive pain associated with the loss of consciousness.
  • the invention relates as well to methods useful for treatment of neurological disorders and diseases, including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage such as in cardiac arrest or neonatal distress, epilepsy or other convulsive disorders without undesirable side effects.
  • neurological disorders and diseases including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage such as in cardiac arrest or neonatal distress, epilepsy or other convulsive disorders without undesirable side effects.
  • the invention provides a method of reducing/alleviating/decreasing the perception of pain by a subject or for inducing analgesia in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a ⁇ -conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the pain may be acute, persistent, inflammatory or neuropathic pain.
  • the ⁇ -conopeptides are useful as an analgesia for chronic and neuropathic pain states, such as trigeminal neuralgia, diabetic neuropathy, post-herpetic neuralgia, neuroma pain, phantom limb pain. These peptides are also useful for treating bum pain and as ocular anesthetics.
  • the invention provides a method of reducing/alleviating/decreasing the perception of pain by a subject or for inducing analgesia, particularly local analgesia, in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a ⁇ -conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof.
  • a ⁇ -conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof are also useful for treating bum pain and as ocular anesthetics.
  • the invention provides a method of treating stroke, head or spinal cord trauma or injury, anoxia, hypoxia-induced nerve cell damage, ischemia, migraine, psychosis, anxiety, schizophrenia, inflammation, movement disorder, epilepsy, any other convulsive disorder or in the prevention of the degenerative changes connected with the same in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a ⁇ -conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method for providing a neuromuscular block or for treating neuromuscular disorders, such as methods for providing relaxation of muscle, for treating benign essential blepharospasm and other forms of focal dystonia and for anti-wrinkle use.
  • the ⁇ -conopeptides are useful as neurmuscular blocking agents in conjunction with surgery or for intubation of the trachea by conventional parenteral administration e.g., intramuscular or intravenous administration in solution.
  • the ⁇ -conopeptides are useful as agents for treating neuromuscular disorders such as myofacial pain syndrome, chronic muscle spasm, dystonias and spasticity.
  • the present invention is also directed to the use of ⁇ -conopeptides for screening small molecule libraries to identify small molecules that are selective blocking agents at specific sodium channel subtypes expressed in mammalian systems.
  • the blocking activity of a small molecule at a particular sodium channel subtype is compared to the blocking activity of a ⁇ -conopeptide at the same sodium channel subtype.
  • the ability of a small molecule to displace a ⁇ -conopeptide from a sodium charmel subtype is determined.
  • the binding affinity of a small molecule for a sodium channel subtype is compared to the binding affinity of a ⁇ -conopeptide for the same sodium channel subtype.
  • ⁇ -conopeptides described herein are sufficiently small to be chemically synthesized.
  • General chemical syntheses for preparing the foregoing ⁇ -conotoxin peptides are described hereinafter.
  • Various ones of the ⁇ -conopeptides can also be obtained by isolation and purification from specific Conus species using the technique described in U.S. Pat. No. 4,447,356 (Olivera et al., 1984); U.S. Pat. Nos. 5,514,774; 5,719,264; and 5,591,821, as well as in PCT published application WO 98/03189, the disclosures of which are incorporated herein by reference.
  • the ⁇ -conopeptides of the present invention can be obtained by purification from cone snails, because the amounts of ⁇ -conopeptides obtainable from individual snails are very small, the desired substantially pure ⁇ -conopeptides are best practically obtained in commercially valuable amounts by chemical synthesis using solid-phase strategy.
  • the yield from a single cone snail may be about 10 micrograms or less of ⁇ -conopeptides peptide.
  • substantially pure is meant that the peptide is present in the substantial absence of other biological molecules of the same type; it is preferably present in an amount of at least about 85% purity and preferably at least about 95% purity. Chemical synthesis of biologically active ⁇ -conopeptides peptides depends of course upon correct determination of the amino acid sequence.
  • the ⁇ -conopeptides can also be produced by recombinant DNA techniques well known in the art. Such techniques are described by Sambrook et al. (1989).
  • a gene of interest i.e., a gene that encodes a suitable ⁇ -conopeptides
  • the expression vector containing the gene of interest may then be used to transfect the desired cell line. Standard transfection techniques such as calcium phosphate co-precipitation, DEAE-dextran transfection or electroporation may be utilized.
  • a wide variety of host/expression vector combinations may be used to express a gene encoding a conotoxin peptide of interest. Such combinations are well known to a skilled artisan.
  • the peptides produced in this manner are isolated, reduced if necessary, and oxidized to form the correct disulfide bonds.
  • One method of forming disulfide bonds in the ⁇ -conopeptides of the present invention is the air oxidation of the linear peptides for prolonged periods under cold room temperatures or at room temperature. This procedure results in the creation of a substantial amount of the bioactive, disulfide-linked peptides.
  • the oxidized peptides are fractionated using reverse-phase high performance liquid chromatography (HPLC) or the like, to separate peptides having different linked configurations. Thereafter, either by comparing these fractions with the elution of the native material or by using a simple assay, the particular fraction having the correct linkage for maximum biological potency is easily determined. However, because of the dilution resulting from the presence of other fractions of less biopotency, a somewhat higher dosage may be required.
  • the peptides are synthesized by a suitable method, such as by exclusively solid-phase techniques, by partial solid-phase techniques, by fragment condensation or by classical solution couplings.
  • the peptide chain can be prepared by a series of coupling reactions in which constituent amino acids are added to the growing peptide chain in the desired sequence.
  • various coupling reagents e.g., dicyclohexylcarbodiimide or diisopropylcarbonyldimidazole
  • various active esters e.g., esters of N-hydroxyphthalimide or N-hydroxy-succinimide
  • the various cleavage reagents to carry out reaction in solution, with subsequent isolation and purification of intermediates, is well known classical peptide methodology.
  • the protecting group preferably retains its protecting properties and is not split off under coupling conditions
  • the protecting group should be stable under the reaction conditions selected for removing the ⁇ -amino protecting group at each step of the synthesis
  • the side chain protecting group must be removable, upon the completion of the synthesis containing the desired amino acid sequence, under reaction conditions that will not undesirably alter the peptide chain.
  • peptides are not so prepared, they are preferably prepared using the Merrifield solid-phase synthesis, although other equivalent chemical syntheses known in the art can also be used as previously mentioned. Solid-phase synthesis is commenced from the C-terminus of the peptide by coupling a protected ⁇ -amino acid to a suitable resin.
  • Such a starting material can be prepared by attaching an ⁇ -amino-protected amino acid by an ester linkage to a chloromethylated resin or a hydroxymethyl resin, or by an amide bond to a benzhydrylamine (BHA) resin or paramethylbenzhydrylamine (MBHA) resin.
  • BHA benzhydrylamine
  • MBHA paramethylbenzhydrylamine
  • Preparation of the hydroxymethyl resin is described by Bodansky et al. (1966). Chloromethylated resins are commercially available from Bio Rad Laboratories (Richmond, Calif.) and from Lab. Systems, Inc. The preparation of such a resin is described by Stewart and Young (1969).
  • BHA and MBHA resin supports are commercially available, and are generally used when the desired polypeptide being synthesized has an unsubstituted amide at the C-terminus.
  • solid resin supports may be any of those known in the art, such as one having the formulae —O—CH 2 -resin support, —NH BHA resin support, or —NH—MBHA resin support.
  • unsubstituted amide use of a BHA or MBHA resin is preferred, because cleavage directly gives the amide.
  • N-methyl amide is desired, it can be generated from an N-methyl BHA resin. Should other substituted amides be desired, the teaching of U.S. Pat. No.
  • the C-terminal amino acid, protected by Boc or Fmoc and by a side-chain protecting group, if appropriate, can be first coupled to a chloromethylated resin according to the procedure set forth in K. Horiki et al. (1978), using KF in DMF at about 60° C. for 24 hours with stirring, when a peptide having free acid at the C-terminus is to be synthesized.
  • the ⁇ -amino protecting group is removed, as by using trifluoroacetic acid (TFA) in methylene chloride or TFA alone.
  • TFA trifluoroacetic acid
  • the deprotection is carried out at a temperature between about 0° C. and room temperature.
  • Other standard cleaving reagents, such as HCl in dioxane, and conditions for removal of specific ⁇ -amino protecting groups may be used as described in Schroder & Lubke (1965).
  • the remaining ⁇ -amino- and side chain-protected amino acids are coupled step-wise in the desired order to obtain the intermediate compound defined hereinbefore, or as an alternative to adding each amino acid separately in the synthesis, some of them may be coupled to one another prior to addition to the solid phase reactor.
  • Selection of an appropriate coupling reagent is within the skill of the art. Particularly suitable as a coupling reagent is N,N′-dicyclohexylcarbodiimide (DCC, DIC, HBTU, HATU, TBTU in the presence of HoBt or HoAt).
  • activating reagents used in the solid phase synthesis of the peptides are well known in the peptide art.
  • suitable activating reagents are carbodiimides, such as N,N′-diisopropylcarbodiimide and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide.
  • Other activating reagents and their use in peptide coupling are described by Schroder & Lubke (1965) and Kapoor (1970).
  • Each protected amino acid or amino acid sequence is introduced into the solid-phase reactor in about a twofold or more excess, and the coupling may be carried out in a medium of dimethylformamide (DMF):CH 2 Cl 2 (1:1) or in DMF or CH 2 Cl 2 alone.
  • DMF dimethylformamide
  • the coupling procedure is repeated before removal of the ⁇ -amino protecting group prior to the coupling of the next amino acid.
  • the success of the coupling reaction at each stage of the synthesis if performed manually, is preferably monitored by the ninhydrin reaction, as described by Kaiser et al. (1970).
  • Coupling reactions can be performed automatically, as on a Beckman 990 automatic synthesizer, using a program such as that reported in Rivier et al. (1978).
  • the intermediate peptide can be removed from the resin support by treatment with a reagent, such as liquid hydrogen fluoride or TFA (if using Fmoc chemistry), which not only cleaves the peptide from the resin but also cleaves all remaining side chain protecting groups and also the -amino protecting group at the N-terminus if it was not previously removed to obtain the peptide in the form of the free acid.
  • a reagent such as liquid hydrogen fluoride or TFA (if using Fmoc chemistry)
  • TFA trifluoroacetic acid
  • one or more scavengers such as anisole, cresol, dimethyl sulfide and methylethyl sulfide are included in the reaction vessel.
  • Cyclization of the linear peptide is preferably affected, as opposed to cyclizing the peptide while a part of the peptido-resin, to create bonds between Cys residues.
  • fully protected peptide can be cleaved from a hydroxymethylated resin or a chloromethylated resin support by ammonolysis, as is well known in the art, to yield the fully protected amide intermediate, which is thereafter suitably cyclized and deprotected.
  • deprotection, as well as cleavage of the peptide from the above resins or a benzhydrylamine (BHA) resin or a methylbenzhydrylamine (MBHA), can take place at 0° C. with hydrofluoric acid (HF) or TFA, followed by oxidation as described above.
  • HF hydrofluoric acid
  • TFA methylbenzhydrylamine
  • the peptides are also synthesized using an automatic synthesizer.
  • Amino acids are sequentially coupled to an MBHA Rink resin (typically 100 mg of resin) beginning at the C-terminus using an Advanced Chemtech 357 Automatic Peptide Synthesizer. Couplings are carried out using 1,3-diisopropylcarbodimide in N-methylpyrrolidinone (NMP) or by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and diethylisopro-pylethylamine (DIEA).
  • NMP N-methylpyrrolidinone
  • HBTU 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • DIEA diethylisopro-pylethylamine
  • the FMOC protecting group is removed by treatment with
  • the ⁇ -conopeptides of the present invention are also useful to reduce neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia which typically follows stroke, cerebrovascular accident, brain or spinal chord trauma, myocardial infarct, physical trauma, drownings, suffocation, perinatal asphyxia, or hypoglycemic events.
  • an ⁇ -conopeptide should be administered in a therapeutically effective amount to the patient within 24 hours of the onset of the hypoxic, anoxic or ischemic condition in order for the ⁇ -conopeptide to effectively minimize the CNS damage which the patient will experience.
  • the ⁇ -conopeptides of the present invention are further useful in controlling pain, e.g., as analgesic agents, and the treatment of migraine, acute pain or persistent pain. They can be used prophylactically or to relieve the symptoms associated with a migraine episode, or to treat acute or persistent pain. For these uses, an ⁇ -conopeptide is administered in a therapeutically effective amount to overcome or to ease the pain.
  • the ⁇ -conopeptides of the present invention are also useful as neuromuscular blockers and for treating neuromuscular disorders. They can be used for providing relaxation of muscle, for treating benign essential blepharospasm and other forms of focal dystonia and for anti-wrinkle use.
  • the ⁇ -conopeptides are used as neurmuscular blocking agents in conjunction with surgery or for intubation of the trachea by conventional parenteral administration e.g., intramuscular or intravenous administration in solution.
  • the ⁇ -conopeptides are used as agents for treating neuromuscular disorders such as myofacial pain syndrome, chronic muscle spasm, dystonias and spasticity.
  • a ⁇ -conopeptide is administered in a therapeutically effective amount to relax muscle or provide a neuromuscular block.
  • compositions containing a compound of the present invention as the active ingredient can be prepared according to conventional pharmaceutical compounding techniques. See, for example, Remington's Pharmaceutical Sciences , 18th Ed. (1990, Mack Publishing Co., Easton, Pa.). Typically, an antagonistic amount of active ingredient will be admixed with a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral, parenteral or intrathecally. For examples of delivery methods see U.S. Pat. No. 5,844,077, incorporated herein by reference.
  • “Pharmaceutical composition” means physically discrete coherent portions suitable for medical administration.
  • “Pharmaceutical composition in dosage unit form” means physically discrete coherent units suitable for medical administration, each containing a daily dose or a multiple (up to four times) or a sub-multiple (down to a fortieth) of a daily dose of the active compound in association with a carrier and/or enclosed within an envelope. Whether the composition contains a daily dose, or for example, a half, a third or a quarter of a daily dose, will depend on whether the pharmaceutical composition is to be administered once or, for example, twice, three times or four times a day, respectively.
  • salt denotes acidic and/or basic salts, formed with inorganic or organic acids and/or bases, preferably basic salts. While pharmaceutically acceptable salts are preferred, particularly when employing the compounds of the invention as medicaments, other salts find utility, for example, in processing these compounds, or where non-medicament-type uses are contemplated. Salts of these compounds may be prepared by art-recognized techniques.
  • salts include, but are not limited to, inorganic and organic addition salts, such as hydrochloride, sulphates, nitrates or phosphates and acetates, trifluoroacetates, propionates, succinates, benzoates, citrates, tartrates, fumarates, maleates, methane-sulfonates, isothionates, theophylline acetates, salicylates, respectively, or the like. Lower alkyl quaternary ammonium salts and the like are suitable, as well.
  • inorganic and organic addition salts such as hydrochloride, sulphates, nitrates or phosphates and acetates, trifluoroacetates, propionates, succinates, benzoates, citrates, tartrates, fumarates, maleates, methane-sulfonates, isothionates, theophylline acetates, salicylates, respectively, or
  • the term “pharmaceutically acceptable” carrier means a non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline.
  • sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethyl
  • wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • antioxidants examples include, but are not limited to, water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, aloha-tocopherol and the like; and the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like
  • oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (B
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions or emulsions.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, suspending agents, and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions); or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets).
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques.
  • the active agent can be encapsulated to make it stable to passage through the gastrointestinal tract while at the same time allowing for passage across the blood brain barrier. See for example, WO 96/11698.
  • the compound may be dissolved in a pharmaceutical carrier and administered as either a solution or a suspension.
  • suitable carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative or synthetic origin.
  • the carrier may also contain other ingredients, for example, preservatives, suspending agents, solubilizing agents, buffers and the like.
  • the compounds When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid.
  • a variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selected, the severity of the disease state being treated and the dosage required for therapeutic efficacy.
  • the methods of this invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
  • modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes.
  • parenteral includes subcutaneous, intravenous, epidural, irrigation, intramuscular, release pumps, or infusion.
  • administration of the active agent according to this invention may be achieved using any suitable delivery means, including:
  • microencapsulation see, e.g., U.S. Pat. Nos. 4,352,883; 4,353,888; and 5,084,350);
  • oral administration in capsule, liquid, tablet, pill, or prolonged release formulation.
  • an active agent is delivered directly into the CNS, preferably to the brain ventricles, brain parenchyma, the intrathecal space or other suitable CNS location, most preferably intrathecally.
  • targeting therapies may be used to deliver the active agent more specifically to certain types of cell, by the use of targeting systems such as antibodies or cell specific ligands. Targeting may be desirable for a variety of reasons, e.g. if the agent is unacceptably toxic, or if it would otherwise require too high a dosage, or if it would not otherwise be able to enter the target cells.
  • the active agents which are peptides, can also be administered in a cell based delivery system in which a DNA sequence encoding an active agent is introduced into cells designed for implantation in the body of the patient, especially in the spinal cord region.
  • a cell based delivery system in which a DNA sequence encoding an active agent is introduced into cells designed for implantation in the body of the patient, especially in the spinal cord region.
  • Suitable delivery systems are described in U.S. Pat. No. 5,550,050 and published PCT Application Nos. WO 92/19195, WO 94/25503, WO 95/01203, WO 95/05452, WO 96/02286, WO 96/02646, WO 96/40871, WO 96/40959 and WO 97/12635.
  • Suitable DNA sequences can be prepared synthetically for each active agent on the basis of the developed sequences and the known genetic code.
  • Exemplary methods for administering such muscle relaxant compounds will be apparent to the skilled artisan.
  • Certain methods suitable for administering compounds useful according to the present invention are set forth in Goodman and Gilman's The Pharmacological Basis of Therapeutics , 7th Ed. (1985).
  • the administration to the patient can be intermittent; or at a gradual, continuous, constant or controlled rate.
  • Administration can be to a warm-blooded animal (e.g. a mammal, such as a mouse, rat, cat, rabbit, dog, pig, cow or monkey); but advantageously is administered to a human being.
  • Administration occurs after general anesthesia is administered.
  • the frequency of administration normally is determined by an anesthesiologist, and typically varies from patient to patient.
  • the active agent is preferably administered in an therapeutically effective amount.
  • a “therapeutically effective amount” or simply “effective amount” of an active compound is meant a sufficient amount of the compound to treat the desired condition at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the actual amount administered, and the rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage, timing, etc., is within the responsibility of general practitioners or spealists, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in Remington's Parmaceutical Sciences.
  • Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically.
  • the active agents of the present invention exhibit their effect at a dosage range from about 0.001 mg/kg to about 250 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg of the active ingredient, more preferably from a bout 0.05 mg/kg to about 75 mg/kg.
  • a suitable dose can be administered in multiple sub-doses per day.
  • a dose or sub-dose may contain from about 0.1 mg to about 500 mg of the active ingredient per unit dosage form.
  • a more preferred dosage will contain from about 0.5 mg to about 100 mg of active ingredient per unit dosage form. Dosages are generally initiated at lower levels and increased until desired effects are achieved.
  • the dosage contemplated is from about 1 ng to about 100 mg per day, preferably from about 100 ng to about 10 mg per day, more preferably from about 1 ⁇ g to about 100 ⁇ g per day. If administered peripherally, the dosage contemplated is somewhat higher, from about 100 ng to about 1000 mg per day, preferably from about 10 ⁇ g to about 100 mg per day, more preferably from about 100 ⁇ g to about 10 mg per day. If the conopeptide is delivered by continuous infusion (e.g., by pump delivery, biodegradable polymer delivery or cell-based delivery), then a lower dosage is contemplated than for bolus delivery.
  • continuous infusion e.g., by pump delivery, biodegradable polymer delivery or cell-based delivery
  • compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients.
  • Tablets, coated tablets, capsules, ampoules and suppositories are examples of dosage forms according to the invention.
  • the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be consistent with the dosage form employed in single or multiple unit doses.
  • a suitable effective dosage will be consistent with the dosage form employed in single or multiple unit doses.
  • the exact individual dosages, as well as daily dosages, are determined according to standard medical principles under the direction of a physician or veterinarian for use humans or animals.
  • the pharmaceutical compositions will generally contain from about 0.0001 to 99 wt. %, preferably about 0.001 to 50 wt. %, more preferably about 0.01 to 10 wt. % of the active ingredient by weight of the total composition.
  • the pharmaceutical compositions and medicaments can also contain other pharmaceutically active compounds.
  • other pharmaceutically active compounds include, but are not limited to, analgesic agents, cytokines and therapeutic agents in all of the major areas of clinical medicine.
  • the conopeptides of the present invention may be delivered in the form of drug cocktails.
  • a cocktail is a mixture of any one of the compounds useful with this invention with another drug or agent.
  • a common administration vehicle e.g., pill, tablet, implant, pump, injectable solution, etc.
  • a common administration vehicle e.g., pill, tablet, implant, pump, injectable solution, etc.
  • the individual drugs of the cocktail are each administered in therapeutically effective amounts.
  • a therapeutically effective amount will be determined by the parameters described above; but, in any event, is that amount which establishes a level of the drugs in the area of body where the drugs are required for a period of time which is effective in attaining the desired effects.
  • the amino acid sequence of the purified peptides were determined by standard methods.
  • the purified peptides were reduced and alkylated prior to sequencing by automated Edman degradation on an Applied Biosystems 477A Protein Sequencer with a 120A Analyzer (DNA/Peptide Facility, University of Utah) (Martinez et al., 1995; Shon et al., 1994).
  • DNA coding for ⁇ -conopeptides was isolated and cloned in accordance with conventional techniques using general procedures well known in the art, such as described in Olivera et al. (1996).
  • cDNA libraries was prepared from Conus venom duct using conventional techniques.
  • DNA from single clones was amplified by conventional techniques using primers which correspond approximately to the M13 universal priming site and the M13 reverse universal priming site.
  • Clones having a size of approximately 300-500 nucleotides were sequenced and screened for similarity in sequence to known ⁇ -conotoxins.
  • the DNA sequences and encoded propeptide sequences are set forth in Table 1.
  • DNA sequences coding for the mature toxin can also be prepared on the basis of the DNA sequences set forth in Tablel.
  • An alignment of the ⁇ -conopeptides of the present invention is set forth in Table 2.
  • mice Male C57 black mice (20-25 g) are obtained from Charles River Laboratories. These mice and the animals are housed in a temperature controlled (23° ⁇ 3° C.) room with a 12 hour light-dark cycle with free access to food and water. All animals are euthanized in accordance with Public Health Service policies on the humane care of laboratory animals.
  • Intrathecal (it) drug injections are performed as described (Hylden and Wilcox, 1980).
  • a ⁇ -conopeptide or vehicle is administered in a volume of 5 ⁇ l. Duration of hind-limb paralysis is assessed. This experiment reveals that injection of ⁇ -conopeptides into the intrathecal space of C57 black mice produced a paralysis of the animal. The animals in this experiment recovered fully.
  • mice Male Hartley guinea pigs (retired breeders) are obtained form Charles River Laboratories. The local anesthetic test is performed essentially as described (Bulbring and Wajda, 1945). On the day prior to test day, a patch on the back of the guinea pig is denuded of hair, first by shaving with electric clippers and subsequently with depilatory cream (Nair®). Depilatory cream is applied for five minutes and removed with a warm washcloth. The guinea pigs are dried and returned to their cages.
  • guinea pigs are reused following at least one week of recovery and injecting into an unused portion of the skin.
  • the stimulus consists of mild pin pricks (not hard enough to break the skin) with a 26G needle.
  • the response is a localized skin twitch caused by contraction of cutaneous muscles.
  • a unit test consisted of six uniform pin pricks, 3-5 seconds apart, within the injected area. Unit scores range from 0 (complete anesthesia) to 6 (no anesthesia). For potency experiments, the unit test is repeated at each site at five minute intervals for 30 minutes, and unit test scores summed (with 36 representing no anesthesia to 0 representing complete anesthesia. For duration experiments, unit tests are performed as described over the course of several hours to days.
  • ⁇ -Conopeptides of the present invention produce a potent and long lasting local anesthetic effect in the intracutaneous wheal test in the guinea pig.
  • bupivacaine has a slightly longer duration thatn lidocaine, consistent with clinical observations.
  • ⁇ -Conopeptides are dissolved 0.9 percent saline at a concentration of 2 mg/ml.
  • Rhesus monkeys are anesthetized with halothane, nitrous oxide and oxygen.
  • the maintenance concentration of halothane is 1.0%.
  • Arterial and venous catheters are placed in the femoral vessels for drug administration and recording of the arterial pressure. Controlled ventilation is accomplished via an endotrachael tube. Twitch and tetanic contractions of the tibialis arterior muscle are elicited indirectly via the sciatic nerve. Recordings of arterial pressure electrocardiogram (lead I), heart rate, and muscle function are made simultaneously. Four to six animals received each listed compound.
  • ⁇ -conopeptides The anti-pain activity of ⁇ -conopeptides is shown in several animal models. These models include the nerve injury model (Chaplan, et al., 1997), the nocioceptive response to s.c. formalin injection in rats (Codene, 1993) and an NMDA-induced persistent pain model (Liu, et al., 1997). In each of these models it is seen that the ⁇ -conopeptides and ⁇ -conopeptides derivatives have analgesic properties.
  • this study evaluates the effect of intrathecal administration of ⁇ -conopeptides in mice models of nocioceptive and neuropathic pain.
  • nocioceptive pain the effect of the ⁇ -conopeptides is studied in two different tests of inflammatory pain.
  • the first is the formalin test, ideal because it produces a relatively short-lived, but reliable pain behavior that is readily quantified.
  • a ⁇ -conopeptide is administered 10 minutes prior to injection of formalin. The number of flinches and/or the duration of licking produced by the injection is monitored. Since the first phase is presumed to be due to direct activation of primary afferents, and thus less dependent on long term changes in the spinal cord, ⁇ -conopeptides are presumed to have greatest effect on the magnitude of pain behavior in the second phase.
  • Acute pain (tail-flick).
  • a ⁇ -conopeptide or saline is administered intrathecally (i.t.) according to the method of Hylden and Wilcox (1980) in a constant volume of 5 ⁇ l.
  • Mice are gently wrapped in a towel with the tail exposed.
  • the tail is dipped in a water bath maintained at 54° C. and the time to a vigorous tail withdrawal is recorded. If there is no withdrawal by 8 seconds, the tail is removed to avoid tissue damage.
  • the partial sciatic nerve ligation model is used to assess the efficacy of ⁇ -conopeptides in neuropathic pain.
  • Nerve injury is produced according to the methods of Malmberg and Basbaum (1998). Animals are anesthetized with a ketamine/xylazine solution, the sciatic nerve is exposed and tightly ligated with 8-0 silk suture around 1 ⁇ 3 to 1 ⁇ 2 of the nerve. In sham-operated mice the nerve is exposed, but not ligated. Animals are allowed to recover for at least 1 week before testing is performed. On the testing day, mice are placed in plexiglass cylinders on a wire mesh frame and allowed to habituate for at least 60 minutes.
  • ⁇ -Conopeptide S3.2 was tested for activity on sodium channels as follows. S3.2 was administered to mice by intracerbroventricular (ICV) injection. Administration of S3.2 in this manner caused mice to show a spectrum of activity that is charcteristic of all sodium channel blockers, including rapid loss of righting reflex, coma-like inactivity and spastic uncontrolled limb movement. Following intrathecal (it) administration to mice, S3.2 causes rapid hindlimb paralysis that spreads to include the entire body over a course of 10-20 minutes followed by death, presumably due to respiratory paralysis. However, unlike classic ⁇ -conopeptides, S3.2 has no significant activity following intravenous administration (iv) to mice.
  • Iv intracerbroventricular
  • Classic ⁇ -conopeptides such as GIIIA and PIIIA, cause rapid paralysis and death following iv administration, indicating their activity at skeletal muscle sodium channels.
  • 80 nmol was administered iv to rats.
  • the effect of S3.2 was measured on skeletal muscle contraction, blood pressure and heart rate.
  • S3.2 was found to have no effect on any of these parameters.
  • Controls were performed using classical ⁇ -conopeptides, including Sm3.1, Sm3.3 and Bu3.1 described herein, also administered iv at 80 nmol. These control peptides caused a dramatic decrease in skeletal muscle contractility, as well as a significant drop in systemic blood pressure.
  • ⁇ -conopeptide S3.2 suprisingly is selective for neuronal sodium channels.
  • the most obvious difference between the S3.2 sequence and the sequences of these other peptides is a shortened first loop (the first loop between cysteine residues) which lacks a charged amino acid.

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Abstract

The present invention is to μ-conopeptides, derivatives or pharmaceutically acceptable salts thereof. The present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated sodium channels. Thus, the μ-conopeptides or derivatives are useful as neuromuscular blocking agents, local anesthetic agents, analgesic agents and neuroprotective agents. The μ-conopeptides are also useful for treating neuromuscular disorders. The invention is further directed to nucleic acid sequences encoding the μ-conopeptides and encoding propeptides, as well as the propeptides.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • The present application is a division of U.S. patent application Ser. No. 09/910,009 filed on 23 Jul. 2001. The present application is also related to and claims benefit under 35 USC §119(e) to U.S. provisional patent applications Serial No. 60/219,619 filed on 21 Jul. 2000, Ser. No. 60/245,157 filed on 3 Nov. 2000, Ser. No. 60/264,319 filed on 29 Jan. 2001 and Ser. No. 60/277,270 filed on 21 Mar. 2001. Each of these applications is incorporated herein by reference.[0001]
  • This invention was made with Government support under Grant No. PO1 GM48677 awarded by the National Institute of General Medical Sciences, National Institutes of Health, Bethesda, Md. The United States Government has certain rights in the invention. [0002]
    • BACKGROUND OF THE INVENTION
  • The present invention is to μ-conopeptides, derivatives or pharmaceutically acceptable salts thereof. The present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated sodium channels. Thus, the μ-conopeptides or derivatives are useful as neuromuscular blocking agents, local anesthetic agents, analgesic agents and neuroprotective agents. The μ-conopeptides are also useful for treating neuromuscular disorders. The invention is further directed to nucleic acid sequences encoding the μ-conopeptides and encoding propeptides, as well as the propeptides. [0003]
  • The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography. [0004]
  • Conus is a genus of predatory marine gastropods (snails) which envenomate their prey. Venomous cone snails use a highly developed projectile apparatus to deliver their cocktail of toxic conotoxins into their prey. In fish-eating species such as [0005] Conus magus the cone detects the presence of the fish using chemosensors in its siphon and when close enough extends its proboscis and fires a hollow harpoon-like tooth containing venom into the fish. This immobilizes the fish and enables the cone snail to wind it into its mouth via an attached filament. For general information on Conus and their venom see the web address grimwade.biochem.unimelb. edu.au/cone/referenc.html. Prey capture is accomplished through a sophisticated arsenal of peptides which target specific ion channel and receptor subtypes. Each Conus species venom appears to contain a unique set of 50-200 peptides. The composition of the venom differs greatly between species and between individual snails within each species, each optimally evolved to paralyze its prey. The active components of the venom are small peptides toxins, typically 10-40 amino acid residues in length and are typically highly constrained peptides due to their high density of disulphide bonds.
  • The venoms consist of a large number of different peptide components that when separated exhibit a range of biological activities: when injected into mice they elicit a range of physiological responses from shaking to depression. The paralytic components of the venom that have been the focus of recent investigation are the α-, ω- and μ-conotoxins. All of these conotoxins act by preventing neuronal communication, but each targets a different aspect of the process to achieve this. The α-conotoxins target nicotinic ligand gated channels, the μ-conotoxins target the voltage-gated sodium channels and the ω-conotoxins target the voltage-gated calcium channels (Olivera et al., 1985; Olivera et al., 1990). For example a linkage has been established between α-, αA- & ψ-conotoxins and the nicotinic ligand-gated ion channel; ω-conotoxins and the voltage-gated calcium channel; μ-conotoxins and the voltage-gated sodium channel; δ-conotoxins and the voltage-gated sodium channel; κ-conotoxins and the voltage-gated potassium channel; conantokins and the ligand-gated glutamate (NMDA) channel. [0006]
  • However, the structure and function of only a small minority of these peptides have been determined to date. For peptides where function has been determined, three classes of targets have been elucidated: voltage-gated ion channels; ligand-gated ion channels, and G-protein-linked receptors. [0007]
  • Conus peptides which target voltage-gated ion channels include those that delay the inactivation of sodium channels, as well as blockers specific for sodium channels, calcium channels and potassium channels. Peptides that target ligand-gated ion channels include antagonists of NMDA and serotonin receptors, as well as competitive and noncompetitive nicotinic receptor antagonists. Peptides which act on G-protein receptors include neurotensin and vasopressin receptor agonists. The unprecedented pharmaceutical selectivity of conotoxins is at least in part defined by a specific disulfide bond frameworks combined with hypervariable amino acids within disulfide loops (for a review see McIntosh et al., 1998). [0008]
  • There are drugs used in the treatment of pain, which are known in the literature and to the skilled artisan. See, for example, Merck Manual, 16th Ed. (1992). However, there is a demand for more active analgesic agents with diminished side effects and toxicity and which are non-addictive. The ideal analgesic would reduce the awareness of pain, produce analgesia over a wide range of pain types, act satisfactorily whether given orally or parenterally, produce minimal or no side effects, be free from tendency to produce tolerance and drug dependence. [0009]
  • Due to the high potency and exquisite selectivity of the conopeptides, several are in various stages of clinical development for treatment of human disorders. For example, two Conus peptides are being developed for the treatment of pain. The most advanced is ω-conotoxin MVIIA (ziconotide), an N-type calcium channel blocker (see Heading, C., 1999; U.S. Pat. No. 5,859,186). ω-Conotoxin MVIIA, isolated from [0010] Conus magus, is approximately 1000 times more potent than morphine, yet does not produce the tolerance or addictive properties of opiates. ω-Conotoxin MVIIA has completed Phase III (final stages) of human clinical trials and has been approved as a therapeutic agent. ω-Conotoxin MVIIA is introduced into human patients by means of an implantable, programmable pump with a catheter threaded into the intrathecal space. Preclinical testing for use in post-surgical pain is being carried out on another Conus peptide, contulakin-G, isolated from Conus geographus (Craig et al. 1999). Contulakin-G is a 16 amino acid 0-linked glycopeptide whose C-terminus resembles neurotensin. It is an agonist of neurotensin receptors, but appears significantly more potent than neurotensin in inhibiting pain in in vivo assays.
  • In view of a large number of biologically active substances in Conus species it is desirable to further characterize them and to identify peptides capable of treating disorders involving voltage gated ion channels, such as stroke and pain. Surprisingly, and in accordance with this invention, Applicants have discovered novel conotoxins that can be useful for the treatment of disorders involving voltage gated ion channels and could address a long felt need for a safe and effective treatment. [0011]
    • SUMMARY OF THE INVENTION
  • The present invention is to μ-conopeptides, derivatives or pharmaceutically acceptable salts thereof. The present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated sodium channels. Thus, the μ-conopeptides or derivatives are useful as neuromuscular blocking agents, local anesthetic agents, analgesic agents and neuroprotective agents. The μ-conopeptides are also useful for treating neuromuscular disorders. The invention is further directed to nucleic acid sequences encoding the μ-conopeptides and encoding propeptides, as well as the propeptides. [0012]
  • More specifically, the present invention is directed to μ-conopeptides, having the amino acid sequences set forth in Tables 1 and 2 below. [0013]
  • The present invention is also directed to derivatives or pharmaceutically acceptable salts of the μ-conopeptides or the derivatives. Examples of derivatives include peptides in which the Arg residues may be substituted by Lys, omithine, homoargine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any synthetic basic amino acid; the Lys residues may be substituted by Arg, ornithine, homoargine, nor-Lys, or any synthetic basic amino acid; the Tyr residues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic hydroxy containing amino acid; the Ser residues may be substituted with Thr or any synthetic hydroxylated amino acid; the Thr residues may be substituted with Ser or any synthetic hydroxylated amino acid; the Phe residues may be substituted with any synthetic aromatic amino acid; the Trp residues may be substituted with Trp (D), neo-Trp, halo-Trp (D or L) or any aromatic synthetic amino acid; and the Asn, Ser, Thr or Hyp residues may be glycosylated. The halogen may be iodo, chloro, fluoro or bromo; preferably iodo for halogen substituted-Tyr and bromo for halogen-substituted Trp. The Tyr residues may also be substituted with the 3-hydroxyl or 2-hydroxyl isomers (meta-Tyr or ortho-Tyr, respectively) and corresponding O-sulpho- and O-phospho-derivatives. The acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g., tetrazolyl derivatives of Gly and Ala. The aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains C[0014] nH2n+2 up to and including n=8. The Met residues may be substituted by norleucine (Nle). The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L).
  • Examples of synthetic aromatic amino acid include, but are not lirnited to, nitro-Phe, 4-substituted-Phe wherein the substituent is C[0015] 1-C3 alkyl, carboxyl, hyrdroxymethyl, sulphomethyl, halo, phenyl, —CHO, —CN, —SO3H and —NHAc. Examples of synthetic hydroxy containing amino acid, include, but are not limited to, such as 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr. Examples of synthetic basic amino acids include, but are not limited to, N-1-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4-piperinyl)-Ala, 2-[3-(2S)pyrrolininyl)-Gly and 2-[3-(2S)pyrrolininyl)-Ala. These and other synthetic basic amino acids, synthetic hydroxy containing amino acids or synthetic aromatic amino acids are described in Building Block Index, Version 3.0 (1999 Catalog, pages 4-47 for hydroxy containing amino acids and aromatic amino acids and pages 66-87 for basic amino acids; see also web address amino-acids. com), incorporated herein by reference, by and available from RSP Amino Acid Analogues, Inc., Worcester, Mass. Examples of synthetic acid amino acids include those derivatives bearing acidic functionality, including carboxyl, phosphate, sulfonate and synthetic tetrazolyl derivatives such as described by Ornstein et al. (1993) and in U.S. Pat. No. 5,331,001, each incorporated herein by reference.
  • Optionally, in the μ-conopeptides of the present invention, the Asn residues may be modified to contain an N-glycan and the Ser, Thr and Hyp residues may be modified to contain an O-glycan (e.g., g-N, g-S, g-T and g-Hyp). In accordance with the present invention, a glycan shall mean any N-, S- or O-linked mono-, di-, tri-, poly- or oligosaccharide that can be attached to any hydroxy, amino or thiol group of natural or modified amino acids by synthetic or enzymatic methodologies known in the art. The monosaccharides making up the glycan can include D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose, D-galactosamine, D-glucosamine, D-N-acetyl-glucosamine (GlcNAc), D-N-acetyl-galactosamine (GalNAc), D-fucose or D-arabinose. These saccharides may be structurally modified, e.g., with one or more O-sulfate, O-phosphate, O-acetyl or acidic groups, such as sialic acid, including combinations thereof. The gylcan may also include similar polyhydroxy groups, such as D-penicillamine 2,5 and halogenated derivatives thereof or polypropylene glycol derivatives. The glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3. The linkage between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-. [0016]
  • Core O-glycans have been described by Van de Steen et al. (1998), incorporated herein by reference. Mucin type O-linked oligosaccharides are attached to Ser or Thr (or other hydroxylated residues of the present peptides) by a GalNAc residue. The monosaccharide building blocks and the linkage attached to this first GalNAc residue define the “core glycans,” of which eight have been identified. The type of glycosidic linkage (orientation and connectivities) are defined for each core glycan. Suitable glycans and glycan analogs are described further in U.S. Ser. No. 09/420,797 filed 19 Oct. 1999 (now U.S. Pat. No. 6,369,193) and in PCT Application No. PCT/US99/24380 filed 19 Oct. 1999 (PCT Published Application No. WO 00/23092), each incorporated herein by reference. A preferred glycan is Gal(β1→3)GalNAc(α1→). [0017]
  • Optionally, in the μ-conopeptides described above, pairs of Cys residues may be replaced pairwise with isoteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/Ala combinations. Sequential coupling by known methods (Barnay et al., 2000; Hruby et al., 1994; Bitan et al., 1997) allows replacement of native Cys bridges with lactam bridges. Thioether analogs may be readily synthesized using halo-Ala residues commercially available from RSP Amino Acid Analogues. [0018]
  • The present invention is further directed to derivatives of the above peptides and peptide derivatives which are acylic permutations in which the cyclic permutants retain the native bridging pattern of native toxin. See, for example, Craik et al. (2001). [0019]
  • The present invention is further directed to a method of treating disorders associated with voltage gated ion channel disorders in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a μ-conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof. The present invention is also directed to a pharmaceutical composition comprising a therapeutically effective amount of a μ-conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. [0020]
  • More specifically, the present invention is further directed to uses of these peptides or nucleic acids as described herein as neuromuscular blocking agents, local anesthetic agents, analgesic agents and neuroprotective agents. The μ-conopeptides are also useful for treating neuromuscular disorders. [0021]
  • The present invention is directed to the use of μ-conopeptides as a local anesthetic for treating pain. The μ-conopeptides have long lasting anesthetic activity and are particularly useful for spinal anesthesia, either administered acutely for post-operative pain or via an intrathecal pump for severe chronic pain situations. The μ-conopeptides are also useful as analgesics in chronic and neuropathic pain states, such as trigeminal neuralgia, diabetic neuropathy, post-herpetic neuralgia, neuroma pain and phantom limb pain. The μ-conopeptides are also useful for treating burn pain and as ocular anesthetics. [0022]
  • The present invention is directed to the use of μ-conopeptides as neuroprotectants. The μ-conopeptides are useful for the treatment and alleviation of epilepsy and as a general anticonvulsant agent. The μ-conopeptides are also useful for treating neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS). The μ-conopeptides are further useful as cerebroprotectants, such as for reducing neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia which typically follows stroke, cerebrovascular accident, brain or spinal cord trauma, myocardial infarct, physical trauma, drowning, suffocation, perinatal asphyxia, or hypoglycemic events. [0023]
  • The present invention is directed to the use of μ-conopeptides as neuromuscular blockers and for treating neuromuscular disorders. As such, the μ-conopeptides are useful for providing relaxation of muscle, for treating benign essential blepharospasm and other forms of focal dystonia and for anti-wrinkle use. [0024]
  • More specifically, the present invention is also directed to nucleic acids which encode μ-conopeptides of the present invention or which encodes precursor peptides for these μ-conopeptides, as well as the precursor peptide. The nucleic acid sequences encoding the precursor peptides of other μ-conopeptides of the present invention are set forth in Table 1. Table 1 also sets forth the amino acid sequences of these precursor peptides. [0025]
  • The present invention is further directed to the use of selectively radioiodinated or radiotritiated μ-conopeptides for characterizing pore occlusion sites on different sodium channel subtypes or for use in screening assays. [0026]
  • The present invention is also directed to the use of μ-conopeptides for screening small molecule libraries to identify small molecules that are selective blocking agents at specific sodium channel subtypes expressed in mammalian systems. In one embodiment, the blocking activity of a small molecule at a particular sodium channel subtype is compared to the blocking activity of a μ-conopeptide at the same sodium channel subtype. In a second embodiment, the ability of a small molecule to displace a μ-conopeptide from a sodium channel subtype is determined. In a third emdiment, the binding affinity of a small molecule for a sodium channel subtype is compared to the binding affinity of a μ-conopeptide for the same sodium channel subtype.[0027]
    • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
  • The present invention is to μ-conopeptides, derivatives or pharmaceutically acceptable salts thereof. The present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated sodium channels. Thus, the μ-conopeptides or derivatives are useful as neuromuscular blocking agents, local anesthetic agents, analgesic agents and neuroprotective agents. The μ-conopeptides are also useful for treating neuromuscular disorders. The invention is further directed to nucleic acid sequences encoding the μ-conopeptides and encoding propeptides, as well as the propeptides. [0028]
  • The present invention, in another aspect, relates to a pharmaceutical composition comprising an effective amount of an μ-conopeptides, a mutein thereof, an analog thereof, an active fragment thereof or pharmaceutically acceptable salts or solvates. Such a pharmaceutical composition has the capability of acting at voltage gated ion channels, and are thus useful for treating a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to the partial or complete blockade of voltage gated ion channels of the central nervous system comprising the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention. [0029]
  • The present invention is directed to the use of μ-conopeptides as neuromuscular blockers and for treating neuromuscular disorders. As such, the μ-conopeptides are useful for providing relaxation of muscle, for treating benign essential blepharospasm and other forms of focal dystonia and for anti-wrinkle use. Thus, in one aspect, the μ-conopeptides are useful as neurmuscular blocking agents in conjunction with surgery or for intubation of the trachea by conventional parenteral administration e.g., intramuscular or intravenous administration in solution. In a second aspect, the μ-conopeptides are useful as agents for treating neuromuscular disorders such as myofacial pain syndrome, chronic muscle spasm, dystonias and spasticity. [0030]
  • The primary factor detrimental to neurons in neurological disorders associated with deficient oxygen supply or mitochondrial dysfunction is insufficient ATP production relative to their requirement. As a large part of the energy consumed by brain cells is used for maintenance of the Na[0031] + gradient across the cellular membrane, reduction of energy demand by down-modulation of voltage-gated Na(+)-channels is one strategy for neuroprotection. In addition, preservation of the inward Na+ gradient may be beneficial because it is an essential driving force for vital ion exchanges and transport mechanisms such as Ca2+ homeostasis and neurotransmitter uptake. Thus, the μ-conopeptides of the present invention are useful as neuroprotectants.
  • Thus, the pharmaceutical compositions of the present invention are useful as neuroprotectants, especially cerebroprotectants, neuromuscular blockers, analgesics (both as a local anesthetic and for general analgesia use) or adjuvants to general anesthetics. A “neurological disorder or disease” is a disorder or disease of the nervous system including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage as in cardiac arrest or neonatal distress or epilepsy. In addition, a “neurological disorder or disease” is a disease state and condition in which a neuroprotectant, anticonvulsant, analgesic and/or as an adjunct in general anesthesia may be indicated, useful, recommended or prescribed. [0032]
  • More specifically, the present invention is directed to the use of these compounds for reducing neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia which typically follows stroke, cerebrovascular accident, brain or spinal cord trauma, myocardial infarct, physical trauma, drowning, suffocation, perinatal asphyxia, or hypoglycemic events. The present invention is further directed to the use of these compounds for treating pain, including acute and chronic pain, such migraine, nociceptive and neuropathic pain. [0033]
  • A “neuroprotectant” is a compound capable of preventing the neuronal death associated with a neurological disorder or disease. An “analgesic” is a compound capable of relieving pain by altering perception of nociceptive stimuli without producing anesthesia or loss of consciousness. A “muscle relaxant” is a compound that reduces muscular tension. An “adjunct in general anesthesia” is a compound useful in conjunction with anesthetic agents in producing the loss of ability to perceive pain associated with the loss of consciousness. [0034]
  • The invention relates as well to methods useful for treatment of neurological disorders and diseases, including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage such as in cardiac arrest or neonatal distress, epilepsy or other convulsive disorders without undesirable side effects. [0035]
  • Thus, in one embodiment, the invention provides a method of reducing/alleviating/decreasing the perception of pain by a subject or for inducing analgesia in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a μ-conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof. The pain may be acute, persistent, inflammatory or neuropathic pain. The μ-conopeptides are useful as an analgesia for chronic and neuropathic pain states, such as trigeminal neuralgia, diabetic neuropathy, post-herpetic neuralgia, neuroma pain, phantom limb pain. These peptides are also useful for treating bum pain and as ocular anesthetics. [0036]
  • In a second embodiment, the invention provides a method of reducing/alleviating/decreasing the perception of pain by a subject or for inducing analgesia, particularly local analgesia, in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a μ-conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof. These peptides are also useful for treating bum pain and as ocular anesthetics. [0037]
  • In a third embodiment, the invention provides a method of treating stroke, head or spinal cord trauma or injury, anoxia, hypoxia-induced nerve cell damage, ischemia, migraine, psychosis, anxiety, schizophrenia, inflammation, movement disorder, epilepsy, any other convulsive disorder or in the prevention of the degenerative changes connected with the same in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a μ-conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof. [0038]
  • In a fourth embodiment, the invention provides a method for providing a neuromuscular block or for treating neuromuscular disorders, such as methods for providing relaxation of muscle, for treating benign essential blepharospasm and other forms of focal dystonia and for anti-wrinkle use. Thus, in one aspect, the μ-conopeptides are useful as neurmuscular blocking agents in conjunction with surgery or for intubation of the trachea by conventional parenteral administration e.g., intramuscular or intravenous administration in solution. In a second aspect, the μ-conopeptides are useful as agents for treating neuromuscular disorders such as myofacial pain syndrome, chronic muscle spasm, dystonias and spasticity. [0039]
  • The present invention is also directed to the use of μ-conopeptides for screening small molecule libraries to identify small molecules that are selective blocking agents at specific sodium channel subtypes expressed in mammalian systems. In one embodiment, the blocking activity of a small molecule at a particular sodium channel subtype is compared to the blocking activity of a μ-conopeptide at the same sodium channel subtype. In a second embodiment, the ability of a small molecule to displace a μ-conopeptide from a sodium charmel subtype is determined. In a third emdiment, the binding affinity of a small molecule for a sodium channel subtype is compared to the binding affinity of a μ-conopeptide for the same sodium channel subtype. [0040]
  • The μ-conopeptides described herein are sufficiently small to be chemically synthesized. General chemical syntheses for preparing the foregoing ω-conotoxin peptides are described hereinafter. Various ones of the μ-conopeptides can also be obtained by isolation and purification from specific Conus species using the technique described in U.S. Pat. No. 4,447,356 (Olivera et al., 1984); U.S. Pat. Nos. 5,514,774; 5,719,264; and 5,591,821, as well as in PCT published application WO 98/03189, the disclosures of which are incorporated herein by reference. [0041]
  • Although the μ-conopeptides of the present invention can be obtained by purification from cone snails, because the amounts of μ-conopeptides obtainable from individual snails are very small, the desired substantially pure μ-conopeptides are best practically obtained in commercially valuable amounts by chemical synthesis using solid-phase strategy. For example, the yield from a single cone snail may be about 10 micrograms or less of μ-conopeptides peptide. By “substantially pure” is meant that the peptide is present in the substantial absence of other biological molecules of the same type; it is preferably present in an amount of at least about 85% purity and preferably at least about 95% purity. Chemical synthesis of biologically active μ-conopeptides peptides depends of course upon correct determination of the amino acid sequence. [0042]
  • The μ-conopeptides can also be produced by recombinant DNA techniques well known in the art. Such techniques are described by Sambrook et al. (1989). A gene of interest (i.e., a gene that encodes a suitable μ-conopeptides) can be inserted into a cloning site of a suitable expression vector by using standard techniques. These techniques are well known to those skilled in the art. The expression vector containing the gene of interest may then be used to transfect the desired cell line. Standard transfection techniques such as calcium phosphate co-precipitation, DEAE-dextran transfection or electroporation may be utilized. A wide variety of host/expression vector combinations may be used to express a gene encoding a conotoxin peptide of interest. Such combinations are well known to a skilled artisan. The peptides produced in this manner are isolated, reduced if necessary, and oxidized to form the correct disulfide bonds. [0043]
  • One method of forming disulfide bonds in the μ-conopeptides of the present invention is the air oxidation of the linear peptides for prolonged periods under cold room temperatures or at room temperature. This procedure results in the creation of a substantial amount of the bioactive, disulfide-linked peptides. The oxidized peptides are fractionated using reverse-phase high performance liquid chromatography (HPLC) or the like, to separate peptides having different linked configurations. Thereafter, either by comparing these fractions with the elution of the native material or by using a simple assay, the particular fraction having the correct linkage for maximum biological potency is easily determined. However, because of the dilution resulting from the presence of other fractions of less biopotency, a somewhat higher dosage may be required. [0044]
  • The peptides are synthesized by a suitable method, such as by exclusively solid-phase techniques, by partial solid-phase techniques, by fragment condensation or by classical solution couplings. [0045]
  • In conventional solution phase peptide synthesis, the peptide chain can be prepared by a series of coupling reactions in which constituent amino acids are added to the growing peptide chain in the desired sequence. Use of various coupling reagents, e.g., dicyclohexylcarbodiimide or diisopropylcarbonyldimidazole, various active esters, e.g., esters of N-hydroxyphthalimide or N-hydroxy-succinimide, and the various cleavage reagents, to carry out reaction in solution, with subsequent isolation and purification of intermediates, is well known classical peptide methodology. Classical solution synthesis is described in detail in the treatise, “Methoden der Organischen Chemie (Houben-Weyl): Synthese von Peptiden,” (1974). Techniques of exclusively solid-phase synthesis are set forth in the textbook, “Solid-Phase Peptide Synthesis,” (Stewart and Young, 1969), and are exemplified by the disclosure of U.S. Pat. No. 4,105,603 (Vale et al., 1978). The fragment condensation method of synthesis is exemplified in U.S. Pat. No. 3,972,859 (1976). Other available syntheses are exemplified by U.S. Pat. No. 3,842,067 (1974) and U.S. Pat. No. 3,862,925 (1975). The synthesis of peptides containing γ-carboxyglutamic acid residues is exemplified by Rivier et al. (1987), Nishiuchi et al. (1993) and Zhou et al. (1996). [0046]
  • Common to such chemical syntheses is the protection of the labile side chain groups of the various amino acid moieties with suitable protecting groups which will prevent a chemical reaction from occurring at that site until the group is ultimately removed. Usually also common is the protection of an α-amino group on an amino acid or a fragment while that entity reacts at the carboxyl group, followed by the selective removal of the α-amino protecting group to allow subsequent reaction to take place at that location. Accordingly, it is common that, as a step in such a synthesis, an intermediate compound is produced which includes each of the amino acid residues located in its desired sequence in the peptide chain with appropriate side-chain protecting groups linked to various ones of the residues having labile side chains. [0047]
  • As far as the selection of a side chain amino protecting group is concerned, generally one is chosen which is not removed during deprotection of the α-amino groups during the synthesis. However, for some amino acids, e.g., His, protection is not generally necessary. In selecting a particular side chain protecting group to be used in the synthesis of the peptides, the following general rules are followed: (a) the protecting group preferably retains its protecting properties and is not split off under coupling conditions, (b) the protecting group should be stable under the reaction conditions selected for removing the α-amino protecting group at each step of the synthesis, and (c) the side chain protecting group must be removable, upon the completion of the synthesis containing the desired amino acid sequence, under reaction conditions that will not undesirably alter the peptide chain. [0048]
  • It should be possible to prepare many, or even all, of these peptides using recombinant DNA technology. However, when peptides are not so prepared, they are preferably prepared using the Merrifield solid-phase synthesis, although other equivalent chemical syntheses known in the art can also be used as previously mentioned. Solid-phase synthesis is commenced from the C-terminus of the peptide by coupling a protected α-amino acid to a suitable resin. Such a starting material can be prepared by attaching an α-amino-protected amino acid by an ester linkage to a chloromethylated resin or a hydroxymethyl resin, or by an amide bond to a benzhydrylamine (BHA) resin or paramethylbenzhydrylamine (MBHA) resin. Preparation of the hydroxymethyl resin is described by Bodansky et al. (1966). Chloromethylated resins are commercially available from Bio Rad Laboratories (Richmond, Calif.) and from Lab. Systems, Inc. The preparation of such a resin is described by Stewart and Young (1969). BHA and MBHA resin supports are commercially available, and are generally used when the desired polypeptide being synthesized has an unsubstituted amide at the C-terminus. Thus, solid resin supports may be any of those known in the art, such as one having the formulae —O—CH[0049] 2-resin support, —NH BHA resin support, or —NH—MBHA resin support. When the unsubstituted amide is desired, use of a BHA or MBHA resin is preferred, because cleavage directly gives the amide. In case the N-methyl amide is desired, it can be generated from an N-methyl BHA resin. Should other substituted amides be desired, the teaching of U.S. Pat. No. 4,569,967 (Kornreich et al., 1986) can be used, or should still other groups than the free acid be desired at the C-terminus, it may be preferable to synthesize the peptide using classical methods as set forth in the Houben-Weyl text (1974).
  • The C-terminal amino acid, protected by Boc or Fmoc and by a side-chain protecting group, if appropriate, can be first coupled to a chloromethylated resin according to the procedure set forth in K. Horiki et al. (1978), using KF in DMF at about 60° C. for 24 hours with stirring, when a peptide having free acid at the C-terminus is to be synthesized. Following the coupling of the BOC-protected amino acid to the resin support, the α-amino protecting group is removed, as by using trifluoroacetic acid (TFA) in methylene chloride or TFA alone. The deprotection is carried out at a temperature between about 0° C. and room temperature. Other standard cleaving reagents, such as HCl in dioxane, and conditions for removal of specific α-amino protecting groups may be used as described in Schroder & Lubke (1965). [0050]
  • After removal of the α-amino-protecting group, the remaining α-amino- and side chain-protected amino acids are coupled step-wise in the desired order to obtain the intermediate compound defined hereinbefore, or as an alternative to adding each amino acid separately in the synthesis, some of them may be coupled to one another prior to addition to the solid phase reactor. Selection of an appropriate coupling reagent is within the skill of the art. Particularly suitable as a coupling reagent is N,N′-dicyclohexylcarbodiimide (DCC, DIC, HBTU, HATU, TBTU in the presence of HoBt or HoAt). [0051]
  • The activating reagents used in the solid phase synthesis of the peptides are well known in the peptide art. Examples of suitable activating reagents are carbodiimides, such as N,N′-diisopropylcarbodiimide and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide. Other activating reagents and their use in peptide coupling are described by Schroder & Lubke (1965) and Kapoor (1970). [0052]
  • Each protected amino acid or amino acid sequence is introduced into the solid-phase reactor in about a twofold or more excess, and the coupling may be carried out in a medium of dimethylformamide (DMF):CH[0053] 2Cl2 (1:1) or in DMF or CH2Cl2 alone. In cases where intermediate coupling occurs, the coupling procedure is repeated before removal of the α-amino protecting group prior to the coupling of the next amino acid. The success of the coupling reaction at each stage of the synthesis, if performed manually, is preferably monitored by the ninhydrin reaction, as described by Kaiser et al. (1970). Coupling reactions can be performed automatically, as on a Beckman 990 automatic synthesizer, using a program such as that reported in Rivier et al. (1978).
  • After the desired amino acid sequence has been completed, the intermediate peptide can be removed from the resin support by treatment with a reagent, such as liquid hydrogen fluoride or TFA (if using Fmoc chemistry), which not only cleaves the peptide from the resin but also cleaves all remaining side chain protecting groups and also the -amino protecting group at the N-terminus if it was not previously removed to obtain the peptide in the form of the free acid. If Met is present in the sequence, the Boc protecting group is preferably first removed using trifluoroacetic acid (TFA)/ethanedithiol prior to cleaving the peptide from the resin with HF to eliminate potential S-alkylation. When using hydrogen fluoride or TFA for cleaving, one or more scavengers such as anisole, cresol, dimethyl sulfide and methylethyl sulfide are included in the reaction vessel. [0054]
  • Cyclization of the linear peptide is preferably affected, as opposed to cyclizing the peptide while a part of the peptido-resin, to create bonds between Cys residues. To effect such a disulfide cyclizing linkage, fully protected peptide can be cleaved from a hydroxymethylated resin or a chloromethylated resin support by ammonolysis, as is well known in the art, to yield the fully protected amide intermediate, which is thereafter suitably cyclized and deprotected. Alternatively, deprotection, as well as cleavage of the peptide from the above resins or a benzhydrylamine (BHA) resin or a methylbenzhydrylamine (MBHA), can take place at 0° C. with hydrofluoric acid (HF) or TFA, followed by oxidation as described above. [0055]
  • The peptides are also synthesized using an automatic synthesizer. Amino acids are sequentially coupled to an MBHA Rink resin (typically 100 mg of resin) beginning at the C-terminus using an Advanced Chemtech 357 Automatic Peptide Synthesizer. Couplings are carried out using 1,3-diisopropylcarbodimide in N-methylpyrrolidinone (NMP) or by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and diethylisopro-pylethylamine (DIEA). The FMOC protecting group is removed by treatment with a 20% solution of piperidine in dimethylformamide(DMF). Resins are subsequently washed with DMF (twice), followed by methanol and NMP. [0056]
  • Muteins, analogs or active fragments, of the foregoing conotoxin peptides are also contemplated here. See, e.g., Hammerland et al. (1992). Derivative muteins, analogs or active fragments of the conotoxin peptides may be synthesized according to known techniques, including conservative amino acid substitutions, such as outlined in U.S. Pat. No. 5,545,723 (see particularly col. 2, line 50—col. 3, line 8); U.S. Pat. No. 5,534,615 (see particularly col. 19, line 45—col 22, line 33); and U.S. Pat. No. 5,364,769 (see particularly col. 4, line 55—col. 7, line 26), each herein incorporated by reference. [0057]
  • The μ-conopeptides of the present invention are also useful to reduce neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia which typically follows stroke, cerebrovascular accident, brain or spinal chord trauma, myocardial infarct, physical trauma, drownings, suffocation, perinatal asphyxia, or hypoglycemic events. To reduce neurotoxic injury, an ω-conopeptide should be administered in a therapeutically effective amount to the patient within 24 hours of the onset of the hypoxic, anoxic or ischemic condition in order for the μ-conopeptide to effectively minimize the CNS damage which the patient will experience. [0058]
  • The μ-conopeptides of the present invention are further useful in controlling pain, e.g., as analgesic agents, and the treatment of migraine, acute pain or persistent pain. They can be used prophylactically or to relieve the symptoms associated with a migraine episode, or to treat acute or persistent pain. For these uses, an μ-conopeptide is administered in a therapeutically effective amount to overcome or to ease the pain. [0059]
  • The μ-conopeptides of the present invention are also useful as neuromuscular blockers and for treating neuromuscular disorders. They can be used for providing relaxation of muscle, for treating benign essential blepharospasm and other forms of focal dystonia and for anti-wrinkle use. Thus, in one aspect, the μ-conopeptides are used as neurmuscular blocking agents in conjunction with surgery or for intubation of the trachea by conventional parenteral administration e.g., intramuscular or intravenous administration in solution. In a second aspect, the μ-conopeptides are used as agents for treating neuromuscular disorders such as myofacial pain syndrome, chronic muscle spasm, dystonias and spasticity. For these uses, a μ-conopeptide is administered in a therapeutically effective amount to relax muscle or provide a neuromuscular block. [0060]
  • Pharmaceutical compositions containing a compound of the present invention as the active ingredient can be prepared according to conventional pharmaceutical compounding techniques. See, for example, [0061] Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa.). Typically, an antagonistic amount of active ingredient will be admixed with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral, parenteral or intrathecally. For examples of delivery methods see U.S. Pat. No. 5,844,077, incorporated herein by reference.
  • “Pharmaceutical composition” means physically discrete coherent portions suitable for medical administration. “Pharmaceutical composition in dosage unit form” means physically discrete coherent units suitable for medical administration, each containing a daily dose or a multiple (up to four times) or a sub-multiple (down to a fortieth) of a daily dose of the active compound in association with a carrier and/or enclosed within an envelope. Whether the composition contains a daily dose, or for example, a half, a third or a quarter of a daily dose, will depend on whether the pharmaceutical composition is to be administered once or, for example, twice, three times or four times a day, respectively. [0062]
  • The term “salt”, as used herein, denotes acidic and/or basic salts, formed with inorganic or organic acids and/or bases, preferably basic salts. While pharmaceutically acceptable salts are preferred, particularly when employing the compounds of the invention as medicaments, other salts find utility, for example, in processing these compounds, or where non-medicament-type uses are contemplated. Salts of these compounds may be prepared by art-recognized techniques. [0063]
  • Examples of such pharmaceutically acceptable salts include, but are not limited to, inorganic and organic addition salts, such as hydrochloride, sulphates, nitrates or phosphates and acetates, trifluoroacetates, propionates, succinates, benzoates, citrates, tartrates, fumarates, maleates, methane-sulfonates, isothionates, theophylline acetates, salicylates, respectively, or the like. Lower alkyl quaternary ammonium salts and the like are suitable, as well. [0064]
  • As used herein, the term “pharmaceutically acceptable” carrier means a non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline. Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. [0065]
  • Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Examples of pharmaceutically acceptable antioxidants include, but are not limited to, water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, aloha-tocopherol and the like; and the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. [0066]
  • For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions or emulsions. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, suspending agents, and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions); or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets). Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. The active agent can be encapsulated to make it stable to passage through the gastrointestinal tract while at the same time allowing for passage across the blood brain barrier. See for example, WO 96/11698. [0067]
  • For parenteral administration, the compound may be dissolved in a pharmaceutical carrier and administered as either a solution or a suspension. Illustrative of suitable carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative or synthetic origin. The carrier may also contain other ingredients, for example, preservatives, suspending agents, solubilizing agents, buffers and the like. When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid. [0068]
  • A variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selected, the severity of the disease state being treated and the dosage required for therapeutic efficacy. The methods of this invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes. The term “parenteral” includes subcutaneous, intravenous, epidural, irrigation, intramuscular, release pumps, or infusion. [0069]
  • For example, administration of the active agent according to this invention may be achieved using any suitable delivery means, including: [0070]
  • (a) pump (see, e.g., Luer & Hatton (1993), Zimm et al. (1984) and Ettinger et al. (1978)); [0071]
  • (b), microencapsulation (see, e.g., U.S. Pat. Nos. 4,352,883; 4,353,888; and 5,084,350); [0072]
  • (c) continuous release polymer implants (see, e.g., U.S. Pat. No. 4,883,666); [0073]
  • (d) macroencapsulation (see, e.g., U.S. Pat. Nos. 5,284,761, 5,158,881, 4,976,859 and 4,968,733 and published PCT patent applications WO92/19195, WO 95/05452); [0074]
  • (e) naked or unencapsulated cell grafts to the CNS (see, e.g., U.S. Pat. Nos. 5,082,670 and 5,618,531); [0075]
  • (f) injection, either subcutaneously, intravenously, intra-arterially, intramuscularly, or to other suitable site; or [0076]
  • oral administration, in capsule, liquid, tablet, pill, or prolonged release formulation. [0077]
  • In one embodiment of this invention, an active agent is delivered directly into the CNS, preferably to the brain ventricles, brain parenchyma, the intrathecal space or other suitable CNS location, most preferably intrathecally. [0078]
  • Alternatively, targeting therapies may be used to deliver the active agent more specifically to certain types of cell, by the use of targeting systems such as antibodies or cell specific ligands. Targeting may be desirable for a variety of reasons, e.g. if the agent is unacceptably toxic, or if it would otherwise require too high a dosage, or if it would not otherwise be able to enter the target cells. [0079]
  • The active agents, which are peptides, can also be administered in a cell based delivery system in which a DNA sequence encoding an active agent is introduced into cells designed for implantation in the body of the patient, especially in the spinal cord region. Suitable delivery systems are described in U.S. Pat. No. 5,550,050 and published PCT Application Nos. WO 92/19195, WO 94/25503, WO 95/01203, WO 95/05452, WO 96/02286, WO 96/02646, WO 96/40871, WO 96/40959 and WO 97/12635. Suitable DNA sequences can be prepared synthetically for each active agent on the basis of the developed sequences and the known genetic code. [0080]
  • Exemplary methods for administering such muscle relaxant compounds (e.g., so as to achieve sterile or aseptic conditions) will be apparent to the skilled artisan. Certain methods suitable for administering compounds useful according to the present invention are set forth in Goodman and Gilman's [0081] The Pharmacological Basis of Therapeutics, 7th Ed. (1985). The administration to the patient can be intermittent; or at a gradual, continuous, constant or controlled rate. Administration can be to a warm-blooded animal (e.g. a mammal, such as a mouse, rat, cat, rabbit, dog, pig, cow or monkey); but advantageously is administered to a human being. Administration occurs after general anesthesia is administered. The frequency of administration normally is determined by an anesthesiologist, and typically varies from patient to patient.
  • The active agent is preferably administered in an therapeutically effective amount. By a “therapeutically effective amount” or simply “effective amount” of an active compound is meant a sufficient amount of the compound to treat the desired condition at a reasonable benefit/risk ratio applicable to any medical treatment. The actual amount administered, and the rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage, timing, etc., is within the responsibility of general practitioners or spealists, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in [0082] Remington's Parmaceutical Sciences.
  • Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically. Typically the active agents of the present invention exhibit their effect at a dosage range from about 0.001 mg/kg to about 250 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg of the active ingredient, more preferably from a bout 0.05 mg/kg to about 75 mg/kg. A suitable dose can be administered in multiple sub-doses per day. Typically, a dose or sub-dose may contain from about 0.1 mg to about 500 mg of the active ingredient per unit dosage form. A more preferred dosage will contain from about 0.5 mg to about 100 mg of active ingredient per unit dosage form. Dosages are generally initiated at lower levels and increased until desired effects are achieved. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous dosing over, for example 24 hours or multiple doses per day are contemplated to achieve appropriate systemic levels of compounds. [0083]
  • For the treatment of pain, if the route of administration is directly to the CNS, the dosage contemplated is from about 1 ng to about 100 mg per day, preferably from about 100 ng to about 10 mg per day, more preferably from about 1 μg to about 100 μg per day. If administered peripherally, the dosage contemplated is somewhat higher, from about 100 ng to about 1000 mg per day, preferably from about 10 μg to about 100 mg per day, more preferably from about 100 μg to about 10 mg per day. If the conopeptide is delivered by continuous infusion (e.g., by pump delivery, biodegradable polymer delivery or cell-based delivery), then a lower dosage is contemplated than for bolus delivery. [0084]
  • Advantageously, the compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients. Tablets, coated tablets, capsules, ampoules and suppositories are examples of dosage forms according to the invention. [0085]
  • It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be consistent with the dosage form employed in single or multiple unit doses. The exact individual dosages, as well as daily dosages, are determined according to standard medical principles under the direction of a physician or veterinarian for use humans or animals. [0086]
  • The pharmaceutical compositions will generally contain from about 0.0001 to 99 wt. %, preferably about 0.001 to 50 wt. %, more preferably about 0.01 to 10 wt. % of the active ingredient by weight of the total composition. In addition to the active agent, the pharmaceutical compositions and medicaments can also contain other pharmaceutically active compounds. Examples of other pharmaceutically active compounds include, but are not limited to, analgesic agents, cytokines and therapeutic agents in all of the major areas of clinical medicine. When used with other pharmaceutically active compounds, the conopeptides of the present invention may be delivered in the form of drug cocktails. A cocktail is a mixture of any one of the compounds useful with this invention with another drug or agent. In this embodiment, a common administration vehicle (e.g., pill, tablet, implant, pump, injectable solution, etc.) would contain both the instant composition in combination supplementary potentiating agent. The individual drugs of the cocktail are each administered in therapeutically effective amounts. A therapeutically effective amount will be determined by the parameters described above; but, in any event, is that amount which establishes a level of the drugs in the area of body where the drugs are required for a period of time which is effective in attaining the desired effects. [0087]
  • The practice of the present invention employs, unless otherwise indicated, conventional techniques of chemistry, molecular biology, microbiology, recombinant DNA, genetics, immunology, cell biology, cell culture and transgenic biology, which are within the skill of the art. See, e.g., Maniatis et al., 1982; Sambrook et al., 1989; Ausubel et al., 1992; Glover, 1985; Anand, 1992; Guthrie and Fink, 1991; Harlow and Lane, 1988; Jakoby and Pastan, 1979[0088] ; Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds. 1984); Transcription And Translation (B. D. Hames & S. J. Higgins eds. 1984); Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds., 1986); Riott, Essential Immunology, 6th Edition, Blackwell Scientific Publications, Oxford, 1988; Hogan et al., Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).
    • EXAMPLES
  • The present invention is described by reference to the following Examples, which are offered by way of illustration and are not intended to limit the invention in any manner. Standard techniques well known in the art or the techniques specifically described below were utilized. [0089]
    • Example 1 Isolation of μ-Conopeptides
  • Crude venom was extracted from venom ducts (Cruz et al., 1976), and the components were purified as previously described (Cartier et al., 1996). The crude extract from venom ducts was purified by reverse phase liquid chromatography (RPLC) using a Vydac C[0090] 18 semi-preparative column (10×250 mm). Further purification of bioactive peaks was done on a Vydac C18 analytical column (4.6×220 mm). The effluents were monitored at 220 nm. Peaks were collected, and aliquots were assayed for activity. Throughout purification, HPLC fractions were assayed by means of intracerebral ventricular (i.c.v.) injection into mice (Clark et al., 1981).
  • The amino acid sequence of the purified peptides were determined by standard methods. The purified peptides were reduced and alkylated prior to sequencing by automated Edman degradation on an Applied Biosystems 477A Protein Sequencer with a 120A Analyzer (DNA/Peptide Facility, University of Utah) (Martinez et al., 1995; Shon et al., 1994). [0091]
  • In accordance with this method, the μ-conopeptides described as “isolated” in Table 1 were obtained. These μ-conopeptides, as well as the other μ-conopeptides and the μ-conopeptide precursors set forth in Table 1 are synthesized as described in U.S. Pat. No. 5,670,622. [0092]
    • Example 2 Isolation of DNA Encoding μ-Conopeptides
  • DNA coding for μ-conopeptides was isolated and cloned in accordance with conventional techniques using general procedures well known in the art, such as described in Olivera et al. (1996). Alternatively, cDNA libraries was prepared from Conus venom duct using conventional techniques. DNA from single clones was amplified by conventional techniques using primers which correspond approximately to the M13 universal priming site and the M13 reverse universal priming site. Clones having a size of approximately 300-500 nucleotides were sequenced and screened for similarity in sequence to known μ-conotoxins. The DNA sequences and encoded propeptide sequences are set forth in Table 1. DNA sequences coding for the mature toxin can also be prepared on the basis of the DNA sequences set forth in Tablel. An alignment of the μ-conopeptides of the present invention is set forth in Table 2. [0093]
    TABLE 1
    DNA and Amino Acid Sequences of μ-Conopeptides and Precursors
    Name:     Ar3.1
    Species:  arenatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTCTTGACCATCTG (SEQ ID NO:1)
    TATGCTTCTGTTTCCCCTTACTGCTCTTCCGCTGGATGGGGATCAACCTGCAGACCG
    ACCTGCAGAGCGTATGCAGGACGACTTTATAACTGAGCATCATCCCCTGTTTGATCC
    TGTCAAACGGTGTTGCGAGAGGCCATGCAACATAGGATGCGTACCTTGTTGTTAATG
    ACCAGCTTTGTCATCGCGGCCTCATCAAGCGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVFLTICMLLFPLTALPLDGDQPADRPAERMQDDFITEHHPLFDPVKRCCERPC (SEQ ID NO:2)
    NIGCVPCC
    Toxin Sequence:
    Cys-Cys-Xaa1-Arg-Xaa3-Cys-Asn-Ile-Gly-Cys-Val-Xaa3-Cys-Cys-{circumflex over ( )} (SEQ ID NO:3)
    Name:     Ak3.1
    Species:  atlanticus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCAC (SEQ ID NO:4)
    TTACTGCTCTTCCGCTGGATGAAGATCAACCGGTACACCGACCTGCAGAGCGTATGC
    AGGACATTTCATCTGATCAACATCTCTTCTTTGATCTCATCAAACGGTGCTGCGAGT
    TGCCATGCGGGCCAGGCTTTTGCGTCCCTTGTTGCTGACATCAATAACGTGTTGATG
    ACCAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTALPLDEDQPVHRPAERMQDISSDQHLFFDLIKRCCELPCG (SEQ ID NO:5)
    PGFCVPCC
    Toxin Sequence:
    Cys-Cys-Xaa1-Leu-Xaa3-Cys-Gly-Xaa3-Gly-Phe-Cys-Val-Xaa3-Cys-Cys-{circumflex over ( )} (SEQ ID NO:6)
    Name:     A3.1
    Species:  aurisiacus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:7)
    TTTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATCAATCTGTAGACCGA
    CCTGAAGAGCGTATGCAGGACGACATTTCATCTGAGCAGCATCCCTTGTTTAATCAG
    AAAAGAATGTGTTGCGGCGAAGGCCGGAAATGCCCCAGCTATTTCAGAAACAGTCA
    GATTTGTCATTGTTGTTAAATGACAACGTGTCGATGACCAACTTCGTTATCACGACT
    AATGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQSVDRPEERMQDDISSEQHPLFNQKRMCCGEGR (SEQ ID NO:8)
    KCPSYFRNSQICHCC
    Toxin Sequence:
    Met-Cys-Cys-Gly-Xaa1-Gly-Arg-Lys-Cys-Xaa3-Ser-Xaa5-Phe-Arg-Asn-Ser-Gln-Ile-Cys-His- (SEQ ID NO:9)
    Cys-Cys-{circumflex over ( )}
    Name:     A3.2
    Species:  aurisiacus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTTTGCTTCTGTTTCCCC (SEQ ID NO:10)
    TTACTGCTCTTCCGATCGATGGAGATCAATCTGTAGACCGACCTGCAGAGCGTATGC
    AGGATGACATTTCATCTGAGCAGCATCGCTTGTTCAATCAGAAAAGAAGGTGCTGC
    CGGTGGCCATGCCCCCGACAAATCGACGGTGAATATTGTGGCTGTTGCCTTGGATGA
    TAACCGTGTTGATGACCAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTALPIDGDQSVDRPAERMQDDISSEQHRLFNQKRRCCRW (SEQ ID NO:11)
    PCPRQIDGEYCGCCLG
    Toxin Sequence:
    Cys-Cys-Arg-Xaa4-Xaa3-Cys-Xaa3-Arg-Gln-Ile-Asp-Gly-Xaa1-Xaa5-Cys-Gly-Cys-Cys-Leu-# (SEQ ID NO:12)
    Name:     A3.3
    Species:  aurisiacus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTACTTCTGTTTCCCC (SEQ ID NO:13)
    TTACTGCTTTTCCGATGGATGGAGATCAACCTGCAGACCAACCTGCAGATCGTATGC
    AGGACGACATTTCATCTGAGCAGTATCCCTTGTTTGATAAGAGACAAAAGTGTTGCA
    CTGGGAAGAAGGGGTCATGCTCCGGCAAAGCATGCAAAAATCTCAAATGTTGCTCT
    GGACGATAACGTGTTGATGACCAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTAFPMDGDQPADQPADRMQDDISSEQYPLFDKRQKCCTG (SEQ ID NO:14)
    KKGSCSGKACKNLKCCSGR
    Toxin Sequence:
    Xaa2-Lys-Cys-Cys-Thr-Gly-Lys-Lys-Gly-Ser-Cys-Ser-Gly-Lys-Ala-Cys-Lys-Asn-Leu-Lys-Cys- (SEQ ID NO:15)
    Cys-Ser-#
    Name:     A3.4
    Species:  aurisiacus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGCTGACCATCTGTCTGCTTCTGTTTCCAC (SEQ ID NO:16)
    TTACTGCTGTTCCGCTGGATGGAGATCAACCTCTAGACCGACACGCGGAGCGTATGC
    ATGATGGCATTTCACCTAAACGCCATCCCTGGTTTGATCCCGTCAAACGGTGTTGCA
    AGGTGCAATGCGAGTCTTGCACCCCTTGTTGCTAACGTGTTGATGACCAACTTTCTC
    GAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTAVPLDGDQPLDRHAERMHDGISPKRHPWFDPVKRCCKV (SEQ ID NO:17)
    QCESCTPCC
    Toxin Sequence:
    Cys-Cys-Lys-Val-Gln-Cys-Xaa1-Ser-Cys-Thr-Xaa3-Cys-Cys-{circumflex over ( )} (SEQ ID NO:18)
    Name:     Bn3.1
    Species:  bandanus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTATGCTTCTGTTTCCCC (SEQ ID NO:19)
    TCACTGCTCTTCCGATGGATGGAGATCAACCTGCAGACCGACCTGCAGAGCGTAGT
    CAGGACGTTTCATCTGAACAGCATCCCTTGTTTGATCCCGTCAAACGGTGTTGCAAC
    TGGCCATGCTCCATGGGATGCATCCCTTGTTGCTACTATTAATAACGTGTTGATGAC
    CAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTICMLLFPLTALPMDGDQPADRPAERSQDVSSEQHPLFDPVKRCCNW (SEQ ID NO:20)
    PCSMGCIPCCYY
    Toxin Sequence:
    Cys-Cys-Asn-Xaa4-Xaa3-Cys-Ser-Met-Gly-Cys-Ile-Xaa3-Cys-Cys-Xaa5-Xaa5-{circumflex over ( )} (SEQ ID NO:21)
    Name:     Bt3.1
    Species:  betulinus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCTTCTG (SEQ ID NO:22)
    TCTGCTTCTGTTTCCCCTGACTGCTCTTCCGCTGGATGAAGATCAACCTGCAGACCG
    ACCTGCAGAGCGTATGCAGGACATTTCATCTGAACAGCATCCCTTGTTTGATCCCGT
    CAAACGGTGTTGCGAATTGCCATGCCATGGATGCGTCCCTTGTTGCTGGCCTTAATA
    ACGTGTGGATGACCAACTGTGTTATCACGGCCACGTCAAGTGTCTAATGAATAAGT
    AAAATGATTGCAGT
    Translation:
    MMSKLGVLLTFCLLLFPLTALPLDEDQPADRPAERMQDISSEQHPLFDPVKRCCELPCHG (SEQ ID NO:23)
    CVPCCWP
    Toxin Sequence:
    Cys-Cys-Xaa1-Leu-Xaa3-Cys-His-Gly-Cys-Val-Xaa3-Cys-Cys-Xaa4-Xaa3-{circumflex over ( )} (SEQ ID NO:24)
    Name:     Bt3.2
    Species:  betulinus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCTTCTG (SEQ ID NO:25)
    TCTGCTTCTGTTTCCCCTGACTGCTCTTCCGCTGGATGAAGATCAACCTGCAGACCG
    ACATGCAGAGCGTATGCAGGACATTTCACCTGAACAGCATCCCTCGTTTGATCCCGT
    CAAACGGTGTTGCGGGCTGCCATGCAATGGATGCGTCCCTTGTTGCTGGCCTTCATA
    ACGTGTGGACGACCAACTTTGTTATCACGGCCACGTCAAGTGTCTGATGAATAAGTA
    AAACGATTGCAGT
    Translation:
    MMSKLGVLLTFCLLLFPLTALPLDEDQPADRHAERMQDISPEQHPSFDPVKRCCGLPCN (SEQ ID NO:26)
    GCVPCCWPS
    Toxin Sequence:
    Cys-Cys-Gly-Leu-Xaa3-Cys-Asn-Gly-Cys-Val-Xaa3-Cys-Cys-Xaa4-Xaa3-Ser-{circumflex over ( )} (SEQ ID NO:27)
    -------------------------------
    Name:     Bt3.3
    Species:  betulinus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTTTAAACTGGGAGTCTTGTTGACCATCTA (SEQ ID NO:28)
    TATGCTTCTGTTTCCCTTTACTGCTCTTCCGCTGGATGGAGATCAACCTGCAGACCAA
    CCTCTAGAGCGCATGCAGTATGACATGTTACGTGCAGTGAATCCCTGGTTTGATCCC
    GTCAAAAGGTGCTGCTCGAGGAACTGCGCAGTATGCATCCCTTGTTGCCCGAATTGG
    CCAGCTTGATTATCGCGGCCAAGAGTCTAATGAATAAGTAAAACGATTGCAGT
    Translation:
    MMFKLGVLLTIYMLLFPFTALPLDGDQPADQPLERMQYDMLRAVNPWFDPVKRCCSR (SEQ ID NO:29)
    NCAVCIPCCPNWPA
    Toxin Sequence:
    Cys-Cys-Ser-Arg-Asn-Cys-Ala-Val-Cys-Ile-Xaa3-Cys-Cys-Xaa3-Asn-Xaa4-Xaa3-Ala-{circumflex over ( )} (SEQ ID NO:30)
    Name:     Bu3.1
    Species:  bullatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:31)
    TCTGCTTCTGTTTCCCCTTTTTGCTCTTCCGCAGGATGGAGATCAACCTGCAGACCGA
    CCTGCAGAGCGTATGCAGGACGACATTTCATCTGAGCAGAATTCCTTGCTTGAGAA
    GAGAGTTACTGACAGGTGCTGCAAAGGGAAGAGGGAATGCGGCAGATGGTGCAGA
    GATCACTCGCGTTGTTGCGGTCGACGATAAGCTGTTGATGACCAGCTTTGTTATCAC
    GGCTACATCAAGTGTCTAGTGAATAAGTAAAATGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLFALPQDGDQPADRPAERMQDDISSEQNSLLEKRVTDRCCKG (SEQ ID NO:32)
    KRECGRWCRDHSRCCGRR
    Toxin Sequence:
    Val-Thr-Asp-Arg-Cys-Cys-Lys-Gly-Lys-Arg-Xaa1-Cys-Gly-Arg-Xaa4-Cys-Arg-Asp-His-Ser- (SEQ ID NO:33)
    Arg-Cys-Cys-#
    Name:     Bu3.1A
    Species:  bullatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:34)
    TCTGCTTCTGTTTCCCCTTTTTGCTCTTCGGCAGGATGGAGATCAACCTGCAGACCGA
    CCTGCAGAGCGTATGCAGGATGACATTTCATCTGAGCAGAATCCCTTGCTTGAGAA
    GAGAGTTGGTGACAGGTGCTGCAAAGGGAAGAGGGGGTGCGGCAGATGGTGCAGA
    GATCACTCACGTTGTTGCGGTCGACGATAACGTGTTGATGACCAGCTTTGTTATCAC
    GGCTACATCAAGTGTCTTAGTGATTAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLFALRQDGDQPADRPAERMQDDISSEQNPLLEKRVGDRCCKG (SEQ ID NO:35)
    KRGCGRWCRDHSRCCGRR
    Toxin Sequence:
    Val-Gly-Asp-Arg-Cys-Cys-Lys-Gly-Lys-Arg-Gly-Cys-Gly-Arg-Xaa4-Cys-Arg-Asp-His-Ser- (SEQ ID NO:36)
    Arg-Cys-Cys-#
    Name:     Bu3.2
    Species:  bullatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:37)
    TCTGCTTCTGTTTCCCCTTTTTGCTCTTCCGCAGGATGGAGATCAACCTGCAGACCGA
    CCTGCAGAGCGTATGCAGGACGACATTTCATCTGAGCAGAATCCCTTGCTTGAGAA
    GAGAGTTGGTGAAAGGTGCTGCAAAAACGGGAAGAGGGGGTGCGGCAGATGGTGC
    AGAGATCACTCACGTTGTTGCGGTCGACGATAACGTGTTGATGACCGAGGCTTTCGT
    TATCACGGCTACATCAAGTGTCTAGTGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLFALPQDGDQPADRPAERMQDDISSEQNPLLEKRVGERCCKN (SEQ ID NO:38)
    GKRGCGRWCRDHSRCCGRR
    Toxin Sequence:
    Val-Gly-Xaa1-Arg-Cys-Cys-Lys-Asn-Gly-Lys-Arg-Gly-Cys-Gly-Arg-Xaa4-Cys-Arg-Asp-His- (SEQ ID NO:39)
    Ser-Arg-Cys-Cys-#
    Name:     Bu3.3
    Species:  bullatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:40)
    TCTGCTTCTGTTTCCCCTTTTTGCTCTTCCGCAGGACGGAGATCAACCTGCAGACCG
    ACCTGCAGAGCGTATGCAGGACGACCTTTCATCTGAGCAGCATCCCTTGTTTGAGAA
    GAGAATTGTTGACAGGTGCTGCAACAAAGGGAACGGGAAGAGGGGGTGCAGCAGA
    TGGTGCAGAGATCACTCACGTTGTTGCGGTCGACGATGAACTGTTGATGACCGAGG
    CTTTGGTTATCACGGCTACATCAAGTGTCTAGTGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLFALPQDGDQPADRPAERMQDDLSSEQHPLFEKRIVDRCCNK (SEQ ID NO:41)
    GNGKRGCSRWCRDHSRCCGRR
    Toxin Sequence:
    Ile-Val-Asp-Arg-Cys-Cys-Asn-Lys-Gly-Asn-Gly-Lys-Arg-Gly-Cys-Ser-Arg-Xaa4-Cys-Arg- (SEQ ID NO:42)
    Asp-His-Ser-Arg-Cys-Cys-#
    Name:     Bu3.4
    Species:  bullatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:43)
    TCTGCTTCTGTTTCCCCTTTTTGCTCTTCCGCAGGATGGAGATCAACCTGCAGACCGA
    CCTGCTGAGCGTATGCAGGACGACATTTCATCTGAGCGGAATCCCTTGTTTGAGAAG
    AGCGTTGGTTTATATTGCTGCCGACCCAAACCCAACGGGCAGATGATGTGCGACAG
    ATGGTGCGAAAAAAACTCACGTTGTTGCGGTCGACGATAATGTGTTGATGACCAGC
    TTTGTTATCAAGGCTACATCAAGTATCTAGTGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLFALPQDGDQPADRPAERMQDDISSERNPLFEKSVGLYCCRPK (SEQ ID NO:44)
    PNGQMMCDRWCEKNSRCCGRR
    Toxin Sequence:
    Val-Gly-Leu-Xaa5-Cys-Cys-Arg-Xaa3-Lys-Xaa3-Asn-Gly-Gln-Met-Met-Cys-Asp-Arg-Xaa4- (SEQ ID NO:45)
    Cys-Xaa1-Lys-Asn-Ser-Arg-Cys-Cys-#
    -------------------------------
    Name:     Bu3.5
    Species:  bullatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTTTTGTTGACCATCTG (SEQ ID NO:46)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATCAATCTGTAGACCGA
    CCTGCAGAACGTATGCAGGACGACCTTTCATCTGAGCAGCATCCCTTGTTTGTTCAG
    AAAAGAAGGTGTTGCGGCGAAGGCTTGACATGCCCCAGATATTGGAAAAACAGTCA
    GATTTGTGCTTGTTGTTAAATGACAACGTGTCGATGACCAACTTCGGTATCACGACT
    ACGCCAAGTGTCTAATGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQSVDRPAERMQDDLSSEQHPLFVQKRRCCGEGL (SEQ ID NO:47)
    TCPRYWKNSQICACC
    Toxin Sequence:
    Arg-Cys-Cys-Gly-Xaa1-Gly-Leu-Thr-Cys-Xaa3-Arg-Xaa5-Xaa4-Lys-Asn-Ser-Gln-Ile-Cys-Ala- (SEQ ID NO:48)
    Cys-Cys-{circumflex over ( )}
    Name:     Bu3.5A
    Species:  bullatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:49)
    TCTGCTTCTGTTTCCCCTTTTTGCTCTTCCGCAGGATGGAGATCAACCTGCAGACCGA
    CCTGCTGAGCGTATGCAGGACGACATTTCATCTGAGCAGGATCCCTTGTTTGTTCAG
    AAAAGAAGGTGTTGCGGCGAAGGCTTGACATGCCCCAGATATTGGAAAAACAGTCA
    GATTTGTGCTTGTTGTTAAATGACAACGTGTGATGACCAACTTCGGTATCACGACTA
    CGCCAAGTGTCTAATGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLFALPQDGDQPADRPAERMQDDISSEQDPLFVQKRRCCGEGL (SEQ ID NO:50)
    TCPRYWKNSQICACC
    Toxin Sequence:
    Arg-Cys-Cys-Gly-Xaa1-Gly-Leu-Thr-Cys-Xaa3-Arg-Xaa5-Xaa4-Lys-Asn-Ser-Gln- (SEQ ID NO:51)
    Ile-Cys-Ala-Cys-Cys-{circumflex over ( )}
    Name:     Cp3.1
    Species:  capitaneus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGGTGACCATCTGCCTGCTTCTGTTTCCC (SEQ ID NO:52)
    CTTGCTGCTTTTCCACTGGATGGAAATCAACCTGCAGACCACCCTGCAAAGCGTACG
    CAAGATGACAGTTCAGCTGCCCTGATCAATACCTGGATTGATCATTCCCATTCTTGC
    TGCAGGGACTGCGGTGAAGATTGTGTTGGTTGTTGCCGGTAACGTGTTGATGACCAA
    CTTTCTCGAG
    Translation:
    GSMMSKLGVLVTICLLLFPLAAFPLDGNQPADHPAKRTQDDSSAALINTWIDHSHSCCR (SEQ ID NO:53)
    DCGEDCVGCCR
    Toxin Sequence:
    Ser-Cys-Cys-Arg-Asp-Cys-Gly-Xaa1-Asp-Cys-Val-Gly-Cys-Cys-Arg-{circumflex over ( )} (SEQ ID NO:54)
    Name:     Ca3.1
    Species:  caracteristicus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:55)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCAATGGATGGAGATCAACCTGCAGACCA
    ACCTGCAGATCGTATGCAGGACGACATTTCATCTGAGCAGTATCCCTTGTTTGATAT
    GAGAAAAAGGTGTTGCGGCCCCGGCGGTTCATGCCCCGTATATTTCAGAGACAATT
    TTATTTGTGGTTGTTGTTAAATGACAACGTGTCGATGACCAACTTCATTATCACGAC
    TACGCCAAGTGTCTAATGAATAAGTAAAATGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQPADQPADRMQDDISSEQYPLFDMRKRCCGPG (SEQ ID NO:56)
    GSCPVYFRDNFICGCC
    Toxin Sequence:
    Cys-Cys-Gly-Xaa3-Gly-Gly-Ser-Cys-Xaa3-Val-Xaa5-Phe-Arg-Asp-Asn-Phe-Ile-Cys-Gly-Cys- (SEQ ID NO:57)
    Cys-{circumflex over ( )}
    Name:     Ca3.2
    Species:  caracteristicus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:58)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATGAACCTGCAAACCG
    ACCTGTCGAGCGTATGCAGGACAACATTTCATCTGAGCAGTATCCCTTGTTTGAGAA
    GAGACGAGATTGTTGCACTCCGCCGAAGAAATGCAAAGACCGACAATGCAAACCCC
    AGAGATGTTGCGCTGGACGATAACGTGTTGATGACCAACTTTATCACGGCTACGTCA
    AGTGTTTAGTGAATAAGTAAAATGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDEPANRPVERMQDNISSEQYPLFEKRRDCCTPPK (SEQ ID NO:59)
    KCKDRQCKPQRCCAGR
    Toxin Sequence:
    Arg-Asp-Cys-Cys-Thr-Xaa3-Xaa3-Lys-Lys-Cys-Lys-Asp-Arg-Gln-Cys-Lys-Xaa3-Gln-Arg-Cys- (SEQ ID NO:60)
    Cys-Ala-#
    Name:     Ca3.3
    Species:  caracteristicus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:61)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCACTGGATGGAGATCAACCTGCAGATCAA
    TCTGCAGAGCGACCTGCAGAGCGTACGCAGGACGACATTCAGCAGCATCCGTTATA
    TGATCCGAAAAGAAGGTGTTGCCGTTATCCATGCCCCGACAGCTGCCACGGATCTTG
    CTGCTATAAGTGATAACATGTTGATGGCCAGCTTTGTTATCACGGCCACGTCAAGTG
    TCTTAATGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPLDGDQPADQSAERPAERTQDDIQQHPLYDPKRRCCRY (SEQ ID NO:62)
    PCPDSCHGSCCYK
    Toxin Sequence:
    Arg-Cys-Cys-Arg-Xaa5-Xaa3-Cys-Xaa3-Asp-Ser-Cys-His-Gly-Ser-Cys-Cys-Xaa5-Lys-{circumflex over ( )} (SEQ ID NO:63)
    Name:     Ca3.4
    Species:  caracteristicus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGCCTTGTTGACCATCT (SEQ ID NO:64)
    GTCTACTTCTGTTTTCCCTTACTGCTGTTCCGCTGGATGGAGATCAACATGCAGACC
    AACCTGCACAGCGTCTGCAGGACCGCATTCCAACTGAAGATCATCCCTTATTTGATC
    CCAACAAACGGTGTTGCCCGCCGGTGGCATGCAACATGGGATGCAAGCCTTGTTGT
    GGATGACCAGCTTTGTTATCGCGGTCTTCATGAAGTGTCTTAATGAATAAGTAAAAT
    GATTGCAGT
    Translation:
    MMSKLGALLTICLLLFSLTAVPLDGDQHADQPAQRLQDRIPTEDHPLFDPNKRCCPVA (SEQ ID NO:65)
    CNMGCKPCCG
    Toxin Sequence:
    Cys-Cys-Xaa3-Xaa3-Val-Ala-Cys-Asn-Met-Gly-Cys-Lys-Xaa3-Cys-Cys-# (SEQ ID NO:66)
    Name:     Ca3.5
    Species:  caracteristicus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGCCTTGTTGACCATCT (SEQ ID NO:67)
    GTCTACTTCTGTTTTCCCTAACTGCTGTTCCGCTGGATGGAGATCAACATGCAGACC
    AACCTGCAGAGCGTCTGCATGACCGCCTTCCAACTGAAAATCATCCCTTATATGATC
    CCGTCAAACGGTGTTGCGATGATTCGGAATGCGACTATTCTTGCTGGCCTTGCTGTA
    TGTTTGGATAACCTTTGTTATCGCGGCCTCATCAAGTGTCTAATGAATAAGTAAAAC
    GATTGCAGT
    Translation:
    MMSKLGALLTICLLLFSLTAVPLDGDQHADQPAERLHDRLPTENHPLYDPVKRCCDDSE (SEQ ID NO:68)
    CDYSCWPCCMFG
    Toxin Sequence:
    Cys-Cys-Asp-Asp-Ser-Xaa1-Cys-Asp-Xaa5-Ser-Cys-Xaa4-Xaa3-Cys-Cys-Met-Phe-# (SEQ ID NO:69)
    Name:     Ca3.6
    Species:  caracteristicus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:70)
    TTACTGCTGTTCCGCTGGATGGAGATCAACCTGCAGACCGACCTGCAGAGCGTAAG
    CAGGACGTTTCATCTGAACAGCATCCCTTCTTTGATCCCGTCAAACGGTGTTGCCGC
    CGGTGTTACATGGGATGCATCCCTTGTTGCTTTTAACGTGTTGATGACCAACTTTCTC
    GAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTAVPLDGDQPADRPAERKQDVSSEQHPFFDPVKRCCRRC (SEQ ID NO:71)
    YMGCIPCCF
    Toxin Sequence:
    Cys-Cys-Arg-Arg-Cys-Xaa5-Met-Gly-Cys-Ile-Xaa3-Cys-Cys-Phe-{circumflex over ( )} (SEQ ID NO:72)
    Name:     Cr3.1
    Species:  circumcisus
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGGGTATTGTTGACCATCT (SEQ ID NO:73)
    GTCTGCTTCTGTTTCCCCTTACTGCTCTTCCAATGGATGGAGATCAACCTGCAGACC
    AACCTGCAGATCGTATGCAGGACGACATTTCATCTGAGCAGTATCCCTTGTTTGATA
    AGAGACGAAAGTGTTGCGGCAAAGACGGGCCATGCCCCAAATATTTCAAAGACAAT
    TTTATTTGTGGTTGTTGTTAAATGACAACGTGTCGATGACCAACTTCGTTATCACGAT
    TCGCCAAGTGTCTTAATGAATAAGTAAAATGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQPADQPADRMQDDISSEQYPLFDKRRKCCGKD (SEQ ID NO:74)
    GPCPKYFKDNFICGCC
    Toxin Sequence:
    Arg-Lys-Cys-Cys-Gly-Lys-Asp-Gly-Xaa3-Cys-Xaa3-Lys-Xaa5-Phe-Lys-Asp-Asn-Phe-Ile-Cys- (SEQ ID NO:75)
    Gly-Cys-Cys-{circumflex over ( )}
    Name:     Da3.1
    Species:  dalli
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGCCTTGTTGACCATCT (SEQ ID NO:76)
    GTCTACTTCTGTTTTCCCTAACTGCTGTTCCGCTGGATGGAGATCAACATGCAGACC
    AACCTGCAGAGCGTCTGCAGGACCGCCTTCCAACTGAAAATCATCCCTTATATGATC
    CCGTCAAACGGTGTTGCGATGATTCGGAATGCGACTATTCTTGCTGGCCTTGCTGTA
    TTTTATCATAACCTTTGTTATCGCGGCCTCATCAAGTGTCAAATGAATAAGTAAAAT
    GATTGCAGT
    Translation:
    MMSKLGALLTICLLLFSLTAVPLDGDQHADQPAERLQDRLPTENHPLYDPVKRCCDDSE (SEQ ID NO:77)
    CDYSCWPCCIILS
    Toxin Sequence:
    Cys-Cys-Asp-Asp-Ser-Xaa1-Cys-Asp-Xaa5-Ser-Cys-Xaa4-Xaa3-Cys-Cys-Ile-Leu-Ser-{circumflex over ( )} (SEQ ID NO:78)
    Name:     Da3.2
    Species:  dalli
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATTTG (SEQ ID NO:79)
    TCTACTTCTGTTTCCCCTTACTGCTGTTCCACTGGATGGAGATCAGCCTGCAGACCG
    ACCTGCAGAGCGTATGCAGGACGGCATTTCATCTGAACATCATCCATTTTTTGATTC
    CGTCAAAAAGAAACAACAGTGTTGCCCGCCGGTGGCATGCAACATGGGATGCGAGC
    CTTGTTGTGGATGACCAGCTTTGTTATCGCGGCTCATGAAGTGTCCTAATGAATAAG
    TAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTAVPLDGDQPADRPAERMQDGISSEHHPFFDSVKKKQQCCP (SEQ ID NO:80)
    PVACNMGCEPCCG
    Toxin Sequence:
    Xaa2-Gln-Cys-Cys-Xaa3-Xaa3-Val-Ala-Cys-Asn-Met-Gly-Cys-Xaa1-Xaa3-Cys-Cys-# (SEQ ID NO:81)
    Name:     Da3.3
    Species:  dalli
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGATCATATG (SEQ ID NO:82)
    TCTATTTCTGTTTCCCCTTACTGCTGTTCAGCTCAATGGAGATCAGCCTGCAGACCAA
    TCTGCAGAGCGTATGCAGGACAAAATTTCATCTGAACATCATCCCTTTTTTGATCCC
    GTCAAACGTTGTTGCAACGCGGGGTTTTGCCGCTTCGGATGCACGCCTTGTTGTTGG
    TGACCAGCTTTGTTATCGCGGCCTCATCAAGTGTCTAATGAATAAGTAAAATGATTG
    CAGT
    Translation:
    MMSKLGVLLIICLFLFPLTAVQLNGDQPADQSAERMQDKISSEHHPFFDPVKRCCNAGFC (SEQ ID NO:83)
    RFGCTPCCW
    Toxin Sequence:
    Cys-Cys-Asn-Ala-Gly-Phe-Cys-Arg-Phe-Gly-Cys-Thr-Xaa3-Cys-Cys-Xaa4-{circumflex over ( )} (SEQ ID NO:84)
    Name:     Di3.1
    Species:  distans
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGCTGACCATCTT (SEQ ID NO:85)
    TCTGCTTCTGTTTCCCCTTACTGCTGTTCCGCTGGATGGAGATCAACCCGCAGACGG
    ACTTGCAGAGCGCATGCAGGACGACAGTTCAGCTGCACTGATTAGAGACTGGCTTC
    TTCAAACCCGACAGTGTTGTGTGCATCCATGCCCATGCACGCCTTGCTGTAGATGAC
    CAGCTTTGTCATCGCGGCTACGTCAAGTATCTAATGAATAAGTAAGTAAAACGATTG
    CAGT
    Translation:
    MMSKLGVLLTIFLLLFPLTAVPLDGDQPADGLAERMQDDSSAALIRDWLLQTRQCCVHP (SEQ ID NO:86)
    CPCTPCCR
    Toxin Sequence:
    Xaa2-Cys-Cys-Val-His-Xaa3-Cys-Xaa3-Cys-Thr-Xaa3-Cys-Cys-Arg-{circumflex over ( )} (SEQ ID NO:87)
    Name:     E3.1
    Species:  ermineus
    Cloned:   Yes
    DNA Sequence:
    ACCTCAAGAGGGATCGATCGCAGTTCATGATGTCTAAACTGGGAGCCTTGTTGACC (SEQ ID NO:88)
    ATCTGTCTGCTTCTGTTTCCCATTACTGCTCTTCTGATGGATGGAGATCAGCCTGCAG
    ACCGACCTGCAGAGCGTACGGAGGATGACATTTCATCTGACTACATTCCCTGTTGCA
    GTTGGCCATGCCCCCGATACTCCAACGGTAAACTTGTTTGTTTTTGTTGCCTTGGATG
    ATAATGTGTTGATGACCAACTTTGTTATCACGGCTACGTCAAGTGTCTACTGAATAA
    GTAAAATGATTGCAGTA
    Translation:
    MMSKLGALLTICLLLFPITALLMDGDQPADRPAERTEDDISSDYIPCCSWPCPRYSNGKL (SEQ ID NO:89)
    VCFCCLG
    Toxin Sequence:
    Cys-Cys-Ser-Xaa4-Xaa3-Cys-Xaa3-Arg-Xaa5-Ser-Asn-Gly-Lys-Leu-Val-Cys-Phe-Cys-Cys- (SEQ ID NO:90)
    Leu-#
    Name:     Ge3.2
    Species:  generalis
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGGTTCTGTTTCCCC (SEQ ID NO:91)
    TTACTGCTCTTCCACTGGATGGAGAACAACCTGTAGACCGACATGCCGAGCATATGC
    AGGATGACAATTCAGCTGCACAGAACCCCTGGGTTATTGCCATCAGACAGTGTTGC
    ACGTTCTGCAACTTTGGATGCCAACCTTGTTGCCTCACCTGATAACGTGTTGATGAC
    CAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTICLVLFPLTALPLDGEQPVDRHAEHMQDDNSAAQNPWVIAIRQCCTF (SEQ ID NO:92)
    CNFGCQPCCLT
    Toxin Sequence:
    Xaa2-Cys-Cys-Thr-Phe-Cys-Asn-Phe-Gly-Cys-Gln-Xaa3-Cys-Cys-Leu-Thr-{circumflex over ( )} (SEQ ID NO:93)
    Name:     Ge3.3
    Species:  generalis
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGGTTCTGTTTCCCC (SEQ ID NO:94)
    TTACTGCTCTTCCACTGGATGGAGAACAACCTGTAGACCGACATGCCGAGCATATGC
    AGGATGACAATTCAGCTGCACAGAACCCCTGGGTTATTGCCATCAGACAGTGTTGC
    ACGTTCTGCAACTTTGGATGCCAGCCTTGTTGCGTCCCCTGATAACGTGTTGATGAC
    CAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTICLVLFPLTALPLDGEQPVDRHAEHMQDDNSAAQNPWVIAIRQCCTF (SEQ ID NO:95)
    CNFGCQPCCVP
    Toxin Sequence:
    Xaa2-Cys-Cys-Thr-Phe-Cys-Asn-Phe-Gly-Cys-Gln-Xaa3-Cys-Cys-Val-Xaa3-{circumflex over ( )} (SEQ ID NO:96)
    Name:     μ-GIIIA
    Species:  geographus
    Cloned:   Yes
    DNA Sequence:
    GTCGACTCTAGAGGATCCGACAACAAAGAGTCAACCCCACTGCCACGTCAAGAGCG (SEQ ID NO:97)
    AAGCGCCACAGCTAAGACAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGG
    AGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGA
    GATGAACCTGCAAACCGACCTGTCGAGCGTATGCAGGACAACATTTCATCTGAGCA
    GTATCCCTTGTTTGAGAAGAGACGAGATTGTTGCACTCCGCCGAAGAAATGCAAAG
    ACCGACAATGCAAACCCCAGAGATGTTGCGCTGGACGATAACGTGTTGATGACCAA
    CTTTATCACGGCTACGTCAAGTGTTTAGTGAATAAGTAAAATGATTGCAGTCTTGCT
    CAGATTTGCTTTTGTGTTTTGGTCTAAAGATCAATGACCAAACCGTTGTTTTGATGCG
    GATTGTCATATATTTCTCGATTCCAATCCAACACTAGATGATTTAATCACGATAGAT
    TAATTTTCTATCAATGCCTTGATTTTTCGTCTGTCATATCAGTTTTGTTTATATTTATT
    TTTTCGTCACTGTCTACACAAACGCATGCATGCACGCATGCACGCACACACGCACGC
    ACGCTCGCACAAACATGCGCGCGCACGCACACACACACACACACACACAAACACA
    CACACAAGCAATCACACAATTATTGACATTATTTATTTATTCATTGATGTATTTGTTA
    TTCGTTTGCTTGTTTTTAGAATAGTTTGAGGCCGTCTTTTTGGATTTATTTGAACTGC
    TTTATTGTATACGAGTACTTCGTGCTTTGAAACACTGCTGAAAATAAAACAAACACT
    GACGTAGC
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDEPANRPVERMQDNISSEQYPLFEKRRDCCTPPK (SEQ ID NO:98)
    KCKDRQCKPQRCCAGR
    Toxin Sequence:
    Arg-Asp-Cys-Cys-Thr-Xaa3-Xaa3-Lys-Lys-Cys-Lys-Asp-Arg-Gln-Cys-Lys-Xaa3-Gln-Arg-Cys- (SEQ ID NO:99)
    Cys-Ala-#
    Name:     μ-GIIIB
    Species:  geographus
    Isolated: Yes
    Cloned:   Yes
    DNA Sequence:
    GGCCAGACGACAACAAAGAGTCAACCCCACTGCCACGTCAAGAGCGAAGCGCCAC (SEQ ID NO:100)
    AGCTAAGACAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTT
    GACCATCTGTCTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATGAACCT
    GCAAACCGACCTGTCGAGCGTATGCAGGACAACATTTCATCTGAGCAGTATCCCTTG
    TTTGAGAAGAGACGAGATTGTTGCACTCCGCCGAGGAAATGCAAAGACCGACGATG
    CAAACCCATGAAATGTTGCGCTGGACGATAACGTGTTGATGACCAACTTTATCACG
    GCTAGCTCAGTGTTTAGTGAATAAGTAAAATGATTGCAGTCTTGCTCAGATTGCTTT
    TGTGTTTTGGTCTAAGATCAATGACCAAACCGTTGTTTTGATGCGGATTGTCATATA
    TTTCTCGATTCCAATCCAACACTAGATGATTTAATCACGATAGATTAATTTTCTATCA
    ATGCCTTGATTTTTCGTCTGTCATATCAGTTTTGTTTATATTTATTTTTTCGTCACTGT
    CTACACAAACGCATGCATGCACGCATGCACGCACACACGCACGCACGCTCGCACAA
    ACATGCGCGCGCACGCACACACACACACACACACAAACACACACACGAAGCAATC
    ACACAATTAGTTGACATTATTTATTTATTCATTGATGTATTTGTTATTCGTTTGCTTGT
    TTTTAGAATAGTTTGAGGCCGTCTTTTTGGATTTATTTGAACTGCTTTATTGTATACG
    AGTACTTCGTGCTTTGAAACACTGCTGAAAATAAAACAAACACTGACGTAGCAAAA
    AAAAAAA
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDEPANRPVERMQDNISSEQYPLFEKRRDCCTPPRK (SEQ ID NO:101)
    CKDRRCKPMKCCAGR
    Toxin Sequence:
    Arg-Asp-Cys-Cys-Thr-Xaa3-Xaa3-Arg-Lys-Cys-Lys-Asp-Arg-Arg-Cys-Lys-Xaa3-Met-Lys-Cys- (SEQ ID NO:102)
    Cys-Ala-#
    Name:     μ-GIIIC
    Species:  geographus
    Isolated: Yes
    Toxin Sequence:
    Arg-Asp-Cys-Cys-Thr-Xaa3-Xaa3-Lys-Lys-Cys-Lys-Asp-Arg-Arg-Cys-Lys-Xaa3-Leu-Lys-Cys- (SEQ ID NO:103)
    Cys-Ala-#
    Name:     Gm3.1
    Species:  gloriamaris
    Cloned:   Yes
    DNA Sequence:
    CTCACTATAGGAATTCGAGCTCGGTACACGGGATCGATAGCAGTTCATGATGTCTAA (SEQ ID NO:104)
    ACTGGGAGCCTTGTTGACCATCTGTCTACTTCTGTTTTCCCTAACTGCTGTTCCGCTG
    GATGGAGATCAACATGCAGACCAACCTGCAGAGCGTCTGCATGACCGCCTTCCAAC
    TGAAAATCATCCCTTATATGATCCCGTCAAACGGTGTTGCGATGATTCGGAATGCGA
    CTATTCTTGCTGGCCTTGCTGTATGTTTGGATAACCTTTGTTATCGCGGCCTCGATAA
    GTGTCTAATGAATAAGTAAAACGATTGCAGTAGGC
    Translation:
    MMSKLGALLTICLLLFSLTAVPLDGDQHADQPAERLHDRLPTENHPLYDPVKRCCDDSE (SEQ ID NO:105)
    CDYSCWPCCMFG
    Toxin Sequence:
    Cys-Cys-Asp-Asp-Ser-Xaa1-Cys-Asp-Xaa5-Ser-Cys-Xaa4-Xaa3-Cys-Cys-Met-Phe-# (SEQ ID NO:106)
    Name:     Gm3.2
    Species:  gloriamaris
    Cloned:   Yes
    DNA Sequence:
    GTTCATGATGTCTAAACTGGGAGTCTTGTTGATCATCTGTCTACTTCTGTTTCCCCTT (SEQ ID NO:107)
    ACTGCTGTTCCGCTGGATGGAGATCAACCTGCAGACCGATATGCAGAGCGTATGCA
    GGACGACATTTCATCTGAACATCATCCCATGTTTGATGCCGTCAGAGGGTGTTGCCA
    TCTGTTGGCATGCCGCTTCGGATGCTCGCCTTGTTGTTGGTGATCAGCTTTGTTATCG
    CGGCCTCATCAAGTGACTCTAATGCAAA
    Translation:
    MMSKLGVLLIICLLLFPLTAVPLDGDQPADRYAERMQDDISSEHHPMFDAVRGCCHLLA (SEQ ID NO:108)
    CRFGCSPCCW
    Toxin Sequence:
    Gly-Cys-Cys-His-Leu-Leu-Ala-Cys-Arg-Phe-Gly-Cys-Ser-Xaa3-Cys-Cys-Xaa4-{circumflex over ( )} (SEQ ID NO:109)
    Name:     Gm3.3
    Species:  gloriamaris
    Cloned:   Yes
    DNA Sequence:
    GAGACGACAAGGAACAGTCAACCCCACAGCCACGCCAAGAGCAGACAGCCACAGC (SEQ ID NO:110)
    TACGTGAAGAAGGGTGGAGAGAGGTTCGTGATGTTGAAAATGGGAGTGGTGCTATT
    CATCTTCCTGGTACTGTTTCCCCTGGCAACGCTCCAGCTGGATGCAGATCAACCTGT
    AGAACGATATGCGGAGAACAAACAGCTCCTCAACCCAGATGAAAGGAGGGAAATC
    ATATTGCATGCTCTGGGGACGCGATGCTGTTCTTGGGATGTGTGCGACCACCCGAGT
    TGTACTTGCTGCGGCGGTTAGCGCCGAACATCCATGGCGCTGTGCTGGGCGGTTTTA
    TCCAACAACGACAGCGTTTGTTGATTTCATGTATCATTGCGCCCACGTCTCTTGTCTA
    AGAATGACGAACATGATTGCACTCTGGTTCAGATTTCGTGTTCTTTTCTGACAATAA
    ATGACAAAACTCCAAAAAA
    Translation:
    MLKMGVVLFIFLVLFPLATLQLDADQPVERYAENKQLLNPDERREIILHALGTRCCSWD (SEQ ID NO:111)
    VCDHPSCTCCGG
    Toxin Sequence:
    Cys-Cys-Ser-Xaa4-Asp-Val-Cys-Asp-His-Xaa3-Ser-Cys-Thr-Cys-Cys-Gly-# (SEQ ID NO:112)
    Name:     La3.1
    Species:  laterculatus
    Cloned:   Yes
    DNA Sequence:
    CGACCTCAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGA (SEQ ID NO:113)
    CCATCTGTCTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATCAACCTGC
    AGACCGACCTGCAGAGCGTATGCAGGACGTTTCATCTGAACAGCATCCCTTGTATG
    ATCCCGTCAAACGGTGTTGCGACTGGCCATGCAGCGGATGCATCCCTTGTTGCTAAT
    AGTAACAACGTGTTGATAACCAACTTTCTTACCACGACTACGTCAAGTGTCTAATGA
    ATAAGTAAAATGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQPADRPAERMQDVSSEQHPLYDPVKRCCDWPC (SEQ ID NO:114)
    SGCIPCC
    Toxin Sequence:
    Cys-Cys-Asp-Xaa4-Xaa3-Cys-Ser-Gly-Cys-Ile-Xaa3-Cys-Cys-{circumflex over ( )} (SEQ ID NO:115)
    Name:     La3.2
    Species:  laterculatus
    Cloned:   Yes
    DNA Sequence:
    CGACCTCAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGA (SEQ ID NO:116)
    CCATCTGTCTGCTTCTGTTTCCCCTTACTGCTCTGGATGGAGATCAACCTGCAGACC
    GACTTGCAGAGCGTATGCAGGACGACATTTCATCTGAGCAGCATCCCTTTGAAAAG
    AGACGAGACTGTTGCACACCTCCGAAGAAATGCAGAGACCGACAATGCAAACCTGC
    ACGTTGTTGCGGAGGATAACGTGTTGATGACCAACTTTGTTATCACGGCTACGTCAA
    GTGTCTAGTGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALDGDQPADRLAERMQDDISSEQHPFEKRRDCCTPPKKCR (SEQ ID NO:117)
    DRQCKPARCCGG
    Toxin Sequence:
    Arg-Asp-Cys-Cys-Thr-Xaa3-Xaa3-Lys-Lys-Cys-Arg-Asp-Arg-Gln-Cys-Lys-Xaa3-Ala-Arg-Cys- (SEQ ID NO:118)
    Cys-Gly-#
    Name:     La3.3
    Species:  laterculatus
    Cloned:   Yes
    DNA Sequence:
    GGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGC (SEQ ID NO:119)
    TTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATCAACTTGCACGCCGATCTGC
    AGAGCGTATGCAGGACAACATTTCATCTGAGCAGCATCACCTCTTTGAAAAGAGAC
    GACCACCATGTTGCACCTATGACGGGAGTTGCCTAAAAGAATCATGCATGCGTAAA
    GCTTGTTGCGGATGATAACGTGTTGATGACCAACTTTGTTATCACGGCTACTCAAGT
    GTCTAATGAATAAGTAAAATGATTGCAGTA
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQLARRSAERMQDNISSEQHHLFEKRRPPCCTYD (SEQ ID NO:120)
    GSCLKESCMRKACCG
    Toxin Sequence:
    Arg-Xaa3-Xaa3-Cys-Cys-Thr-Xaa5-Asp-Gly-Ser-Cys-Leu-Lys-Xaa1-Ser-Cys-Met-Arg-Lys- (SEQ ID NO:121)
    Ala-Cys-Cys-#
    Name:     La3.3A
    Species:  laterculatus
    Cloned:   Yes
    DNA Sequence:
    GGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCACCTGTCTGC (SEQ ID NO:122)
    TTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATCAACTTGCACGCCGACCTG
    CAGAGCGTATGCAGGACAACATTTCATCTGAGCAGCATCCCTTCTTTGAAAGGAGA
    CGACCACCATGTTGCACCTATGACGGGAGTTGCCTAAAAGAATCATGCAAGCGTAA
    AGCTTGTTGCGGATAATAACGTGTTGATGACCAACTTTGTTATCACGGCTACTCAAG
    TGTCTAATGAATAAGTAAAATGATTGCAGTA
    Translation:
    MMSKLGVLLTTCLLLFPLTALPMDGDQLARRPAERMQDNISSEQHPFFERRRPPCCTYD (SEQ ID NO:123)
    GSCLKESCKRKACCG
    Toxin Sequence:
    Arg-Xaa3-Xaa3-Cys-Cys-Thr-Xaa5-Asp-Gly-Ser-Cys-Leu-Lys-Xaa1-Ser-Cys-Lys-Arg-Lys-Ala- (SEQ ID NO:124)
    Cys-Cys-#
    Name:     Lp3.1
    Species:  leopardus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCGTCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:125)
    TTACTGCTCTTCGGCTGGTTGGAGATCAACCTGCAGAGCGACCTGCAAAGCGTACGC
    AGGACGACATTCCAGATGGACAGCATCCGTTAAATGATAGGCAGATAAACTGTTGC
    CCGTGGCCATGCCCTAGTACATGCCGCCATCAATGCTGCCATTAATGATAACGTGTT
    GATGACCAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTVCLLLFPLTALRLVGDQPAERPAKRTQDDIPDGQHPLNDRQINCCPW (SEQ ID NO:126)
    PCPSTCRHQCCH
    Toxin Sequence:
    Xaa2-Ile-Asn-Cys-Cys-Xaa3-Xaa4-Xaa3-Cys-Xaa3-Ser-Thr-Cys-Arg-His-Gln-Cys-Cys-His-{circumflex over ( )} (SEQ ID NO:127)
    Name:     Lv3.1
    Species:  lividus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCGTCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:128)
    TTACTGCTCTTCGGCTGGTTAGAGATCAACCTGCAGAGCGACCTGCAAAGCGTACGC
    AGGACGACATTCCAAATGGACAGGATCCGTTAATTGATAGGCAGATAAATTGTTGC
    CCTTGGCCATGCCCTGATTCATGCCACTATCAATGCTGCCACTGATAACGTGTTGAT
    GACCAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTVCLLLFPLTALRLVRDQPAERPAKRTQDDIPNGQDPLIDRQINCCPWP (SEQ ID NO:129)
    CPDSCHYQCCH
    Toxin Sequence:
    Xaa2-Ile-Asn-Cys-Cys-Xaa3-Xaa4-Xaa3-Cys-Xaa3-Asp-Ser-Cys-His-Xaa5-Gln-Cys-Cys-His-{circumflex over ( )} (SEQ ID NO:130)
    Name:     L3.1
    Species:  lynceus
    Cloned:   Yes
    DNA Sequence:
    AAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTG (SEQ ID NO:131)
    CTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATCAATCTGCAGACCGACTTG
    CAGAGCGTATGCAGGACAACATTTCATCTGAGCAGCATCCCTTCTTTGAAAAGAGA
    GGACGAGACTGTTGCACACCTCCGAGGAAATGCAGAGACCGAGCCTGCAAACCTCA
    ACGTTGTTGCGGAGGATAAGCTGTTGATGACCAACTTTGTTATACGGC
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQSADRLAERMQDNISSEQHPFFEKRGRDCCTPP (SEQ ID NO:132)
    RKCRDRACKPQRCCGG
    Toxin Sequence:
    Gly-Arg-Asp-Cys-Cys-Thr-Xaa3-Xaa3-Arg-Lys-Cys-Arg-Asp-Arg-Ala-Cys-Lys-Xaa3-Gln-Arg- (SEQ ID NO:133)
    Cys-Cys-Gly-#
    Name:     M3.1
    Species:  magus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:134)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATGAACCTGCAAACCG
    ACCTGTCGAGCGTATGCAGGACAACATTTCATCTGAGCAGTATCCCTTGTTTGAGAA
    GAGACGAGATTGTTGCACTCCGCCGAAGAAATGCAAAGACCGACAATGCAAACCCC
    AGAGATGTTGCGCTGGACGATAACGTGTTGATGACCAACTTTATCACGGCTACGTCA
    AGTGTTTAGTGAATAAGTAAAATGATTGCAGTCTTGCTCAGATTTGCTTTTGTGTTTT
    GGTCTAAAGATCAATGACCAAACCGTTGTTTTGATGCGGATTGTCATATATTTCTCG
    ATTCCAATCCAACACTAGATGATTTAATCACGATAGATTAATTTTCTATCAATGCCT
    TGATTTTTCGTCTGTCATATCAGTTTTGTTTATATTTATTTTTTCGTCACTGTCTACAC
    AAACGCATGCATGCACGCATGCACGCACACACGCACGCACGCTCGCACAAACATGC
    GCGCGCACGCACACACACACACACACACACAAACACACACACGAAGCAATCACAC
    AATTAGTTGACATTATTTATTTATTCATTGATGTATTTGTTATTCGTTTGCTTGTTTTT
    AGAATAGTTTGAGGCCGTCTTTTTGGATTTATTTGAACTGCTTTATTGTATACGAGTA
    CTTCGTGCGGGGAAACACTGCTGAAAATAAAACAAACACTGACGTAGCAAAAAAA
    AAAAA
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDEPANRPVERMQDNISSEQYPLFEKRRDCCTPPK (SEQ ID NO:135)
    KCKDRQCKPQRCCAGR
    Toxin Sequence:
    Arg-Asp-Cys-Cys-Thr-Xaa3-Xaa3-Lys-Lys-Cys-Lys-Asp-Arg-Gln-Cys-Lys-Xaa3-Gln-Arg-Cys- (SEQ ID NO:136)
    Cys-Ala-#
    Name:     M3.2
    Species:  magus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:137)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCAATGGATGGAGATCAACCTGCAGACCA
    ACCTGCAGATCGTATGCAGGACGACATTTCATCTGAGCAGTATCCCTTGTTTGATAT
    GAGAAAAAGGTGTTGCGGCCCCGGCGGTTCATGCCCCGTATATTTCAGAGACAATT
    TTATTTGTGGTTGTTGTTAAATGACAACGTGTCGATGACCAACTTCATTATCACGAC
    TACGCCAAGTGTCTAATGAATAAATAAAATGATTGCAGTCTCGCTCAGATTTGCTTT
    TGTATTTTGGTCTAAAGATCAATGACCAAACCGTTGTTTTGGTGTGGATTTTCATATA
    TTTCTCGAGTCCTATCCAACACTAGATGATTTAATCACGATAGATCTGATTTTTTTAT
    CAAAGGCTTGGTTTTTCGTCTGTCACATCAGTTTTGTTTATATTTAATTTTTCGTCACT
    GATTACACACACGCATGAACGCACAGAGTACTAACACATACACACACACACACACA
    CACACACACACACACACACACACACACACACACACACACACGCGCGCGCGCGGCG
    CCATCTAGTAGCGCCGCGACGACACACAC
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQPADQPADRMQDDISSEQYPLFDMRKRCCGPG (SEQ ID NO:138)
    GSCPVYFRDNFICGCC
    Toxin Sequence:
    Cys-Cys-Gly-Xaa3-Gly-Gly-Ser-Cys-Xaa3-Val-Xaa5-Phe-Arg-Asp-Asn-Phe-Ile-Cys-Gly-Cys- (SEQ ID NO:139)
    Cys-{circumflex over ( )}
    Name:     M3.3
    Species:  magus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:140)
    TTTGCTTCTGTTTCCCCTTACTGCTCTTCCGAGGGATGGAGATCAATCTGTAGACCGA
    CCTGCAGAGCGTATGCAGGACGACATTTCATCTGAGCTGCATCCCTTGTCAATCAGA
    AAAAGAATGTGTTGCGGCGAGAGTGCGCCATGCCCCAGCTATTTCAGAAACAGTCA
    GATTTGTCATTGTTGTTAAATGACAACGTGTCGATGACCACCTTCGTTATCACGACT
    AATGATAAGTAAAATGATTGCAGTCTCGCTCAGATTTGCTTTTGTATTTTGGTCTAA
    AGATCAATGACCAAACCGTTGTTTTGATGTGGATTTTCATATATTTCTCGAGTCCTAT
    CCAACACTAGATGATTTAATCACGATAGATCTGATTTTTTTATCAAAGCCTTGGTTTT
    TCGTCTGTCACATCAGTTTTGTTTATATTTAATTTTTCGTCACTGATTACACACACGC
    ATGAACGCACAGACGTACTAACACATACACACACACACACACACACACACACACAC
    ACACACACACACACACACACAC
    Translation:
    MMSKLGVLLTICLLLFPLTALPRDGDQSVDRPAERMQDDISSELHPLSIRKRMCCGESAP (SEQ ID NO:141)
    CPSYFRNSQICHCC
    Toxin Sequence:
    Met-Cys-Cys-Gly-Xaa1-Ser-Ala-Xaa3-Cys-Xaa3-Ser-Xaa5-Phe-Arg-Asn-Ser-Gln-Ile-Cys-His- (SEQ ID NO:142)
    Cys-Cys-{circumflex over ( )}
    Name:     M3.4
    Species:  magus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:143)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCAATGGATGGAGATCAACCTGCAGACCA
    ACCTGCAGATCGTATGCAGGACGACATTTCATCTGAGCAGTATCCCTTGTTTGATAA
    GAGACAAAAGTGTTGCGGCCCCGGCGGTTCATGCCCCGTATATTTCACAGACAATTT
    TATTTGTGGTTGTTGTTAAATGACAACGTGTCGATGACCAACTTCATTATCACGACT
    ACGCCAAGTGTCTAATGAATAAATAAAATGATTGCAGTCTCGCTCAGATTTGCTTTT
    GTATTTGGTCTAAAGATCAATGACCAAACCGTTGTTTTGGTGCTGGATTTTCATATA
    TTTCTCGATTCCTATCCAACACTAGATGATTTAATCACGATAGATCTGATTTTTTTAT
    CAATGCCTTAATTTTTTGCTCTGTCATATCAGTTTTGTTTATAT
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQPADQPADRMQDDISSEQYPLFDKRQKCCGPGG (SEQ ID NO:144)
    SCPVYFTDNFICGCC
    Toxin Sequence:
    Xaa2-Lys-Cys-Cys-Gly-Xaa3-Gly-Gly-Ser-Cys-Xaa3-Val-Xaa5-Phe-Thr-Asp-Asn-Phe-Ile-Cys- (SEQ ID NO:145)
    Gly-Cys-Cys-{circumflex over ( )}
    Name:     M3.5
    Species:  magus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:146)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCAATGGATGGAGATCAACCTGCAGACCA
    ACCTGCAGATCGTATGCAGGACGACATTTCATCTGAGCAGTATCCCTTGTTTGATAA
    GAGACAAAAGTGTTGCGGCCCCGGCGGTTCATGCCCCGTATATTTCAGAGACAATTT
    TATTTGTGGTTGTTGTTAAATGACAACGTGTCGATGACCATCTTCATTATCACGACT
    ACGCCAAGTGTCTAATGAATAAATAAAATGATTGCAGTCTCGCTCAGATTTGCTTTT
    GTATTTTGGTCTAAAGATCAATGACCAAACCGTTGTTTTGGTGTGGATTTTCATATAT
    TTCTCGATTCCTATCCAACACTAGATGATTTAATCACGATAGATCTGATTTTTT
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQPADQPADRMQDDISSEQYPLFDKRQKCCGPGG (SEQ ID NO:147)
    SCPVYFRDNFICGCC
    Toxin Sequence:
    Xaa2-Lys-Cys-Cys-Gly-Xaa3-Gly-Gly-Ser-Cys-Xaa3-Val-Xaa5-Phe-Arg-Asp-Asn-Phe-Ile-Cys- (SEQ ID NO:148)
    Gly-Cys-Cys-{circumflex over ( )}
    Name:     U001
    Species:  magus
    Isolated: No
    Toxin Sequence:
    Xaa2-Lys-Cys-Cys-Ser-Gly-Gly-Ser-Cys-Xaa3-Leu-Xaa5-Phe-Arg-Asp-Arg-Leu-Ile-Cys-Xaa3- (SEQ ID NO:149)
    Cys-Cys-{circumflex over ( )}
    Name:     Comatose/Death
    Species:  marmoreus
    Isolated: Yes
    Toxin Sequence:
    Ser-Lys-Gln-Cys-Cys-His-Leu-Ala-Ala-Cys-Arg-Phe-Gly-Cys-Thr-Xaa3-Cys-Cys-Asn-{circumflex over ( )} (SEQ ID NO:150)
    Name:     Mr3.1
    Species:  marmoreus
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:151)
    TCTGCTTCTGTTTCCCGTTACTGCTCTTCCGATGGATGGTGATCAACCTGCAGACCGA
    CTTGTAGAGCGTATGCAGGACAACATTTCATCTGAGCAGCATCCCTTCTTTGAAAAG
    AGAAGAGGAGGCTGTTGCACACCTCCGAGGAAATGCAAAGACCGAGCCTGCAAAC
    CTGCACGTTGCTGCGGCCCAGGATAACGTGTTGATGACCAACTTTGTTATCACGGCT
    ACGTCAAGTGTCTAGTGAATAAGTAAAACGATTGCAG
    Translation:
    MMSKLGVLLTICLLLFPVTALPMDGDQPADRLVERMQDNISSEQHPFFEKRRGGCCTPP (SEQ ID NO:152)
    RKCKDRACKPARCCGPG
    Toxin Sequence:
    Arg-Gly-Gly-Cys-Cys-Thr-Xaa3-Xaa3-Arg-Lys-Cys-Lys-Asp-Arg-Ala-Cys-Lys-Xaa3-Ala-Arg- (SEQ ID NO:153)
    Cys-Cys-Gly-Xaa3-#
    Name:     Mr3.2
    Species:  marmoreus
    Cloned:   Yes
    DNA Sequence:
    GAGCTCGGTACCCCGACCTCAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTG (SEQ ID NO:154)
    GGAATCTTGTTGACCATCTGTCTACTTCTATTTCCCCTTACTGCTGTTCCGCTGGATG
    GAGATCAACCTGCAGACCGACCTGCAGAGCGTATGCAGGACGACATTTCATCTGAA
    CATCATCCCTTTTTTGATCCCGTCAAACGGTGTTGCAGGTTATCATGCGGCCTGGGA
    TGCCACCCTTGTTGTGGATGACCAGCTTTGTTATCGCGGCCTCATCAAGTGTCTAAT
    GAATAAGTAAAA
    Translation:
    MMSKLGILLTICLLLFPLTAVPLDGDQPADRPAERMQDDISSEHHPFFDPVKRCCRLSCG (SEQ ID NO:155)
    LGCHPCCG
    Toxin Sequence:
    Cys-Cys-Arg-Leu-Ser-Cys-Gly-Leu-Gly-Cys-His-Xaa3-Cys-Cys-# (SEQ ID NO:156)
    Name:     Mr3.3
    Species:  marmoreus
    Cloned:   Yes
    DNA Sequence:
    GGCCTACACCAAGCTTGCATGCCTGCAGGTCGACTCTAGAGGATCCCCGATCGATA (SEQ ID NO:157)
    GCAGTTCATGATGTCTAGACTGGGAGTCTTGTTGACCATCTGTCTACTTCTGTTTCCC
    CTTACTGCTGTTCCGCTGGATGGAGATCAACCTGCGGACCGACCTGCAGAGCGCCTG
    CAGGACGACATTTCATCTGAACATCATCCCCATTTTGATTCCGGCAGAGAGTGTTGC
    GGTTCGTTCGCATGCCGCTTTGGATGCGTGCCTTGTTGTGTATGACCAGCTTTGTTAT
    CACGGCCTCATCGAGTGTCTAATGAATAAGTAAAACGATTGCAGTAGGCGGGTACC
    GAGCTCGAATTCC
    Translation:
    MMSRLGVLLTICLLLFPLTAVPLDGDQPADRPAERLQDDISSEHHPHFDSGRECCGSFAC (SEQ ID NO:158)
    RFGCVPCCV
    Toxin Sequence:
    Xaa1-Cys-Cys-Gly-Ser-Phe-Ala-Cys-Arg-Phe-Gly-Cys-Val-Xaa3-Cys-Cys-Val-{circumflex over ( )} (SEQ ID NO:159)
    Name:     Mr3.4
    Species:  marmoreus
    Cloned:   Yes
    DNA Sequence:
    CGACCTCAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGA (SEQ ID NO:160)
    CCATCTGTCTACTTCTATTTCCCCTTACTGCTGTTCCGCTGGATGGAGACCAACCTGC
    AGACCGACCTGCAGAGCGTATGCAGGACGACATTTCATCTGAACGTCATCCTTTTTT
    TGATCGCAGCAAACAGTGTTGCCATCTGCCGGCATGCCGCTTCGGATGTACGCCTTG
    TTGTTGGTGATCAGCTTTGTTATCGCGTCCTCATCAAGTGTCTAATGAATAAGTAAA
    ATGATTGCAG
    Translation:
    MMSKLGVLLTICLLLFPLTAVPLDGDQPADRPAERMQDDISSERHPFFDRSKQCCHLPAC (SEQ ID NO:161)
    RFGCTPCCW
    Toxin Sequence:
    Ser-Lys-Gln-Cys-Cys-His-Leu-Xaa3-Ala-Cys-Arg-Phe-Gly-Cys-Thr-Xaa3-Cys-Cys-Xaa4-{circumflex over ( )} (SEQ ID NO:162)
    Name:     Mr3.5
    Species:  marmoreus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:163)
    TTACTGCTCTTCCGCTGGATGGAGATCAACCTGCAGACCAACGTGCAGAGCGTACG
    CAGGCCGAGAAGCATTCCTTGCCTGATCCGAGAATGGGCTGTTGCCCGTTTCCATGC
    AAAACCAGTTGCACTACTTTGTGTTGCGGGTGATGATAACGTGTTGATGACCAACTT
    TCTCGAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTALPLDGDQPADQRAERTQAEKHSLPDPRMGCCPFPCKT (SEQ ID NO:164)
    SCTTLCCG
    Toxin Sequence:
    Met-Gly-Cys-Cys-Xaa3-Phe-Xaa3-Cys-Lys-Thr-Ser-Cys-Thr-Thr-Leu-Cys-Cys-# (SEQ ID NO:165)
    Name:     U014
    Species:  marmoreus
    Isolated: Yes
    Toxin Sequence:
    Cys-Cys-His-Xaa4-Asn-Xaa4-Cys-Asp-His-Leu-Cys-Ser-Cys-Cys-Gly-Ser-{circumflex over ( )} (SEQ ID NO:166)
    Name:     U017
    Species:  marmoreus
    Cloned:   Yes
    DNA Sequence:
    GCCAAGCTTGCATGCCTGCAGGATGACTCTAGAGGATCCCCACCTCAAGAGGGATC (SEQ ID NO:167)
    GATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTACTTCTGTT
    TGCCCTTACTGCTGTTCCGCTGGATGGAGATCAACCTGCAGACCGACCTGCAGAACG
    TATGCAGGACGACATTTCATCTGAACGTCATCCCATGTTTGATGCCGTCAGAGATTG
    TTGCCCGTTGCCGGCATGCCCCTTTGGATGCAACCCTTGTTGTGGATGACCAGCTTT
    GTTATCGGGACCTCATCAAGTGTCTAATGAATAAGTAAAAAACGATTCGAGTGGGT
    ACCGAGCTCGAATTCC
    Translation:
    MMSKLGVLLTICLLLFALTAVPLDGDQPADRPAERMQDDISSERHPMFDAVRDCCPLPA (SEQ ID NO:168)
    CPFGCNPCCG
    Toxin Sequence:
    Asp-Cys-Cys-Xaa3-Leu-Xaa3-Ala-Cys-Xaa3-Phe-Gly-Cys-Asn-Xaa3-Cys-Cys-# (SEQ ID NO:169)
    Name:     U019
    Species:  marmoreus
    Isolated: Yes
    Toxin Sequence:
    Cys-Cys-Ala-Xaa3-Ser-Ala-Cys-Arg-Leu-Gly-Cys-Arg-Xaa3-Cys-Cys-Arg-{circumflex over ( )} (SEQ ID NO:170)
    Name:     U020
    Species:  marmoreus
    Isolated: Yes
    Toxin Sequence:
    Cys-Cys-Ala-Xaa3-Ser-Ala-Cys-Arg-Leu-Gly-Cys-Arg-Xaa3-Cys-Cys-Arg-{circumflex over ( )} (SEQ ID NO:171)
    Name:     U022
    Species:  marmoreus
    Isolated: Yes
    Toxin Sequence:
    Cys-Cys-Ala-Xaa3-Ser-Ala-Cys-Arg-Leu-Gly-Cys-Arg-Xaa3-Cys-Cys-Arg-{circumflex over ( )} (SEQ ID NO:172)
    Name:     U024
    Species:  marmoreus
    Isolated: Yes
    Toxin Sequence:
    Gly-Cys-Cys-Gly-Ser-Phe-Ala-Cys-Arg-Phe-Gly-Cys-Val-Xaa3-Cys-Cys-Val-{circumflex over ( )} (SEQ ID NO:173)
    Name:     Nb3.1
    Species:  nobilis
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTACTTCTGTTTCCCC (SEQ ID NO:174)
    TTACTGCTCTTCCGCTGGATGAAGATCAACCGGTACACCGACCTGCAGAGCGTATGC
    AGGACATTTCATCTGATCAACATCTCTTCTTTGATCTCATCAAACGGTGCTGCGAGT
    TGCCATGCGGGCCAGGCTTTTGCGTCCCTTGTTGCTGACATCAATAACGTGTTGATG
    ACCAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTALPLDEDQPVHRPAERMQDISSDQHLFFDLIKRCCELPCG (SEQ ID NO:175)
    PGFCVPCC
    Toxin Sequence:
    Cys-Cys-Xaa1-Leu-Xaa3-Cys-Gly-Xaa3-Gly-Phe-Cys-Val-Xaa3-Cys-Cys-{circumflex over ( )} (SEQ ID NO:176)
    Name:     Nb3.2
    Species:  nobilis
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTACTTCTGTTTCCCC (SEQ ID NO:177)
    TTACTGCTTTTCCGATGGATGGAGATCAACCTGCAGACCAACCTGCAGATCGTATGC
    AGGACGACATTTCATCTGAGCAGTATCCCTTGTTTGATAAGAGACAAAAGTGTTGCA
    CTGGGAAGAAGGGGTCATGCTCCGGCAAAGCATGCAAAAATCTCAAATGTTGCTCT
    GGACGATAACGTGTTGATGACCAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTAFPMDGDQPADQPADRMQDDISSEQYPLFDKRQKCCTG (SEQ ID NO:178)
    KKGSCSGKACKNLKCCSGR
    Toxin Sequence:
    Xaa2-Lys-Cys-Cys-Thr-Gly-Lys-Lys-Gly-Ser-Cys-Ser-Gly-Lys-Ala-Cys-Lys-Asn-Leu-Lys-Cys- (SEQ ID NO:179)
    Cys-Ser-#
    Name:     Pu3.1
    Species:  pulicarius
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTTTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:180)
    TTACTGCTGTTCCGCTGGATGGAGATCAACCTGCAGACCGACCTGCAGAGCGTATGC
    AGGACATTGCAACTGAACAGCATCCCTTCTTTGATCCCGTCAAACGGTGTTGCAACA
    GCTGTTACATGGGATGCATCCCTTGTTGCTTCTAGTAATAACGTGTTGATGACCAAC
    TTTCTCGAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTAVPLDGDQPADRPAERMQDIATEQHPFFDPVKRCCNSC (SEQ ID NO:181)
    YMGCIPCCF
    Toxin Sequence:
    Cys-Cys-Asn-Ser-Cys-Xaa5-Met-Gly-Cys-Ile-Xaa3-Cys-Cys-Phe-{circumflex over ( )} (SEQ ID NO:182)
    Name:     Qc3.1
    Species:  quercinus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:183)
    TTACAGCTCTTCAGCTGGATGGAGATCAACCTGCAGACCGACCTGCAGAGCGTACG
    CAGGACATTGCATCTGAACAGTATCGAAAGTTTGATCAGAGACAGAGGTGTTGCCA
    GTGGCCATGCCCCGGTAGTTGCAGATGCTGCCGTACTGGTTAACGTGTTGATGACCA
    ACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTALQLDGDQPADRPAERTQDIASEQYRKFDQRQRCCQWP (SEQ ID NO:184)
    CPGSCRCCRTG
    Toxin Sequence:
    Xaa2-Arg-Cys-Cys-Gln-Xaa4-Xaa3-Cys-Xaa3-Gly-Ser-Cys-Arg-Cys-Cys-Arg-Thr-# (SEQ ID NO:185)
    Name:     QcIIIA
    Species:  quercinus
    Isolated: Yes
    Toxin Sequence:
    Cys-Cys-Ser-Gln-Asp-Cys-Leu-Val-Cys-Ile-Xaa3-Cys-Cys-Xaa3-Asn-# (SEQ ID NO:186)
    Name:     QcIIIB
    Species:  quercinus
    Isolated: Yes
    Toxin Sequence:
    Cys-Cys-Ser-Arg-His-Cys-Xaa4-Val-Cys-Ile-Xaa3-Cys-Cys-Xaa3-Asn-? (SEQ ID NO:187)
    Name:     R3.1
    Species:  radiatus
    Isolated: Yes
    Cloned:   Yes
    DNA Sequence:
    TCAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCT (SEQ ID NO:188)
    GTCTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATCAACCTGTAGACCG
    ACTTGCAGAGCGTATGCAGGACAACATTTCATCTGAGCAGCATACCTTCTTTGAAAA
    GAGACTACCATCGTGTTGCTCCCTTAACTTGCGGCTTTGCCCAGTACCAGCATGCAA
    ACGTAACCCTTGTTGCACAGGATAACGTGTTGATGACCAACTTTGTTATCACGGCTA
    CGTCAAGTGTCTAGTGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQPVDRLAERMQDNISSEQHTFFEKRLPSCCSLNL (SEQ ID NO:189)
    RLCPVPACKRNPCCTG
    Toxin Sequence:
    Leu-Xaa3-Ser-Cys-Cys-Ser-Leu-Asn-Leu-Arg-Leu-Cys-Xaa3-Val-Xaa3-Ala-Cys-Lys-Arg-Asn- (SEQ ID NO:190)
    Xaa3-Cys-Cys-Thr-#
    Name:     R3.2
    Species:  radiatus
    Cloned:   Yes
    DNA Sequence:
    AGGTCGACTCTAGAGGATCCCCAAGGATCGATAGCAGTTCATGATGTCTAAACTGG (SEQ ID NO:191)
    GAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGG
    AGATCAACCTGCAGACCGACTTGCAGAGCGTATGCAGGACGACATTTCATCTGAGC
    AGCATCCCTTCTTTAAAAAGAGACAACAAAGATGTTGCACCGTTAAGAGGATTTGT
    CCAGTACCAGCATGCAGAAGTAAACCTTGTTGCAAATCATAACGTATTGATGACCA
    ACTTTGTTATCACGGCTACGTCAAGTGTCTAGTGAATAAGTAAAATGATTGCAG
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQPADRLAERMQDDISSEQHPFFKKRQQRCCTVK (SEQ ID NO:192)
    RICPVPACRSKPCCKS
    Toxin Sequence:
    Xaa2-Gln-Arg-Cys-Cys-Thr-Val-Lys-Arg-Ile-Cys-Xaa3-Val-Xaa3-Ala-Cys-Arg-Ser-Lys-Xaa3- (SEQ ID NO:193)
    Cys-Cys-Lys-Ser-{circumflex over ( )}
    Name:     R3.3
    Species:  radiatus
    Cloned:   Yes
    DNA Sequence:
    ACCTCAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACC (SEQ ID NO:194)
    ATCTGTCTGCTTCTGTTTCCCGTTACTGCTCTTCCGATGGATGGTGATCAACCTGCAG
    ACCGACTTGTAGAGCGTATGCAGGACAACATTTCATCTGAGCAGCATCCCTTCTTTG
    AAAAGAGAAGAGGAGGCTGTTGCACACCTCCGAGGAAATGCAAAGACCGAGCCTG
    CAAACCTGCACGTTGCTGCGGCCCAGGATAACGTGTTGATGACCAACTTTGTTATCA
    CGGCTACGTCAAGTGTCTAGTGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPVTALPMDGDQPADRLVERMQDNISSEQHPFFEKRRGGCCTPP (SEQ ID NO:195)
    RKCKDRACKPARCCGPG
    Toxin Sequence:
    Arg-Gly-Gly-Cys-Cys-Thr-Xaa3-Xaa3-Arg-Lys-Cys-Lys-Asp-Arg-Ala-Cys-Lys-Xaa3-Ala-Arg- (SEQ ID NO:196)
    Cys-Cys-Gly-Xaa3-#
    Name:     Ra3.1
    Species:  rattus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGGTGACCATCTGCCTGCTTCTGTTCCCT (SEQ ID NO:197)
    CTTGCTGCTTTTCCACTGGATGGAGATCAACCTGCAGACCACCCTGCAAAGCGTACG
    CAAGATGACAGTTCAGCTGCCCTGATCAATGCCTGGCTTGATGAATCCCAGACTTGC
    TGCAGTAACTGCGGTGAAGATTGTGATGGTTGTTGCCAGTAACGTGTTGATGACCAA
    CTTTCTCGAG
    Translation:
    GSMMSKLGVLVTICLLLFPLAAFPLDGDQPADHPAKRTQDDSSAALINAWLDESQTCCS (SEQ ID NO:198)
    NCGEDCDGCCQ
    Toxin Sequence:
    Xaa2-Thr-Cys-Cys-Ser-Asn-Cys-Gly-Xaa1-Asp-Cys-Asp-Gly-Cys-Cys-Gln-{circumflex over ( )} (SEQ ID NO:199)
    Name:     Sm3.1
    Species:  stercusmuscarum
    Cloned:   Yes
    DNA Sequence:
    GACCTCAAGAGGGATCGATAGCAGTTCGTGATGTCTAAACTGGGAGTCTTGTTGAC (SEQ ID NO:200)
    CATCTGTCTGCTTCTGTTTCCTCTTACTGCTCTTCCGATGGATGGAGATCAACCTGCA
    GACCAACCTGCAGATCGTATGCAGGACGACATTTCATCTGAGCAGTATCCCTTGTTT
    GATAAGAGACAAAAGTGTTGCACTGGGAAGAAGGGGTCATGCTCCGGCAAAGCAT
    GCAAAAATCTCAAATGTTGCTCTGGACGATAACGTGTTGATGACCAACTTTGTTATC
    ACGGCTACGTCAAGTGTCTAATGAATAAGTAAAACGATTGCAGT
    Translation:
    MSKLGVLLTICLLLFPLTALPMDGDQPADQPADRMQDDISSEQYPLFDKRQKCCTGKKG (SEQ ID NO:201)
    SCSGKACKNLKCCSGR
    Toxin Sequence:
    Xaa2-Lys-Cys-Cys-Thr-Gly-Lys-Lys-Gly-Ser-Cys-Ser-Gly-Lys-Ala-Cys-Lys-Asn-Leu-Lys-Cys- (SEQ ID NO:202)
    Cys-Ser-#
    Name:     U034
    Species:  stercusmuscarum
    Isolated: Yes
    Cloned:   Yes
    DNA Sequence:
    GATCGATAGCAGTTCGTGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTT (SEQ ID NO:203)
    CTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATCAACCTGCAGACCAACCTGCA
    GATCGTATGCAGAACGACATTTCATCTGAGCAGTATCCCTTGTTTGATAAGAGACAA
    AAGTGTTGCGGCCCCGGCGCGTCATGCCCCAGATATTTCAAAGACAATTTTATTTGT
    GGTTGTTGTTAAATGACAACGTGTCGATGACCAACTTCGTTATCACGACTTCGCCAA
    GTGTCTAATGAATAAGTAAAACGATTGCAGT
    Translation:
    MSKLGVLLTICLLLFPLTALPMDGDQPADQPADRMQNDISSEQYPLFDKRQKCCGPGAS (SEQ ID NO:204)
    CPRYFKDNFICGCC
    Toxin Sequence:
    Xaa2-Lys-Cys-Cys-Gly-Xaa3-Gly-Ala-Ser-Cys-Xaa3-Arg-Xaa5-Phe-Lys-Asp-Asn-Phe-Ile-Cys- (SEQ ID NO:205)
    Gly-Cys-Cys-{circumflex over ( )}
    Name:     S3.1
    Species:  striatus
    Cloned:   Yes
    DNA Sequence:
    CGACCTTTCAAGAGGGATCGATAGCAGTTCGCGATGTCTAAACTGGGGGTATTGTTG (SEQ ID NO:206)
    ACCATCTGTCTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGAAGATCAACCTG
    CAGACCAACTTGAAGATCGTATGCAGGACGACATTTCATCTGAGCAGTATCCCTCGT
    TTGTTAGGAGACAAAAGTGTTGCGGCGAAGGCTCGTCATGCCCCAAATATTTCAAA
    AACAATTTTATTTGTGGTTGTTGTTAAATGACAACGTGTCGATGACCAACTTCGTTA
    TCACGACTACGCCAAGTGTCTTGTCTAATGATAATAAAATGATTCC
    Translation:
    MSKLGVLLTICLLLFPLTALPMDEDQPADQLEDRMQDDISSEQYPSFVRRQKCCGEGSSC (SEQ ID NO:207)
    PKYFKNNFICGCC
    Toxin Sequence:
    Xaa2-Lys-Cys-Cys-Gly-Xaa1-Gly-Ser-Ser-Cys-Xaa3-Lys-Xaa5-Phe-Lys-Asn-Asn-Phe-Ile-Cys- (SEQ ID NO:208)
    Gly-Cys-Cys-{circumflex over ( )}
    Name:     S3.2
    Species:  striatus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCGTCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:209)
    TTACTGCTCTTCCGCTGGATGGAGATCAACCTGCAGACCGACCTGCAGAGCGTATGC
    AGGACGACATTTCATCTGACGAGCATCCCTTGTTTGATAAGAGACAAAACTGTTGCA
    ATGGGGGATGCTCCAGCAAATGGTGCAGAGATCACGCACGTTGTTGCGGTCGATGA
    TAACGTGTTGATGACCAACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTVCLLLFPLTALPLDGDQPADRPAERMQDDISSDEHPLFDKRQNCCNG (SEQ ID NO:210)
    GCSSKWCRDHARCCGR
    Toxin Sequence:
    Xaa2-Asn-Cys-Cys-Asn-Gly-Gly-Cys-Ser-Ser-Lys-Xaa4-Cys-Arg-Asp-His-Ala-Arg-Cys-Cys-# (SEQ ID NO:211)
    Name:     Ts3.1
    Species:  tessulatus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATGTGTCTGCTTCTGTTTCCCC (SEQ ID NO:212)
    TTACTGCTGTTCCGCTGGATGGAGATCAACCTGCAGACCGACCTGCAGAGCGTAGG
    CAGGACATTGCAACTGACGATCATCCTTTGTTTGATCCCGTCAAACGGTGCTGCCAC
    AAATGCTATATGGGATGCATCCCTTGTTGCATTTAGTAACGTGTTGATGACCAACTT
    TCTCGAG
    Translation:
    GSMMSKLGVLLTMCLLLFPLTAVPLDGDQPADRPAERRQDIATDDHPLFDPVKRCCHK (SEQ ID NO:213)
    CYMGCIPCCI
    Toxin Sequence:
    Cys-Cys-His-Lys-Cys-Xaa5-Met-Gly-Cys-Ile-Xaa3-Cys-Cys-Ile-{circumflex over ( )} (SEQ ID NO:214)
    Name:     Ts3.2
    Species:  tessulatus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTGTGCTTCTGTTTCCCC (SEQ ID NO:215)
    TTACTGCTGTTCCGCTGGATGGAGATCAACCTGCAGACCAACCTGCAGAGCGTACG
    CAGAACGAGCAGCATCCCTTGTATGATCAGAAAAGAAAGTGTTGCCGGCCGCCATG
    CGCCATGAGCTGCGGCATGGCTAGGTGTTGCTATTAATGATAACGTGTTGATGACCA
    ACTTTCTCGAG
    Translation:
    GSMMSKLGVLLTICVLLFPLTAVPLDGDQPADQPAERTQNEQHPLYDQKRKCCRPPCA (SEQ ID NO:216)
    MSCGMARCCY
    Toxin Sequence:
    Lys-Cys-Cys-Arg-Xaa3-Xaa3-Cys-Ala-Met-Ser-Cys-Gly-Met-Ala-Arg-Cys-Cys-Xaa5-{circumflex over ( )} (SEQ ID NO:217)
    Name:     Circling
    Species:  textile
    Isolated: Yes
    Cloned:   Yes
    DNA Sequence:
    GAGTCAACCCACTGTCACGCCAAGAGCGGACGCCACAGCTAAGGCAAGAAGGATC (SEQ ID NO:218)
    GATAGCAGTTCATGATGTCTAAACTGGGAGCCTTGTTGACCATCTGTCTACTTCTGT
    TTTCCCTTACTGCTGTTCCGCTGGATGGAGATCAACATGCAGACCAACCTGCACAGC
    GTCTGCAGGACCGCATTCCAACTGAAGATCATCCCTTATTTGATCCCAACAAACGGT
    GTTGCCCGCCGGTGGCATGCAACATGGGATGCAAGCCTTGTTGTGGATGACCAGCTT
    TGTTATCGCGGTCTCATGAAGTGTCTAATGAATAAGTAAAACGATTGCAGTTTCGTT
    CAGATTTGCTGTTGTATTTTGGTCTAAAGATTAATGACCAAACTGTTCTTTTGATCCG
    GATTTTCACGTATTTCTCGATTCCTATTCAACACTAGATAAGTTAATCACGACAGAT
    CTGATTTTCCATCAATGCCTTGCTTTTTGGTCTGTCATATAAATCTTGTTTATATTTAA
    TTTCTCGTCACTTTCAACACGCACACACACACACACACACACGCGCGCGC
    Translation:
    MMSKLGALLTICLLLFSLTAVPLDGDQHADQPAQRLQDRIPTEDHPLFDPNKRCCPPVA (SEQ ID NO:219)
    CNMGCKPCCG
    Toxin Sequence:
    Cys-Cys-Xaa3-Xaa3-Val-Ala-Cys-Asn-Met-Gly-Cys-Lys-Xaa3-Cys-Cys-Gly-{circumflex over ( )} (SEQ ID NO:220)
    Name:     Scratcher I
    Species:  textile
    Cloned:   Yes
    DNA Sequence:
    GGATCCAGACGACAAAGAAGAGTCAACCCACTGCCACGTCAAGAGCAGAGCCCAC (SEQ ID NO:221)
    AGCTAAGACAAGAAGGATCGATAGCAGTTCATGATGTTTAAACTGGGAGTCTTGTT
    GACCATCTGTCTCCTTCTGTTTTCCCTTAATGCTGTTCCGTTGGATGGAGATCAACCT
    GCAGACCAACCTGCAGAGCGTCTGCTGGACGACATTTCATTTGAAAATAATCCCTTT
    TATGATCCCGCCAAACGGTGTTGCAGGACTTGCTTCGGTTGCACACCTTGTTGTGGA
    TGACCAGCCTCATCAAGTGTCTAACGAATAAGTAAAGCGATTGCAGTCTCGTTCAG
    ATTTACTTTTGTATTCTGGTCTAAAGATTAATGACCAAACTCTTCTTTTGATCCGGAT
    GTACATATATTTCTCGATTCCTATCCAACGCTAGATAAGCTAATCACGACAGATCTG
    ATTTTCTGTCAATGCCTTGCTTTTTGGTCTCTCATATCACTCTTGTTTATATTTAATTT
    CTCGTCACTATATATATATATACACACACACACACACGGAATTCCGATTGTCCAGTA
    CCGTTCTTGGGATCGAGGTATTGCTGCGATGGCTTATTCTGTACTCTTTTCTTCTGCG
    CTTGATAGTGATGTCTTCTACTCCCATCTGTGCTACCCCTGGCTTGATCTTTGATAGG
    CGTGTGCCCTTCACTGGTTATAAACCCCTCTGATCCTACTCTCTGGACGCCTCGGGG
    GCCCAACCTCCAAATAAAGCGACATCCAATGAAAAAA
    Translation:
    MMFKLGVLLTICLLLFSLNAVPLDGDQPADQPAERLLDDISFENNPFYDPAKRCCRTCFG (SEQ ID NO:222)
    CTPCCG
    Toxin Sequence:
    Cys-Cys-Arg-Thr-Cys-Phe-Gly-Cys-Thr-Xaa3-Cys-Cys-# (SEQ ID NO:223)
    Name:     Tx3.1
    Species:  textile
    Cloned:   Yes
    DNA Sequence:
    GGAACAGTCAACCCCACAGCCACGCCAAGAGCAGACAGCCACAGCTACGTGAAGA (SEQ ID NO:224)
    AGGGTGGAGAGAGGTTCATGATGTTGAAAATGGGAGTGGTGCTATTCATCTTTCTGG
    TACTGTTTCCCCTGGCAACGCTCCAGCTGGATGCAGATCAACCTGTAGAACGATATG
    CGGAGAACAAACAGCTCCTCAACCCAGATGAAAGGAGGGAAATCCTATTGCCTGCT
    CTGAGGAAGTTCTGCTGTGATTCGAATTGGTGCCACATTTCGGATTGTGAGTGCTGC
    TACGGTTAGCGCCGAACATCCATGGCACTGTGCTGGGCGGTTTCATCCCAACAACG
    ACAGCGTTTGTTGATTTCATGTATCATTGCGCCCACGTCTCTTGTCTAAGAATGACG
    AACATGATTGCACTCTGGTTCAGATTTCGTGTTCTTTTCTGACAATAAATGACAAAcC
    TCC
    Translation:
    MMLKMGVVLFIFLVLFPLATLQLDADQPVERYAENKQLLNPDERREILLPALRKFCCDS (SEQ ID NO:225)
    NWCHISDCECCYG
    Toxin Sequence:
    Phe-Cys-Cys-Asp-Ser-Asn-Xaa4-Cys-His-Ile-Ser-Asp-Cys-Xaa1-Cys-Cys-Xaa5-# (SEQ ID NO:226)
    Name:     U031
    Species:  textile
    Isolated: Yes
    Cloned:   Yes
    DNA Sequence:
    CAAGGAACAGTCAACCCCACAGCCACGCCAAGAGCAGACAGCCACAGCTACGTGA (SEQ ID NO:227)
    AGAAGGGTGGAGAGAGGTTCGTGATGTTGAAAATGGGAGTGGTGCTATTCATCTTC
    CTGGTACTGTTTCCCCTGGCAACGCTCCAGCTGGATGCAGATCAACCTGTAGAACGA
    TATGCGGAGAACAAACAGCTCCTCAGCCCAGATGAAAGGAGGGAAATCATATTGCA
    TGCTCTGGGGACGCGATGCTGTTCTTGGGATGTGTGCGACCACCCGAGTTGTACTTG
    CTGCGGTTAGCGCCGAACATCCATGGCGCTGTGCTGGGCGGTTTTATCCCAACAACG
    ACAGCGTTTGTTGATTTCATGTATCATTGCGCCCACGTCTCTTGTCTAAGAATGACG
    AACATGATTGCACTCTGGTTCAGATTTCGTGTTCTTTTCTGACAATAAATGACAAAA
    CNCC
    Translation:
    MLKMGVVLFIFLVLFPLATLQLDADQPVERYAENKQLLSPDERREIILHALGTRCCSWD (SEQ ID NO:228)
    VCDHPSCTCCG
    Toxin Sequence:
    Cys-Cys-Ser-Xaa4-Asp-Val-Cys-Asp-His-Xaa3-Ser-Cys-Thr-Cys-Cys-# (SEQ ID NO:229)
    Name:     U032
    Species:  textile
    Isolated: Yes
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:230)
    TTACTGCTCTTCCGCTGGATGGAGATCAACCCGCAGACCAAGCTGCAGAGCGTATG
    CAGGCCGAGCAGCATCCCTTGTTTGATCAGAAAAGACGGTGCTGCAAGTTTCCATG
    CCCCGATAGTTGCAGATATTTGTGTTGCGGGTGATGATAACGTGTTGATGACCAACT
    TTCTCGAG
    Translation:
    GSMMSKLGVLLTICLLLFPLTALPLDGDQPADQAAERMQAEQHPLFDQKRRCCKFPCPD (SEQ ID NO:231)
    SCRYLCCG
    Toxin Sequence:
    Arg-Cys-Cys-Lys-Phe-Xaa3-Cys-Xaa3-Asp-Ser-Cys-Arg-Xaa5-Leu-Cys-Cys-# (SEQ ID NO:232)
    Name:     T3.1
    Species:  tulipa
    Cloned:   Yes
    DNA Sequence:
    CGACCTCAAGAGGGATCGATAGCAGTTCATGTCTAAACTGGGAGTCTTGTTGACAA (SEQ ID NO:233)
    TCTGTCTGCTTCTGTTTCCCCTTACTGCTCTGCCGATGGATGGAGATGAACCTGCAG
    ACCGACCTGCAGAGCGTATGCAGGACAACATTTCATCTGAGCAGCATCCCTTGTTTG
    AGGAGAGACACGGATGTTGCAAGGGGCCCGAAGGATGCTCCTCCAGAGAATGCAG
    ACCCCAACATTGTTGCGGTCGACGATAACGTGTTGAGGGCCAACTTTGTTATCACGG
    CTACGTCAAGTGTTTAGTGAATAAGTAAAATGATTGCAG
    Translation:
    MSKLGVLLTICLLLFPLTALPMDGDEPADRPAERMQDNISSEQHPLFEERHGCCKGPEGC (SEQ ID NO:234)
    SSRECRPQHCCGRR
    Toxin Sequence:
    His-Gly-Cys-Cys-Lys-Gly-Xaa3-Xaa1-Gly-Cys-Ser-Ser-Arg-Xaa1-Cys-Arg-Xaa3-Gln-His-Cys- (SEQ ID NO:235)
    Cys-#
    Name:     Fi3.1
    Species:  figulinus
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGCTGACCATCT (SEQ ID NO:236)
    GTCTGCTTCTGATTCCCCTTACTGCTCTTTCGCTGGATGGAGATCAACCTGCAGACC
    GACCTGCAGAGCGTATGCAGGATGGAATTTCATCTGAACAGCATCCCATGTTTGATC
    CCGTCAGACGGTGTTGCCCGTGGCCATGCAACATAGGATGCGTACCTTGTTGTTGAT
    GACCAGTTTTGTTATCGCGGCCTCATCAAATGTCTAATGAATAAGTAAAACGATTGC
    AGT
    Translation:
    MMSKLGVLLTICLLLIPLTALSLDGDQPADRPAERMQDGISSEQHPMFDPVRRCCPWPC (SEQ ID NO:237)
    NIGCVPCC
    Toxin Sequence:
    Cys-Cys-Xaa3-Xaa4-Xaa3-Cys-Asn-Ile-Gly-Cys-Val-Xaa3-Cys-Cys-{circumflex over ( )} (SEQ ID NO:238)
    Name:     Fi3.2
    Species:  figulinus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTTTAAACTGGGAGTCCTGTTGACCATCTG (SEQ ID NO:239)
    TATGCTTCTGTTTCCCTTTACTGCTCTTCCGCTGGATGGAGAGCAACCTGCAGACCA
    ACCTGCAGAGCGCATGCAGTATGACATGTTACGTGCAATGAATCCCTGGTTTGATCC
    CGTCAAAAGGTGCTGCTCGAAGAACTGCGCAGTATGCATCCCTTGTTGCCCGTAACT
    GACCAGCTTGATTATCGCGGCCAAGGCTCTAATGAATAAGTAAAACGATTGCAGT
    Translation:
    MMFKLGVLLTICMLLFPFTALPLDGEQPADQPAERMQYDMLRAMNPWFDPVKRCCSK (SEQ ID NO:240)
    NCAVCIPCCP
    Toxin Sequence:
    Cys-Cys-Ser-Lys-Asn-Cys-Ala-Val-Cys-Ile-Xaa3-Cys-Cys-Xaa3-{circumflex over ( )} (SEQ ID NO:241)
    Name:     Fi3.3
    Species:  figulinus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGAGAGTCTTGTTGACCTTATG (SEQ ID NO:242)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCGCTGAATGAAGATCAACCTGCAGAGCGT
    ATGCAGGACGACAATTCATCTGAGCAGCACCCCTTGTATGACCACAAACGAAAGTG
    TTGCCGGTGGCCATGCCCCGCAAGATGCGGCTCTTGTTGCCTGTAATAACGTGTTGG
    CCAACTTTGTTATCACGGCCACGTCAAATGTTTAATGAATAAGTAAAACGATTGCAG
    T
    Translation:
    MMSKLRVLLTLCLLLFPLTALPLNEDQPAERMQDDNSSEQHPLYDHKRKCCRWPCPAR (SEQ ID NO:243)
    CGSCCL
    Toxin Sequence:
    Cys-Cys-Arg-Xaa4-Xaa3-Cys-Xaa3-Ala-Arg-Cys-Gly-Ser-Cys-Cys-Leu-{circumflex over ( )} (SEQ ID NO:244)
    Name:     Fi3.4
    Species:  figulinus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCTTATG (SEQ ID NO:245)
    TCTGCTTCTGTTTCCCCTGACTGCTCTTCCGCTGGATGAAGATCAAGCTGCAGACCG
    ACCTGCAGAGCGTATGCAGGGCATGTCATCTGAACAGCATCCCTTCTTTGATCCCGT
    CAAACGGTGTTGCGAGTTGTCACGCTGCCTTGGATGCGTCCCTTGTTGCACATCTTA
    ATAACGTGTGGATGACCAACTGTGTTATCACGGCCACGTCAAGTGTCTAATGAATA
    AGTAAAATGATTGCAGT
    Translation:
    MMSKLGVLLTLCLLLFPLTALPLDEDQAADRPAERMQGMSSEQHPFFDPVKRCCELSRC (SEQ ID NO:246)
    LGCVPCCTS
    Toxin Sequence:
    Cys-Cys-Xaa1-Leu-Ser-Arg-Cys-Leu-Gly-Cys-Val-Xaa3-Cys-Cys-Thr-Ser-{circumflex over ( )} (SEQ ID NO:247)
    Name:     Fi3.5
    Species:  figulinus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCTTATG (SEQ ID NO:248)
    TCTGCTTCTGTTTCCCCTGACTGCTCTTCCGCTGGATGAAGATCAACCTGCAGACCG
    ACCTGCAGAGCGTATGCAGGGCATGTCATCTGAACAGCATCCCTTCTTTGATCCCGT
    CAAACGGTGTTGCGAGTTGTCAAAATGCCATGGATGCGTCCCTTGTTGCATACCTTA
    ATAACGTGCGGATGACCAACTGTGTTATCACGGCCACGTCAAGTGTCTAATGAATA
    AGTAAAATGATTGCAGT
    Translation:
    MMSKLGVLLTLCLLLFPLTALPLDEDQPADRPAERMQGMSSEQHPFFDPVKRCCELSKC (SEQ ID NO:249)
    HGCVPCCIP
    Toxin Sequence:
    Cys-Cys-Xaa1-Leu-Ser-Lys-Cys-His-Gly-Cys-Val-Xaa3-Cys-Cys-Ile-Xaa3-{circumflex over ( )} (SEQ ID NO:250)
    Name:     Qc3.2
    Species:  quercinus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTCGGAGTCTTGTTGACCATCTG (SEQ ID NO:251)
    TCTGGTTCTGTTTCCCCTTACAGCTCTTCAGCTGGATGGAGATCAACCTGCAGACCG
    ACCTGCAGAGCGTACGCAGGACATTTCATCTGAACAGTATCGAAAGTTTGATCAGA
    GACAGAGGTGTTGCCGGTGGCCATGCCCCGGTAGTTGCAGATGCTGCCGTTATCGTT
    AACGTGTTGGTGACCAGCTTTGTTATCACGACCACGCCAAGTGTCTAACGAATAAGT
    AAAATGATTGCAGT
    Translation:
    MMSKLGVLLTICLVLFPLTALQLDGDQPADRPAERTQDISSEQYRKFDQRQRCCRWPCP (SEQ ID NO:252)
    GSCRCCRYR
    Toxin Sequence:
    Xaa2-Arg-Cys-Cys-Arg-Xaa4-Xaa3-Cys-Xaa3-Gly-Ser-Cys-Arg-Cys-Cys-Arg-Xaa5-Arg-{circumflex over ( )} (SEQ ID NO:253)
    Name:     Qc3.3
    Species:  quercinus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:254)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCACTGGATGGAGATCAACCTGCAGATCAA
    TCTGCAGAGCGACCTGCAGAGCGTACGCAGGACGACATTCAGCAGCATCCGTTATA
    TGATCCGAAAAGAAGGTGTTGCCGTTATCCATGCCCCGACAGCTGCCACGGATCTTG
    CTGCTATAAGTGATAACATGTTGATGGCCAGCTTTGTTATCACGGCCACGTCAAGTG
    TCTAATGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPLDGDQPADQSAERPAERTQDDIQQHPLYDPKRRCCRY (SEQ ID NO:255)
    PCPDSCHGSCCYK
    Toxin Sequence:
    Arg-Cys-Cys-Arg-Xaa5-Xaa3-Cys-Xaa3-Asp-Ser-Cys-His-Gly-Ser-Cys-Cys-Xaa5-Lys-{circumflex over ( )} (SEQ ID NO:256)
    Name:     Wi3.1
    Species:  wittigi
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCA (SEQ ID NO:257)
    TTACTGCTCTTCCGGTGGGTGGAGATCAGCCTGCAGACCGACTTGCAGAGCGTATGC
    AGGACGACACTTCATCTGAGCAGCATCCCTTTGAAAAGAGACTACCATCATGTTGC
    GACTTTGAGAGGCTTTGCGTAGTACCAGCATGCATACGTCATCAGTGTTGCACAGGA
    TAACGTGTTGATGACCAACTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPITALPVGGDQPADRLAERMQDDTSSEQHPFEKRLPSCCDFERL (SEQ ID NO:258)
    CVVPACIRHQCCTG
    Toxin Sequence:
    Leu-Xaa3-Ser-Cys-Cys-Asp-Phe-Xaa1-Arg-Leu-Cys-Val-Val-Xaa3-Ala-Cys-Ile-Arg-His-Gln- (SEQ ID NO:259)
    Cys-Cys-Thr-#
    Name:     bt3a
    Species:  betulinus
    Isolated: Yes
    Toxin Sequence:
    Cys-Cys-Lys-Gln-Ser-Cys-Thr-Thr-Cys-Met-Xaa3-Cys-Cys-Xaa4-{circumflex over ( )} (SEQ ID NO:260)
    Name:     T3.2
    Species:  tulipa
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACAATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:261)
    TTACTGCTCTGCCGATGGATGGAGATGAACCTGCAGACCGACCTGCAGAGCGTATG
    CAGGACAACATTTCATCTGAGCAGCATCCCTTGTTTGAGGAGAGACACGGATGTTG
    CGAGGGGCCGAAGGGATGCTCCTCCAGAGAATGCAGACCCCAACATTGTTGCGGTC
    GACGATAACGTGTTGATGACCAACTNTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDEPADRPAERMQDNISSEQHPLFEERHGCCEGPK (SEQ ID NO:262)
    GCSSRECRPQHCCGRR
    Toxin Sequence:
    His-Gly-Cys-Cys-Xaa1-Gly-Xaa3-Lys-Gly-Cys-Ser-Ser-Arg-Xaa1-Cys-Arg-Xaa3-Gln-His-Cys- (SEQ ID NO:263)
    Cys-#
    Name:     A3.5
    Species:  aurisiacus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTACTTCTGTTTCCCC (SEQ ID NO:264)
    TTACTGCTTTTCCGATGGATGGAGATCAACCTGCAGACCAACCTGCAGATCGTATGC
    AGGACGACATTTCATCTGAGCAGTATCCCTTGTTTGATAAGAGACAAAAGTGTTGCA
    CTGGGAGGAAGGGGTCATGCTCCGGCAAAGCATGCAAAAATCTCAAATGTTGCTCT
    GGACGATAACGTGTTGATGACCAACTTTCTCGAN
    Translation:
    MMSKLGVLLTICLLLFPLTAFPMDGDQPADQPADRMQDDISSEQYPLFDKRQKCCTGRK (SEQ ID NO:265)
    GSCSGKACKNLKCCSGR
    Toxin Sequence:
    Xaa2-Lys-Cys-Cys-Thr-Gly-Arg-Lys-Gly-Ser-Cys-Ser-Gly-Lys-Ala-Cys-Lys-Asn-Leu-Lys-Cys- (SEQ ID NO:266)
    Cys-Ser-#
    Name:     Bt3.5
    Species:  betulinus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:267)
    TTACTGCTGTTCCGTTGGATGGAGATCAACCTGCAGACCAACCTGCAGAGCGTATGC
    AGAACGAGCAGCATCCCTCGTTTGATCAGAAAAGAAGGTGCTGCCGGTGGCCATGC
    CCCAGTATATGCGGCATGGCTAGGTGTTGCTTCGTCATGATAACGTGTTGATGACCA
    ACTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPLTAVPLDGDQPADQPAERMQNEQHPSFDQKRRCCRWPCPSIC (SEQ ID NO:268)
    GMARCCFVMITC
    Toxin Sequence:
    Arg-Cys-Cys-Arg-Xaa4-Xaa3-Cys-Xaa3-Ser-Ile-Cys-Gly-Met-Ala-Arg-Cys-Cys-Phe-Val-Met (SEQ ID NO:269)
    Ile-Thr-Cys-{circumflex over ( )}
    Name:     Bt3.6
    Species:  betulinus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGATCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:270)
    TTACTGCTGTTCCGCTGGATGGAGATCAGCCTGCAGAGCGTACGCAGATCGAGCAG
    CATCCCTTGTTTGACCAGAAAAGAAGGTGTTGCCGGTGGCCATGCCCCAGTAGATG
    CGGCATGGCTAGGTGTTGCTTCGTCATGATAACGTGTTGATGANCGACCTCTCNAG
    Translation:
    MMSKLGVLLIICLLLFPLTAVPLDGDQPAERTQIEQHPLFDQKRRCCRWPCPSRCGMAR (SEQ ID NO:271)
    CCFVMITC
    Toxin Sequence:
    Arg-Cys-Cys-Arg-Xaa4-Xaa3-Cys-Xaa3-Ser-Arg-Cys-Gly-Met-Ala-Arg-Cys-Cys-Phe-Val-Met- (SEQ ID NO:272)
    Ile-Thr-Cys-{circumflex over ( )}
    Name:     Pr3.1
    Species:  parius
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:273)
    TTACTGCTCTTCCGATGGATGGTGATCAACCTGCAGACCGACTTGTAGAGCGTATGC
    AGGACAACATTTCATCTGAGCAGCATCCCTTCTTTGAAAAGAGAAGAGGAGGCTGT
    TGCACACCTCCGAAGAAATGCAAAGACCGAGCCTGCAAACCTGCACGTTGCTGCGG
    CCCAGGATAACGTGTTGATGACCAACTTTCTCGCC
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQPADRLVERMQDNISSEQHPFFEKRRGGCCTPP (SEQ ID NO:274)
    KKCKDRACKPARCCGPG
    Toxin Sequence:
    Arg-Gly-Gly-Cys-Cys-Thr-Xaa3-Xaa3-Lys-Lys-Cys-Lys-Asp-Arg-Ala-Cys-Lys-Xaa3-Ala-Arg- (SEQ ID NO:275)
    Cys-Cys-Gly-Xaa3-#
    Name:     Pr3.2
    Species:  parius
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:276)
    TTACTGCTCTTCCGATGGATGGTGATCAACCTGCAGACCGACTTGTAGAGCGTATGC
    AGGACAACATTTCATCTGAGCAGCATCCCTTCTTTGAAAAGAGAAGAGGCTGTTGC
    ACACCTCCGAGGAAATGCAAAGACCGAGCCTGCAAACCTGCACGTTGTTGCGGCCC
    AGGATAACGTGTTGATGACCAACTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQPADRLVERMQDNISSEQHPFFEKRRGCCTPPR (SEQ ID NO:277)
    KCKDRACKPARCCGPG
    Toxin Sequence:
    Arg-Gly-Cys-Cys-Thr-Xaa3-Xaa3-Arg-Lys-Cys-Lys-Asp-Arg-Ala-Cys-Lys-Xaa3-Ala-Arg-Cys- (SEQ ID NO:278)
    Cys-Gly-Xaa3-#
    Name:     Ct3.1
    Species:  coronatus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCAA (SEQ ID NO:279)
    TTACTGCCCTTCCGCTGGATGAAGATCAACCTGCAGACCGACCTGCAGAGCGTATGC
    AGGACATTGCAACTGAACAGCATCCCTTGTTTGATCCCGTCAAACGGTGCTGCGATT
    GGCCATGCATCCCAGGATGCACCCCTTGTTGCTTGCCTTGATAACGTGTTGATGACC
    AACTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPITALPLDEDQPADRPAERMQDIATEQHPLFDPVKRCCDWPCIP (SEQ ID NO:280)
    GCTPCCLP
    Toxin Sequence:
    Cys-Cys-Asp-Xaa4-Xaa3-Cys-Ile-Xaa3-Gly-Cys-Thr-Xaa3-Cys-Cys-Leu-Xaa3-{circumflex over ( )} (SEQ ID NO:281)
    Name:     Ms3.1
    Species:  musicus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCCTGTTGACCATCTGTCTGCTTCTGTTTCCTC (SEQ ID NO:282)
    TTTCTGCTCTTCCGATGGATGAAGATCAACTTGCAGACCTACCTGCAGAGCGTATGC
    GGGACACTGCAACTGTAGATCATCCCTCCTATGATCCTGACAAAGCGTGCTGCGAG
    CAGAGCTGTACAACATGCTTTCCGTGCTGCTAGCCTTGAACACAGTAACGTGTTGAT
    GACCAACTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPLSALPMDEDQLADLPAERMRDTATVDHPSYDPDKACCEQSCT (SEQ ID NO:283)
    TCFPCC
    Toxin Sequence:
    Ala-Cys-Cys-Xaa1-Gln-Ser-Cys-Thr-Thr-Cys-Phe-Xaa3-Cys-Cys-{circumflex over ( )} (SEQ ID NO:284)
    Name:     bt3b
    Species:  betulinus
    Isolated: Yes
    Toxin Sequence:
    Ala-Cys-Cys-Xaa1-Gln-Ser-Cys-Thr-Thr-Cys-Met-Xaa3-Cys-Cys-{circumflex over ( )} (SEQ ID NO:285)
    Name:     bt3c
    Species:  betulinus
    Isolated: Yes
    Toxin Sequence:
    Cys-Cys-Xaa1-Gln-Ser-Cys-Thr-Thr-Cys-Met-Xaa3-Cys-Cys-Xaa4-? (SEQ ID NO:286)
    Name:     Pn3.2
    Species:  pennaceus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:287)
    TTACTGCTCTTCCGCTGGATGGAGATCAACCTGCATACCAAGCTGCAGAGCGTATGC
    AGGCCGAGCATCATCCCTTGTTTGATCAGAAAAGACGGTGCTGCAAGTTTCCATGCC
    CCGATAGTTGCAAATATTTGTGTTGCGGGTGATGATAACATGTTGATGACCAACTTT
    CTTGAG
    Translation:
    MMSKLGVLLTICLLLFPLTALPLDGDQPAYQAAERMQAEHHPLFDQKRRCCKFPCPDSC (SEQ ID NO:288)
    KYLCCG
    Toxin Sequence:
    Arg-Cys-Cys-Lys-Phe-Xaa3-Cys-Xaa3-Asp-Ser-Cys-Lys-Xaa5-Leu-Cys-Cys-# (SEQ ID NO:289)
    Name:     Pu3.2
    Species:  pulicarius
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:290)
    TTACTGCTCTTCCGATGGATGGTGATCAACTTGCAGACCGACTTGTAGAGCGTATGC
    AGGACAACATTTCATCTGAGCAGCATCCCTTCTTTGATCCCGTCAAACGGTGTTGCG
    TCAGCTGTTACATGGGATGCATCCCTTGTTGCTTCTAGTAATAACGTGTTGATGACC
    AACTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQLADRLVERMQDNISSEQHPFFDPVKRCCVSCY (SEQ ID NO:291)
    MGCIIPCCF
    Toxin Sequence:
    Cys-Cys-Val-Ser-Cys-Xaa5-Met-Gly-Cys-Ile-Xaa3-Cys-Cys-Phe-{circumflex over ( )} (SEQ ID NO:292)
    Name:     Pu3.3
    Species:  pulicarius
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCGTCTGTCTGCTTCTGTGTCCCC (SEQ ID NO:293)
    TTACTGCTCTTCCACTGGATGAAGATCAACTTGCAGACCGACCTGCAGAGCGTATGC
    AGGATGACACTTCAGCTGCACAGATTTTCGGGTTTGATCCCGTCAAACGGTGCTGCA
    AATTGCTATGCTACTCGGGATGCACTCCTTGTTGCCATATTTGATAACGTGTTGATG
    ACCAACTTTCTCGAG
    Translation:
    MMSKLGVLLTVCLLLCPLTALPLDEDQLADRPAERMQDDTSAAQIFGFDPVKRCCKLLC (SEQ ID NO:294)
    YSGCTPCCHI
    Toxin Sequence:
    Cys-Cys-Lys-Leu-Leu-Cys-Xaa5-Ser-Gly-Cys-Thr-Xaa3-Cys-Cys-His-Ile-{circumflex over ( )} (SEQ ID NO:295)
    Name:     Ra3.2
    Species:  rattus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTGTGTTTCCGC (SEQ ID NO:296)
    TTACTGCTCTTCCGATGGATGGTGATCAACCTGCAGACCGACTTGTAGAGCGTATAC
    AGGACAACATTTCATCTGAGCAGCATCCCTTCTTTGAAAAGAGAAGAGGCTGTTGC
    GCACCTCCGAGGAAATGCAAAGACCGAGCCTGCAAACCTGCACGTTGCTGCGGCCC
    AGGATAACGTGTTGATGACCAACTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLVFPLTALPMDGDQPADRLVERIQDNISSEQHPFFEKRRGCCAPPRK (SEQ ID NO:297)
    CKDRACKPARCCGPG
    Toxin Sequence:
    Arg-Gly-Cys-Cys-Ala-Xaa3-Xaa3-Arg-Lys-Cys-Lys-Asp-Arg-Ala-Cys-Lys-Xaa3-Ala-Arg-Cys- (SEQ ID NO:298)
    Cys-Gly-Xaa3-#
    Name:     Sm3.3
    Species:  stercusmuscarum
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACAATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:299)
    TTATTGCTCTTCCGCTGGATGGAGATCAACCTGCAGACCGACCTGCAGAGCGTATGC
    AGGACGACATTTCATCTGAGAAGCATCCCTTGTTTGATAAGAGACAACGGTGTTGC
    AATGGGCGGAGGGGATGCTCCAGCAGATGGTGCAGAGATCACTCACGTTGTTGCGG
    TCGACGATAACGTGTTGATGACCAACTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPLIALPLDGDQPADRPAERMQDDISSEKHPLFDKRQRCCNGRRG (SEQ ID NO:300)
    CSSRWCRDHSRCCGRR
    Toxin Sequence:
    Xaa2-Arg-Cys-Cys-Asn-Gly-Arg-Arg-Gly-Cys-Ser-Ser-Arg-Xaa4-Cys-Arg-Asp-His-Ser-Arg- (SEQ ID NO:301)
    Cys-Cys-#
    Name:     Eb3.1
    Species:  ebraeus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:302)
    TTACTGCTCTTCCACTGGATGAAGGTCAACCTGCAGACCTACCTGCAGAGCGTATGC
    AGGACATTGCAACTGAACAGCATCCCTTGTTTGATCCTGTCAAACGGTGTTGCGAGC
    AGCCATGCTACATGGGATGCATCCCTTGTTGCTTCTAATAATAACGTGTTGATGACC
    AACTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPLTALPLDEGQPADLPAERMQDIATEQHPLFDPVKRCCEQPCY (SEQ ID NO:303)
    MGCIPCCF
    Toxin Sequence:
    Cys-Cys-Xaa1-Gln-Xaa3-Cys-Xaa5-Met-Gly-Cys-Ile-Xaa3-Cys-Cys-Phe-{circumflex over ( )} (SEQ ID NO:304)
    Name:     Eb3.2
    Species:  ebraeus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:305)
    TTACTGCTCTTCCACTGGATGAAGATCAACCTGCAGACCTACCTGCAGAGCGTATGC
    AGGACATTGCAACTGAACAGCATCCCTTGTTTGATCCTGTCAAACGGTGCTGCGCGC
    AGCCATGCTACATGGGATGCATCCCTTGTTGCTTCTAATAATAACGTGTTGATGACC
    AACTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPLTALPLDEDQPADLPAERMQDIATEQHPLFDPVKRCCAQPCY (SEQ ID NO:306)
    MGCIPCCF
    Toxin Sequence:
    Cys-Cys-Ala-Gln-Xaa3-Cys-Xaa5-Met-Gly-Cys-Ile-Xaa3-Cys-Cys-Phe-{circumflex over ( )} (SEQ ID NO:307)
    Name:     Fd3.2
    Species:  flavidus
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCCC (SEQ ID NO:308)
    TTACTGCTGTTCCGTTGGATGGAGATCAACCTGCAGACCAGCCTGCAGAGCGTATGC
    AGAACGAGCAGCATCCCTTGTTTGATCAGAAAAGAAGGTGCTGCCGGTGGCCATGC
    CCCAGTATATGCGGCATGGCTAGGTGTTGCTCGTCATGATAACGTGTTGATGACCAA
    CTTTCTCGAG
    Translation:
    MMSKLGVLLTICLLLFPLTAVPLDGDQPADQPAERMQNEQHPLFDQKRRCCRWPCPSIC (SEQ ID NO:309)
    GMARCCSS
    Toxin Sequence:
    Arg-Cys-Cys-Arg-Xaa4-Xaa3-Cys-Xaa3-Ser-Ile-Cys-Gly-Met-Ala-Arg-Cys-Cys-Ser-Ser-{circumflex over ( )} (SEQ ID NO:310)
    Name:     Mf3.1
    Species:  miliaris
    Cloned:   Yes
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTGTCTGCTTCTGTTTCCAA (SEQ ID NO:311)
    TTACTGCCCTTCCACTGGATGAAGATCAACCTGCAGACCGACCTGCAGAGCGTATGC
    AGGACATTGCAACTGAACAGCATCCCTTGTTTGATCCCGTCAAACGGTGTTGCGATT
    GGCCATGCAGCGCAGGATGCTACCCTTGTTGCTTCCCTTAATAACGTGTTGATGACC
    AACTNANGNAAAAAAA
    Translation:
    MMSKLGVLLTICLLLFPITALPLDEDQPADRPAERMQDIATEQHPLFDPVKRCCDWPCSA (SEQ ID NO:312)
    GCYPCCFP
    Toxin Sequence:
    Cys-Cys-Asp-Xaa4-Xaa3-Cys-Ser-Ala-Gly-Cys-Xaa5-Xaa3-Cys-Cys-Phe-Xaa3-{circumflex over ( )} (SEQ ID NO:313)
    Name:     Mf3.2
    Species:  miliaris
    Cloned:   Yes
    Notes:
    DNA Sequence:
    GGATCCATGATGTCTAAACTGGGAGTGGTGCCATTCGTCTTTCTGGTCCTGTTTCCCC (SEQ ID NO:314)
    TGGCAACACTCCAACTGGATGCAGATCAACCTGCAGACCGACCTGCGCGTAAAAAG
    GGCATTGCAACTAAACGGCATCCCTTGTCTGATCCTGTCAGAGGGTGTTGCCCTCCA
    ATGTGCACACCATGCTTCCCTTGCTGTTTTCGTTAATAACGTGTTGATGNATGATGN
    AN
    Translation:
    MMSKLGVVPFVFLVLFPLATLQLDADQPADRPARKKGIATKRHPLSDPVRGCCPPMCTPCFPCC (SEQ ID NO:315)
    FR
    Toxin Sequence:
    Gly-Cys-Cys-Xaa3-Xaa3-Met-Cys-Thr-Xaa3-Cys-Phe-Xaa3-Cys-Cys-Phe-Arg-{circumflex over ( )} (SEQ ID NO:316)
    Name:     Af3.1
    Species:  ammiralis
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:317)
    TCTGCTTCTGTTTCCCCTTACTGCTCTTCCGCTGGATGGAGATCAACCTGCAGACCA
    AGCTGCAGAGCGTATGCAGGCCGAGCAGCATCCCTTGTTTGATCAGAAAAGACGGT
    GTTGCAGGTTTCCATGCCCCGATACTTGCAGACATTTGTGTTGCGGGTGATGATAAC
    GTGCTGATGACCCACTTTGTCATCACGGCTACGTCAAGTGTCTAATGAATAAGTAAA
    ATGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPLDGDQPADQAAERMQAEQHPLFDQKRRCCRFPCPDTC (SEQ ID NO:318)
    RHLCCG
    Toxin Sequence:
    Arg-Cys-Cys-Arg-Phe-Xaa3-Cys-Xaa3-Asp-Thr-Cys-Arg-His-Leu-Cys-Cys-# (SEQ ID NO:319)
    Name:     Af3.2
    Species:  ammiralis
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTTTAAACTGGGAGTCTTGCTGACCATCTG (SEQ ID NO:320)
    TCTACTTCTGTTTTCCCTTAATGCTGTTCCGCTGGATGGAGATCAACCTGCAGACCA
    ACCTGCAGAGCGTCTGCTGGACGACATTTCATCTGAAAATAATCCCTTTTATGATCC
    CGCCAAACGGTGTTGCATGACTTGCTTCGGTTGCACACCTTGTTGTGGATGACCAGC
    CTCATCAAGTGTCTAACGAATAAGTAAAACGATTGCAGT
    Translation:
    MMFKLGVLLTICLLLFSLNAVPLDGDQPADQPAERLLDDISSENNPFYDPAKRCCMTCF (SEQ ID NO:321)
    GCTPCCG
    Toxin Sequence:
    Cys-Cys-Met-Thr-Cys-Phe-Gly-Cys-Thr-Xaa3-Cys-Cys-# (SEQ ID NO:322)
    Name:     Af3.3
    Species:  ammiralis
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGCCTTGTTGACCATCT (SEQ ID NO:323)
    GTCTACTTCTGTTTTCCCTTACTGCTGTTCCGCTGGATGGAGATCAACATGCAGACC
    AACCTGCAGAGCGTCTGCAGGACCGCCTTCCAACTGAAAATCATCCCTTATATGATC
    CCGTCAAACGGTGTTGCGATGATTCGGAATGCGACTATTCTTGCTGGCCTTGCTGTA
    TTTTTTCATAACCTTTGTTATCGCGGCCTCATCCTAGTGTCAAATGAATAAGTAAAA
    CGATTGCAGT
    Translation:
    MMSKLGALLTICLLLFSLTAVPLDGDQHADQPAERLQDRLPTENHPLYDPVKRCCDDSE (SEQ ID NO:324)
    CDYSCWPCCIFS
    Toxin Sequence:
    Cys-Cys-Asp-Asp-Ser-Xaa1-Cys-Asp-Xaa5-Ser-Cys-Xaa4-Xaa3-Cys-Cys-Ile-Phe-Ser-{circumflex over ( )} (SEQ ID NO:325)
    Name:     Af3.4
    Species:  ammiralis
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTTTAAACTCGGAGTCTTGCTGACCATCTG (SEQ ID NO:326)
    TCTACTTCTGTTTTCCCTAATtGCTGTTCCGCTGGATGGAGATCAACATGCAGACCAA
    CCTGCAGAGCGTCTGCAGGACCGCCTTCCAACTGAAAATCATCCCTTATATGATCCC
    GTCAAACGGTGTTGCAGGTTGTTATGCCTCAGTTGCAACCCTTGTTGTGGATGACCA
    GCTTTGTTATCACGGCCTCATCAAGTGTCTAATGAATAAGTAAAACGATTGCAGT
    Translation:
    MMFKLGVLLTICLLLFSLIAVPLDGDQHADQPAERLQDRLPTENHPLYDPVKRCCRLLCL (SEQ ID NO:327)
    SCNPCCG
    Toxin Sequence:
    Cys-Cys-Arg-Leu-Leu-Cys-Leu-Ser-Cys-Asn-Xaa3-Cys-Cys-# (SEQ ID NO:328)
    Name:     Af3.6
    Species:  ammiralis
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGCCTTGTTGACCATCT (SEQ ID NO:329)
    GTCTACTTCTGTTTTCCCTTACTGCTGTTCCGCTGGATGGAGATCAACATGCAGACC
    AACCTGCAGAGCGTCTGCAGGACCGCATTCCAACTGAAGATCATCCCTTATTTGATC
    CCAACAAACGGTGTTGCGATGATTCGGAATGCGGCTATTCATGCTGGCCTTGCTGTT
    ATGGATAAGCTTTGTTATCGCGGCCTCATCCAGTGTCAACGAATAAGTAAAACGATT
    GCAGT
    Translation:
    MMSKLGALLTICLLLFSLTAVPLDGDQHADQPAERLQDRIPTEDHPLFDPNKRCCDDSEC (SEQ ID NO:330)
    GYSCWPCCYG
    Toxin Sequence:
    Cys-Cys-Asp-Asp-Ser-Xaa1-Cys-Gly-Xaa5-Ser-Cys-Xaa4-Xaa3-Cys-Cys-Xaa5-# (SEQ ID NO:331)
    Name:     Sf3.1
    Species:  spurius
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGCTGACCATCT (SEQ ID NO:332)
    GTCTGCTTCTGTTTCCACGTACTTCTCTTCCGCTGGATGGAGATCAACCTGCAGTCCG
    ATCTGCAAAGCGTATGCATTCATCTATACAGCGTCGTTTCTTTGATCCCGTCAAACG
    GTGTTGCCCTAGATGCAGCGAGTGCAACCCTTGTTGTGGATGACCAGCTTTGTCATC
    GCGGCCTCATTAAGTGTCTAATGAATAAGTAAAATGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPRTSLPLDGDQPAVRSAKRMHSSIQRRFFDPVKRCCPRCSECNP (SEQ ID NO:333)
    CCG
    Toxin Sequence:
    Cys-Cys-Xaa3-Arg-Cys-Ser-Xaa1-Cys-Asn-Xaa3-Cys-Cys-# (SEQ ID NO:334)
    Name:     Om3.1
    Species:  omaria
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTCGTTGACCATCT (SEQ ID NO:335)
    GTCTACTTCTATTTTCCCTTACTGCTGTTCCGCTTGATGGAGATCAACATGCAGACCA
    ACCTGCAGAGCGTCTGCAGGGCGACATTTTATCTGAAAAGCATCCCTTATTTAATCC
    CGTCAAACGGTGTTGCGATGAGGAAGAATGCAGCAGTGCATGCTGGCCTTGTTGTT
    GGGGGTGATCAGCTTTGTTATCGCGGCCTCATCAAGTGTCTAATGAATAAGTAAAAT
    GATTGCAGT
    Translation:
    MMSKLGVSLTICLLLFSLTAVPLDGDQHADQPAERLQGDILSEKHPLFNPVKRCCDEEEC (SEQ ID NO:336)
    SSACWPCCWG
    Toxin Sequence:
    Cys-Cys-Asp-Xaa1-Xaa1-Xaa1-Cys-Ser-Ser-Ala-Cys-Xaa4-Xaa3-Cys-Cys-Xaa4-# (SEQ ID NO:337)
    Name:     Om3.2
    Species:  omaria
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGATCATCTG (SEQ ID NO:338)
    TCTACTTCTGTGTCCCCTTACTGCTGTTCTGGAGGATGGAGATCAACCTGCAGACCG
    ACCTGCAGAGCGTATGCAGGACGACATTTCAACTGAGCATCATCCCTTTTATGATCC
    CGTCAAACGGTGTTGCAAGTACGGGTGGACATGCTTGCTAGGATGCACTCCTTGTGA
    TTGTTGACCAGTTTTGTTATCGCGGCCTCGTCAAGTGTCTAATGAATAAGTAAAACG
    ATTGCAGT
    Translation:
    MMSKLGVLLIICLLLCPLTAVLEDGDQPADRPAERMQDDISTEHHPFYDPVKRCCKYGW (SEQ ID NO:339)
    TCLLGCTPCDC
    Toxin Sequence:
    Cys-Cys-Lys-Xaa5-Gly-Xaa4-Thr-Cys-Leu-Leu-Gly-Cys-Thr-Xaa3-Cys-Asp-Cys-{circumflex over ( )} (SEQ ID NO:340)
    Name:     Om3.3
    Species:  omaria
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTATACTGGGAGTCTTGTTGATCATCTG (SEQ ID NO:341)
    TCTACTTCTGTGTCCCCTTACTGCTGTTCTGGAGGATGGAGATCAACCTGCAGACCG
    ACCTGCAGAGCGTATGCAGGACGGCATTTCATCTGAACATCATCCCTTTTTGGATCC
    CGTCAAACGGTGTTGCCATCTATTGGCATGCCGCTTTGGATGCTCGCCTTGTTGTTG
    GTGACCAGCTTTGTTATCGCGGCCTCATCAAGTGTCTAATGAATAAGTAAAACGATT
    GCAGT
    Translation:
    MMSILGVLLIICLLLCPLTAVLEDGDQPADRPAERMQDGISSEHHPFLDPVKRCCHLLAC (SEQ ID NO:342)
    RFGCSPCCW
    Toxin Sequence:
    Cys-Cys-His-Leu-Leu-Ala-Cys-Arg-Phe-Gly-Cys-Ser-Xaa3-Cys-Cys-Xaa4-{circumflex over ( )} (SEQ ID NO:343)
    Name:     Om3.4
    Species:  omaria
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGATCATCTG (SEQ ID NO:344)
    TCTACTTCTTTGTCCCCTTACTGCTGTTCCGCAGGATGGAGATCAACCTGCAGACCG
    ACCTGCAGAGCGTATGCAGGGCGGCATTTCATCTGAACATCATCCCTTTTTTGATCC
    CGTCAAACGGTGTTGCAGGTACGGGTGGACATGCTGGCTAGGATGCACTCCCTGTG
    GTTGTTGACCAGCTTTGTTATCGCGGCCTCATCAAGTGTCTAATGAATAAGTAAAAC
    GATTGCAGT
    Translation:
    MMSKLGVLLIICLLLCPLTAVPQDGDQPADRPAERMQGGISSEHHPFFDPVKRCCRYGW (SEQ ID NO:345)
    TCWLGCTPCGC
    Toxin Sequence:
    Cys-Cys-Arg-Xaa5-Gly-Xaa4-Thr-Cys-Xaa4-Leu-Gly-Cys-Thr-Xaa3-Cys-Gly-Cys-{circumflex over ( )} (SEQ ID NO:346)
    Name:     Ep3.1
    Species:  episcopatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:347)
    TCTACTTCTGTTTTCCCTTATTGCTGTTCCGCTTGATGGAGATCAACATGCAGACCAA
    CCTGCAGAGCGTCTGCAGGGCGACATTTTATCTGAAAAGCATCCCTTATTTATGCCT
    GTCAAACGGTGTTGCGATGAGGACGAATGCAACAGTTCATGCTGGCCTTGTTGTTGG
    GGGTGATCAGCTTTGTTATCGCGGCCTGATCAAGTGTATAATGAATAAGTAAAACG
    ATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFSLIAVPLDGDQHADQPAERLQGDILSEKHPLFMPVKRCCDEDEC (SEQ ID NO:348)
    NSSCWPCCWG
    Toxin Sequence:
    Cys-Cys-Asp-Xaa1-Asp-Xaa1-Cys-Asn-Ser-Ser-Cys-Xaa4-Xaa3-Cys-Cys-Xaa4-# (SEQ ID NO:349)
    Name:     Ep3.2
    Species:  episcopatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:350)
    TCTACTTCTGTTTTCCCTTATTGCTGTTCCGCTTGATGGAGATCAACATGCAGACCAA
    CCTGCAGAGCGTCTGCAGGGCGACATTTTATCTGAAAAGCATCCCTTATTTATGCCT
    GTCAAACGGTGTTGCGATGAGGACGAATGCAGCAGTTCATGCTGGCCTTGTTGTTGG
    GGATGAGCAGCTTTGTTATCGCGGCCTCATCAAGTGTCTAATGAATAAGTAAAACG
    ATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFSLIAVPLDGDQHADQPAERLQGDILSEKHPLFMPVKRCCDEDEC (SEQ ID NO:351)
    SSSCWPCCWG
    Toxin Sequence:
    Cys-Cys-Asp-Xaa1-Asp-Xaa1-Cys-Ser-Ser-Ser-Cys-Xaa4-Xaa3-Cys-Cys-Xaa4-# (SEQ ID NO:352)
    Name:     Ep3.3
    Species:  episcopatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:353)
    TCTACTTCTGTTTTCCCTTACTGCTGTTCCGCTTGATGGAGATCAACATGCAGACCAA
    CCTGCAGAGCGTCTGCAGGGCGACATTTTATCTGAAAAGCATCCCTTATTTAATCCC
    GTCAAACGGTGTTGCCCGGCGGCGGCATGTGCCATGGGATGCAAGCCTTGTTGTGG
    ATGAGCAGCTTTGTTATCGTGGCCTCATCAAGTGTCTAATGAATAAGTAAAACGATT
    GCAGT
    Translation:
    MMSKLGVLLTICLLLFSLTAVPLDGDQHADQPAERLQGDILSEKHPLFNPVKRCCPAAA (SEQ ID NO:354)
    CAMGCKPCCG
    Toxin Sequence:
    Cys-Cys-Xaa3-Ala-Ala-Ala-Cys-Ala-Met-Gly-Cys-Lys-Xaa3-Cys-Cys-# (SEQ ID NO:355)
    Name:     Au3.2
    Species:  aulicus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:356)
    TCTGCTTCTGTTTTCCGTTACTGCTCTTCCGCCGGATGGAGATCAACCTGCAGACCG
    AGCTGCAGAGCGTAGGCAGGTCGAGCAGCATCCCGTGTTTGATCATGAAAGAGGGT
    GTTGCTCGCCACCATGCCACAGTATTTGCGCTGCTTTCTGTTGCGGGTGATGATAAC
    GTGTTGATGACCCACTTTGTCATCACGGCTGCGTCAAGTGTCTAATGAATAAGTAAA
    ATGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFSVTALPPDGDQPADRAAERRQVEQHPVFDHERGCCSPPCHSIC (SEQ ID NO:357)
    AAFCCG
    Toxin Sequence:
    Gly-Cys-Cys-Ser-Xaa3-Xaa3-Cys-His-Ser-Ile-Cys-Ala-Ala-Phe-Cys-Cys-# (SEQ ID NO:358)
    Name:     Au3.3
    Species:  aulicus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:359)
    TCTACTTCTGTTTTCCCTTACTGCTGTTCCGCTTGATGGAGATCAACATGCAGACCAA
    CCTGCAGAGCGTCTGCAGGGCGACATTTTATCTGAAAAGCATCCCTTATTTAATCCC
    GTCAAACGGTGTTGCCGACCGGTGGCATGTGCCATGGGATGCAAGCCTTGTTGTGG
    ATGAGCAGCTTTGTTATCGTGGCCTCATCAAGTGTCTAATGAATAAGTAAAATGATT
    GCAGT
    Translation:
    MMSKLGVLLTICLLLFSLTAVPLDGDQHADQPAERLQGDILSEKHPLFNPVKRCCRPVA (SEQ ID NO:360)
    CAMGCKPCCG
    Toxin Sequence:
    Cys-Cys-Arg-Xaa3-Val-Ala-Cys-Ala-Met-Gly-Cys-Lys-Xaa3-Cys-Cys-# (SEQ ID NO:361)
    Name:     Au3.4
    Species:  aulicus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCaTGATGTCTAAACTGGGAGTCTTGTTGATCATCTG (SEQ ID NO:362)
    TCTACTTCTGTCTCCCCTTACTGCTGTTCCGCTGGATGGAGATCAACCTGCAGACCG
    ACCTGCAGAGCGTATGCAGGACGACATTTCATCTGAACATCAACCCATGTTTGATGC
    CATCAGACAGTGTTGCCCGGCGGTGGCATGCGCCATGGGATGCGAGCCTTGTTGTG
    GATGACCAGCTTTGTTATCGCGGCCTCATCAAGTGTCTAATGAATAAGTAAAATGAT
    TGCAGT
    Translation:
    MMSKLGVLLIICLLLSPLTAVPLDGDQPADRPAERMQDDISSEHQPMFDAIRQCCPAVAC (SEQ ID NO:363)
    AMGCEPCCG
    Toxin Sequence:
    Xaa2-Cys-Cys-Xaa3-Ala-Val-Ala-Cys-Ala-Met-Gly-Cys-Xaa1-Xaa3-Cys-Cys-# (SEQ ID NO:364)
    Name:     Ae3.1
    Species:  aureus
    Cloned:   Yes
    DNA Sequence:
    CAAGAAGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGCCTTGTTGACCATCT (SEQ ID NO:365)
    GTCTACTTCTGTTTTCCCTTACTGCTGTTCCGCTGGATGGAGATCAACATGCAGACC
    AACATGCAGAGCGTCTGCATGACCGCCTTCCAACTGAAAATCATCCCTTATATGATC
    CCGTCAAACGGTGTTGCGATGATTCGGAATGCGACTATTCTTGCTGGCCTTGCTGTA
    TTTTTGGATAACCTTTGTTATCGCGGCCTCATCAAGTGTCAAATGAATAAGTAAAAC
    GATTGCAGT
    Translation:
    MMSKLGALLTICLLLFSLTAVPLDGDQHADQHAERLHDRLPTENHPLYDPVKRCCDDSE (SEQ ID NO:366)
    CDYSCWPCCIFG
    Toxin Sequence:
    Cys-Cys-Asp-Asp-Ser-Xaa1-Cys-Asp-Xaa5-Ser-Cys-Xaa4-Xaa3-Cys-Cys-Ile-Phe-# (SEQ ID NO:367)
    Name:     Ae3.2
    Species:  aureus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGCCTTGTTGACCATCT (SEQ ID NO:368)
    GTCTACTTCTGTTTTCCCTAACTGCTGTTCCGCTGGATGGAGATCAACATGCAGACC
    AACCTGCAGAGCGTCTGCAGGACCGCATTCCAACTGAAAATCATCCCTTATTTGATC
    CGAACAAACGGTGTTGCAATGATTGGGAATGCGACGATTCATGCTGGCCTTGCTGTT
    ATGGATAACCTTTGTTATCGCGGCCTCATCAAGTGTCAAATGAATAAGTAAAACGAT
    TGCAGT
    Translation:
    MMSKLGALLTICLLLFSLTAVPLDGDQHADQPAERLQDRIPTENHPLFDPNKRCCNDWE (SEQ ID NO:369)
    CDDSCWPCCYG
    Toxin Sequence:
    Cys-Cys-Asn-Asp-Xaa4-Xaa1-Cys-Asp-Asp-Ser-Cys-Xaa4-Xaa3-Cys-Cys-Xaa5-# (SEQ ID NO:370)
    Name:     Cn3.1
    Species:  consors
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:371)
    TTTGCTTCTGTTTCCCCTTACTGCTCTTCCAATGGATGGAGATCAATCTGTAGACCGA
    CCTGCAGAGCGTATGCAGGACGACATTTCATCTGAGCTGCATCCCTTGTTCAATCAG
    AAAAGAATGTGTTGCGGCGAAGGTGCGCCATGCCCCAGCTATTTCAGAAACAGTCA
    GATTTGTCATTGTTGTTAAATGACAACGTGTCGATGACCAACTTCGTTATCACGACT
    AATGAATAAGTAAAATGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTALPMDGDQSVDRPAERMQDDISSELHPLFNQKRMCCGEGA (SEQ ID NO:372)
    PCPSYFRNSQICHCC
    Toxin Sequence:
    Met-Cys-Cys-Gly-Xaa1-Gly-Ala-Xaa3-Cys-Xaa3-Ser-Xaa5-Phe-Arg-Asn-Ser-Gln-Ile-Cys-His- (SEQ ID NO:373)
    Cys-Cys-{circumflex over ( )}
    Name:     Cn3.3
    Species:  consors
    Cloned:   Yes
    DNA Sequence:
    TAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACCATCTG (SEQ ID NO:374)
    TCTGCTTCTGTTTCCCCTTATTGCTCTTCCAATGGATGGAGATCAACCTGCAGACCGA
    CCTGCAGAGCGTATGCAgGACGACATTTCATCTCAGCAGCATCCCTTGTTTGATAAG
    AGAGGCCGCTGTTGCGATGTGCCGAACGCATGCTCCGGCAGATGGTGCAGAGATCA
    CGCACAATGTTGCGGATGACGATAACGTGTTGATGACCAACTTTGTGATCACGGCTA
    CATCAAGTGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLIALPMDGDQPADRPAERMQDDISSQQHPLFDKRGRCCDVPN (SEQ ID NO:375)
    ACSGRWCRDHAQCCG
    Toxin Sequence:
    Gly-Arg-Cys-Cys-Asp-Val-Xaa3-Asn-Ala-Cys-Ser-Gly-Arg-Xaa4-Cys-Arg-Asp-His-Ala-Gln- (SEQ ID NO:376)
    Cys-Cys-#
    Name:     Cn3.4
    Species:  consors
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGTTGACTGTCTG (SEQ ID NO:377)
    TTTGCTTCTGTTTCCCCTTACTGCTCTTCCGATGGATGGAGATCAACCTGCAGACCAA
    CCTGCAGAGCGTATGCAGGACGACATTTCATCTGAGCAGCATCCCTTGTTTGATAAG
    AGACAAAGGTGTTGCACTGGGAAGAAGGGGTCATGCTCCGGTAAAGCATGCAAAA
    GTCTCAAATGTTGCTCTGGACGATAACGTGTTGATGACCAACTTTGTTATCACGGCT
    ACGTCAAGTGTCTAGTGAATAAGTAAAACGATTGCAGT
    Translation:
    MMSKLGVLLTVCLLLFPLTALPMDGDQPADQPAERMQDDISSEQHPLFDKRQRCCTGK (SEQ ID NO:378)
    KGSCSGKACKSLKCCSGR
    Toxin Sequence:
    Xaa2-Arg-Cys-Cys-Thr-Gly-Lys-Lys-Gly-Ser-Cys-Ser-Gly-Lys-Ala-Cys-Lys-Ser-Leu-Lys- (SEQ ID NO:379)
    Cys-Cys-Ser-#
    Name:     Em3.1
    Species:  emaciatus
    Cloned:   Yes
    DNA Sequence:
    CAAGAGGGATCGATAGCAGTTCATGATGTCTAAACTGGGAGTCTTGCTGACCATCTGTCTGCTTCTGTT (SEQ ID NO:380)
    TCCCCTTACTGTTCTTCCGATGGATGGAGATCAACCTGCAGACCTACCTGCATTGCGTGCGCAGTTCTT
    TGCACCTGAACATAGTCCCCGGTTTGACCCCGTCAAACGGTGCTGCTCGCGGGATTGCAGTGTTTGCA
    TCCCTTGTTGCCCGTATGGATCACCTTGATTATTGCGGCCACGTCAAGTGTCTAATGAATAAGTAAAAT
    GATTGCAGT
    Translation:
    MMSKLGVLLTICLLLFPLTVLPMDGDQPADLPALRAQFFAPEHSPRFDPVKRCCSRDCSVCIPCCPYGSP (SEQ ID NO:381)
    Toxin Sequence:
    Cys-Cys-Ser-Arg-Asp-Cys-Ser-Val-Cys-Ile-Xaa3-Cys-Cys-Xaa3-Xaa5-Gly-Ser-Xaa3-{circumflex over ( )} (SEQ ID NO:382)
    -------------------------------
  • [0094]
    TABLE 2
    Alignment of μ-Conopeptides (SEQ ID NO:)
    TYPE 1
    A3.4 (F283) ---CCKVQ-CES--C---TPCC{circumflex over ( )} (383)
    Ak3.1 (F585) ---CCELP-CGPGFC---VPCC{circumflex over ( )} (384)
    Ar3.1 ---CCERP-CNIG-C---VPCC{circumflex over ( )} (385)
    Bn3.1 (F586) ---CCNWP-CSMG-C---IPCCYY{circumflex over ( )} (386)
    Bt3.1 ---CCELP-CH-G-C---VPCCWP{circumflex over ( )} (387)
    Bt3.2 ---CCGLP-CN-G-C---VPCCWPS{circumflex over ( )} (388)
    Bt3.3 ---CCSRN-CAV--C---IPCCPNWPA{circumflex over ( )} (389)
    bt3a ---CCKQS-CTT--C---MPCCW{circumflex over ( )} (390)
    bt3b --ACCXQS-CTT--C---MPCC{circumflex over ( )} (391)
    bt3c ---CCEQS-CTT--C---MPCCW? (392)
    Ca3.3 R--CCRYP-CPDS-C--HGSCCYK{circumflex over ( )} (393)
    Ca3.4 ---CCPPVACNMG-C---KPCC# (394)
    Ca3.5 ---CCDDSECDYS-C---WPCCMF# (395)
    Ca3.6 (F349) ---CCRR--CYMG-C---IPCCF{circumflex over ( )} (396)
    Circling ---CCPPVACNMG-C---KPCCG{circumflex over ( )} (397)
    Comatose/ SKQCCHLAACRFG-C---TOCCN{circumflex over ( )} (398)
    Death
    Cp3.1 (F594) S--CCR--DCGED-C---VGCCR{circumflex over ( )} (399)
    Ct3.1 (Z726) ---CCDWP-CIPG-C---TPCCLP{circumflex over ( )} (400)
    Da3.1 ---CCDDSECDYS-C---WPCCILS{circumflex over ( )} (401)
    Da3.2 Z-QCCPPVACNMG-C---EPCC# (402)
    Da3.3 ---CCNAGFCRFG-C---TPCCW{circumflex over ( )} (403)
    Di3.1 Z--CCVHP-C-P---C---TPCCR{circumflex over ( )} (404)
    Fi3.1 ---CCPWP--CNIG-C---VPCC{circumflex over ( )} (405)
    Fi3.2 ---CCSKN-CAV--C---IPCCP{circumflex over ( )} (406)
    Fi3.3 ---CCRWP-CP-ARC---GSCCL{circumflex over ( )} (407)
    Fi3.4 ---CCELSRCL-G-C---VPCCTS{circumflex over ( )} (408)
    Fi3.5 ---CCELSKCH-G-C---VPCCIP{circumflex over ( )} (409)
    Ge3.1 (F590) Z--CCTF--CNFG-C---QPCCVP{circumflex over ( )} (410)
    Ge3.2 (F343/ Z--CCTF--CNFG-C---QPCCLT{circumflex over ( )} (411)
    Z734)
    Ge3.3 (F590 Z--CCTF--CNFG-C---QPCCVP{circumflex over ( )} (412)
    Gm3.1 ----CCDDSECDYS-C---WPCCMF# (413)
    Gm3.2 G--CCHLLACRFG-C---SPCCW{circumflex over ( )} (414)
    Gm3.3 ---CCSWDVCDHPSC---T-CCG# (415)
    La3.1 ---CCDWP-CS-G-C---IPCC{circumflex over ( )} (416)
    Lp3.1 (F340) ZINCCPWP-CPST-C--RHQCCH{circumflex over ( )} (417)
    Lv3.1 (F341) ZINCCPWP-CPDS-C--HYQCCH{circumflex over ( )} (418)
    Mr3.2 ---CCRLS-CGLG-C---HPCC# (419)
    Mr3.3 --ECCGSFACRFG-C---VPCCV{circumflex over ( )} (420)
    Mr3.4 SKQCCHLPACRFG-C---TPCCW{circumflex over ( )} (421)
    Mr3.5 (F286) -MGCCPFP-CKTS-C--TTLCC# (422)
    Ms3.1 (Z738) --ACCEQS-CTT--C---FPCC{circumflex over ( )} (423)
    Nb3.1 (F87) ---CCELP-CGPGFC---VPCC{circumflex over ( )} (424)
    Pu3.1 (F339) ---CCN-S-CYMG-C---IPCCF{circumflex over ( )} (425)
    Qc3.1 (F342) ZR-CCQWP-CPGS-C----RCCRT# (426)
    Qc3.2 ZR-CCRWP-CPGS-C----RCCRYR{circumflex over ( )} (427)
    Qc3.3 R--CCRYP-CPDS-C--HGSCCYK{circumflex over ( )} (428)
    QcIIIA ---CCSQD-CLV--C---IOCCPN# (429)
    QcIIIB ---CCSRH-CWV--C---IOCCPN? (430)
    Ra3.1 (F351) Z-TCCS-N-CGED-C---DGCCQ{circumflex over ( )} (431)
    Scratcher I ---CCR-T-C-FG-C---TOCC# (433)
    Ts3.1 (F592) ---CCH-K-CYMG-C---IPCCI{circumflex over ( )} (434)
    Ts3.2 (F345) K--CCRPP-CAMS-C-GMARCCY{circumflex over ( )} (435)
    Bt3.5 (Z495) R--CCRWP-CPSI-C-GMARCCFVMITC{circumflex over ( )} (436)
    Bt3.6 (Z497) R--CCRWP-CP-SRC-GMARCCFVMITC{circumflex over ( )} (437)
    Tx3.1 F--CCDSNWCHISDC----ECCY# (438)
    U014 ---CCHWNWCDHL-C----SCCGS{circumflex over ( )} (439)
    U017 --DCCOLPACPFG-C---NOCC# (440)
    U019 ---CCAPSACRLG-C---ROCCR{circumflex over ( )} (441)
    U020 ---CCAOSACRLG-C---ROCCR{circumflex over ( )} (442)
    U022 ---CCAPSACRLG-C---RPCCR{circumflex over ( )} (443)
    U024 --GCCGSFACRFG-C---VOCCV{circumflex over ( )} (444)
    U031 ---CCSWDVCDHPSC----TCC# (445)
    U032 (F353) R--CCKFP-CPDS-C--RYLCC# (446)
    Ae3.1 ---CCDDSECDYS-C---WPCCIF# (447)
    Ae3.2 ---CCNDWECDDS-C---WPCCY# (448)
    Af3.1 R--CCR-FPCPDT-C---RHLCC# (449)
    Af3.2 ---CC--MTC-FG-C---TPCC# (450)
    Af3.3 ---CCDDSECDYS-C---WPCCIFS{circumflex over ( )} (451)
    Af3.4 ---CCR-LLC-LS-C---NPCC# (452)
    Af3.6 ---CCDDSECGYS-C---WPCCY# (453)
    Au3.2 G--CCS-PPCHSI-C--AAFCC# (454)
    Au3.3 ---CCRPVACAMG-C---KPCC# (455)
    Au3.4 Z--CCPAVACAMG-C---EPCC# (456)
    Em3.1 ---CCS-RDC-SV-C---IPCCPYGSP{circumflex over ( )} (457)
    Ep3.1 ---CCDEDECNSS-C---WPCCW# (458)
    Ep3.2 ---CCDEDECSSS-C---WPCCW# (459)
    Ep3.3 ---CCPAAACAMG-C---KPCC# (460)
    Om3.1 ---CCDEEECSSA-C---WPCCW# (461)
    Om3.3 ---CCHLLACRFG-C---SPCCW{circumflex over ( )} (462)
    Sf3.1 ---CC--PRC-SE-C---NPCC# (463)
    TYPE 2
    Pn3.2 (AA049) -RCC--KFP-CPDS-C--KYLCC# (464)
    Fd3.2 (Z831) -RCC--RWP-CPSI-C-GMARCCSS{circumflex over ( )} (465)
    Pu3.3 (AA405) --CC--KLL-CYSG-C---TPCCHI{circumflex over ( )} (466)
    Eb3.1 (Z821) --CC--EQP-CYMG-C---IPCCF{circumflex over ( )} (467)
    Eb3.2 (Z822) --CC--AQP-CYMG-C---IPCCF{circumflex over ( )} (468)
    Pu3.2 (AA403) --CC--V-S-CYMG-C---IPCCF{circumflex over ( )} (469)
    Mf3.1 (Z882) --CC--DWP-CSAG-C---YPCCFP{circumflex over ( )} (470)
    Mf3.2 (Z885) -GCC---PPM-C-TP-C---FPCCFR{circumflex over ( )} (471)
    Ra3.2 (AA414) RGCCAPPRK-CKDRACK-PARCCGP# (472)
    Sm3.3 (AA419) ZRCCNGRRG-CSSRWCRDHSRCC# (473)
    Cn3.3 GRCCDVPNA-CSGRWCRDHAQCC# (474)
    Cn3.4 ZRCCTGKKGSCSGKACKSL-KCCS# (475)
    TYPE 3
    A3. 1 -MCCGEGRKCPSYFRNSQICHCC{circumflex over ( )} (476)
    A3.2 (F84) --CCR--WPCPRQIDGEY-CGCCL# (477)
    Bu3.5 -RCCGEGLTCPRYWKNSQICACC{circumflex over ( )} (478)
    Ca3.1 --CCGPGGSCPVYFRDNFICGCC{circumflex over ( )} (479)
    Cr3.1 RKCCGKDGPCPKYFKDNFICGCC{circumflex over ( )} (480)
    E3.1 --CCS--WPCPRYSNGKLVCFCCL# (481)
    M3.2 --CCGPGGSCPVYFRDNFICGCC{circumflex over ( )} (482)
    M3.3 -MCCGESAPCPSYFRNSQICHCC{circumflex over ( )} (483)
    M3.4 ZKCCGPGGSCPVYFTDNFICGCC{circumflex over ( )} (484)
    M3.5 ZKCCGPGGSCPVYFRDNFICGCC{circumflex over ( )} (485)
    S3.1 ZKCCGEGSSCPKYFKNNFICGCC{circumflex over ( )} (486)
    U001 ZKCCS-GGSCPLYFRDRLICPCC{circumflex over ( )} (487)
    U034 ZKCCGPGASCPRYFKDNFICGCC{circumflex over ( )} (488)
    Cn3.1 -MCCGEGAPCPSYFRNSQICHCC{circumflex over ( )} (489)
    TYPE 4
    A3.3 (F83) ZK--CCTGK---KGSCSGKACKNL-KCCS# (490)
    A3.5 (Z488) ZK--CCTGR---KGSCSGKACKNL-KCCS# (491)
    Bu3.1 VTDRCCK----GKREC-GRWCRDHSRCC# (492)
    Bu3.1A VGDRCCK----GKRGC-GRWCRDHSRCC# (493)
    Bu3.2 VGERCCK---NGKRGC-GRWCRDHSRCC# (494)
    Bu3.3 IVDRCCN-KGNGKRGC-SRWCRDHSRCC# (495)
    Bu3.4 VGLYCCRPKPNGQMMC-DRWCEKNSRCC# (496)
    Ca3.2 -RD-CCTPP---KK-CKDRQCKPQ-RCCA# (497)
    L3.1 GRD-CCTPP---RK-CRDRACKPQ-RCCG# (498)
    L3.2 ZRL-CCGFP---KS-CRSRQCKPH-RCC# (499)
    La3.2 -RD-CCTPP---KK--CRDRQCKPA-RCCG# (500)
    La3.3 RPP-CCTYD---GS--CLKESCMRK-ACC# (501)
    La3.3A RPP-CCTYD---GS-CLKESCKRK-ACC# (502)
    μ-GIIIA -RD-CCTOO---KK-CKDRQCKOQ-RCCA# (503)
    μ-GIIIB -RD-CCTOO---RK-CKDRRCKOM-KCCA# (504)
    μ-GIIIC -RD-CCTOO---KK-CKDRRCKOL-KCCA# (505)
    μ-PIIIA ZRL-CCGFO---KS-CRSRQCKOH-RCC# (506)
    M3.1 -RD-CCTPP---KK-CKDRQCKPQ-RCCA# (507)
    Mr3.1 RGG-CCTPP---RK-CKDRACKPA-RCCGP# (508)
    Nb3.2 (F582) ZK--CCTGK---KGSCSGKACKNL-KCCS# (509)
    Pr3.1 (Z500) RGG-CCTPP---KK-CKDRACKPA-RCCGP# (510)
    Pr3.2 (Z501) -RG-CCTPP---RK-CKDPACKPA-RCCGP# (511)
    R3.1 LOS-CCSLN---LRLCOVOACKRN-OCCT# (512)
    R3.2 ZQR-CCTVK----RICOVOACRSK-OCCKS{circumflex over ( )} (513)
    R3.3 RGG-CCTPP---RK-CKDPACKPA-RCCGP# (514)
    Sm3.1 ZK--CCTGK---KGSCSGKACKNL-KCCS# (515)
    T3.1 H-G-CCKGO---EG-CSSRECROQ--HCC# (516)
    T3.2 (Y088) H-G-CCEGP---KG-CSSRECRPQ-HCC# (517)
    Wi3.1 (M548) LPS-CCDFE----RLCVVPACIRH-QCCT# (518)
    Type 5
    Om3.2 CCKYGWTCLLGCTPCDC{circumflex over ( )} (519)
    Om3.4 CCRYGWTCWLGCTPCGC{circumflex over ( )} (520)
    Type 6
    S3.2 (F352) Z-NCCNGG-CSSKWCRDHARCC# (432)
    • Example 3 Effect of Intrathecal Administration of μ-Conopeptides
  • Male C57 black mice (20-25 g) are obtained from Charles River Laboratories. These mice and the animals are housed in a temperature controlled (23°±3° C.) room with a 12 hour light-dark cycle with free access to food and water. All animals are euthanized in accordance with Public Health Service policies on the humane care of laboratory animals. [0095]
  • Intrathecal (it) drug injections are performed as described (Hylden and Wilcox, 1980). A μ-conopeptide or vehicle is administered in a volume of 5 μl. Duration of hind-limb paralysis is assessed. This experiment reveals that injection of μ-conopeptides into the intrathecal space of C57 black mice produced a paralysis of the animal. The animals in this experiment recovered fully. [0096]
    • Example 4 Effect of μ-Conopeptides as a Local Anesthetic
  • Male Hartley guinea pigs (retired breeders) are obtained form Charles River Laboratories. The local anesthetic test is performed essentially as described (Bulbring and Wajda, 1945). On the day prior to test day, a patch on the back of the guinea pig is denuded of hair, first by shaving with electric clippers and subsequently with depilatory cream (Nair®). Depilatory cream is applied for five minutes and removed with a warm washcloth. The guinea pigs are dried and returned to their cages. On the following day, intradermal injections (0.1 ml vols) of lidocaine, bupivacaine, a μ-conopeptide or vehicle (0.5% cyclodextran) are made into the denuded patch. The injection produced a raised wheal on the surface of the skin which is circled with a felt-tipped pen. Typically, four injections are made on the back of each guinea pig. In some cases, guinea pigs are reused following at least one week of recovery and injecting into an unused portion of the skin. The stimulus consists of mild pin pricks (not hard enough to break the skin) with a 26G needle. The response is a localized skin twitch caused by contraction of cutaneous muscles. A unit test consisted of six uniform pin pricks, 3-5 seconds apart, within the injected area. Unit scores range from 0 (complete anesthesia) to 6 (no anesthesia). For potency experiments, the unit test is repeated at each site at five minute intervals for 30 minutes, and unit test scores summed (with 36 representing no anesthesia to 0 representing complete anesthesia. For duration experiments, unit tests are performed as described over the course of several hours to days. [0097]
  • μ-Conopeptides of the present invention produce a potent and long lasting local anesthetic effect in the intracutaneous wheal test in the guinea pig. As expected, bupivacaine has a slightly longer duration thatn lidocaine, consistent with clinical observations. [0098]
    • Example 5 Muscle Relaxant Effect of μ-Conopeptides in Anesthetized Monkeys
  • μ-Conopeptides are dissolved 0.9 percent saline at a concentration of 2 mg/ml. Rhesus monkeys are anesthetized with halothane, nitrous oxide and oxygen. The maintenance concentration of halothane is 1.0%. Arterial and venous catheters are placed in the femoral vessels for drug administration and recording of the arterial pressure. Controlled ventilation is accomplished via an endotrachael tube. Twitch and tetanic contractions of the tibialis arterior muscle are elicited indirectly via the sciatic nerve. Recordings of arterial pressure electrocardiogram (lead I), heart rate, and muscle function are made simultaneously. Four to six animals received each listed compound. Four additional animals received succinylcholine chloride or d-tubocurarine chloride as controls. It is seen that the tested μ-conopeptides generally provide similar or better results than those seen for succinylcholine chloride or d-tubocurarine chloride. [0099]
    • Example 6 In vivo Activity of μ-Conopeptides in Pain Models
  • The anti-pain activity of μ-conopeptides is shown in several animal models. These models include the nerve injury model (Chaplan, et al., 1997), the nocioceptive response to s.c. formalin injection in rats (Codene, 1993) and an NMDA-induced persistent pain model (Liu, et al., 1997). In each of these models it is seen that the μ-conopeptides and μ-conopeptides derivatives have analgesic properties. [0100]
  • More specifically, this study evaluates the effect of intrathecal administration of μ-conopeptides in mice models of nocioceptive and neuropathic pain. For nocioceptive pain, the effect of the μ-conopeptides is studied in two different tests of inflammatory pain. The first is the formalin test, ideal because it produces a relatively short-lived, but reliable pain behavior that is readily quantified. There are two phases of pain behavior, the second of which is presumed to result largely from formalin-evoked inflammation of the hind paw. A μ-conopeptide is administered 10 minutes prior to injection of formalin. The number of flinches and/or the duration of licking produced by the injection is monitored. Since the first phase is presumed to be due to direct activation of primary afferents, and thus less dependent on long term changes in the spinal cord, μ-conopeptides are presumed to have greatest effect on the magnitude of pain behavior in the second phase. [0101]
  • The mechanical and thermal thresholds in animals that received an injection of complete Freund's adjuvant into the hind paw are also studied. This produces a localized inflammation including swelling of the hind paw and a profound decrease in mechanical and thermal thresholds, that are detected within 24 hours after injection. The changes in thresholds in rats that receive μ-conopeptides are compared with those of rats that receive vehicle intrathecal injections. [0102]
  • An important issue is whether the drugs are effective when administered after the pain model has been established, or whether they are effective only if used as a pretreatment. Clearly, the clinical need is for drugs that are effective after the pain has developed. To address this issue, animals are studied in which μ-conopeptides are administered repeatedly, after the inflammation (CFA) or nerve injury has been established. In these experiments, a μ-conopeptide is injected daily by the intrathecal (i.t.) route. The mechanical and thermal thresholds (measured, respectively, with von Frey hairs in freely moving animals and with the Hargreave's test, also in freely moving animals) are repeated for a 2 to 4 week period after the injury is induced and the changes in pain measured monitored over time. [0103]
    • Example 7 Effect of μ-Conotoxins in a Pain Model
  • Analgesic activity of μ-conotoxins is also tested in pain models as follows. [0104]
  • Persistent pain (formalin test). Intrathecal (it) drug injections are performed as described by Hylden and Wilcox (1980). An μ-conopeptide or vehicle is administered in a volume of 5 μl. Fifteen minutes after the i.t. injection, the right hindpaw is injected with 20 μl of 5% formalin. Animals are placed in clear plexiglass cylinders backed by mirrors to facilitate observation. Animals are closely observed for 2 minutes per 5 minute period, and the amount of time the animal spent licking the injected paw is recorded in this manner for a total of 45-50 minutes. Results are expressed as licking time in seconds per five minutes. At the end of the experiment, all animals are placed on an accelerating rotorod and the latency to first fall was recorded. μ-Conopeptides are found to be active in this model which is predictive of efficacy for treating neuropathic pain. [0105]
  • Acute pain (tail-flick). A μ-conopeptide or saline is administered intrathecally (i.t.) according to the method of Hylden and Wilcox (1980) in a constant volume of 5 μl. Mice are gently wrapped in a towel with the tail exposed. At various time-points following the i.t. injection, the tail is dipped in a water bath maintained at 54° C. and the time to a vigorous tail withdrawal is recorded. If there is no withdrawal by 8 seconds, the tail is removed to avoid tissue damage. [0106]
  • Neuropathic pain. The partial sciatic nerve ligation model is used to assess the efficacy of μ-conopeptides in neuropathic pain. Nerve injury is produced according to the methods of Malmberg and Basbaum (1998). Animals are anesthetized with a ketamine/xylazine solution, the sciatic nerve is exposed and tightly ligated with 8-0 silk suture around ⅓ to ½ of the nerve. In sham-operated mice the nerve is exposed, but not ligated. Animals are allowed to recover for at least 1 week before testing is performed. On the testing day, mice are placed in plexiglass cylinders on a wire mesh frame and allowed to habituate for at least 60 minutes. Mechanical allodynia is assessed with calibrated von Frey filaments using the up-down method as described by Chaplan et al. (1994), and the 50% withdrawal threshold is calculated. Animals that did not respond to any of the filaments in the series are assigned a maximal value of 3.6 grams, which is the filament that typically lifted the hindlimb without bending, and corresponds to approximately {fraction (1/10)} the animal's body weight. [0107]
  • The data obtained demonstrate that μ-conopeptides have potent analgesic properties in three commonly used models of pain: acute, persistent/inflammatory and neuropathic pain models. [0108]
    • Example 8 Activity of μ-Conopeptide S3.2 on Neuronal Sodium Channels
  • μ-Conopeptide S3.2 was tested for activity on sodium channels as follows. S3.2 was administered to mice by intracerbroventricular (ICV) injection. Administration of S3.2 in this manner caused mice to show a spectrum of activity that is charcteristic of all sodium channel blockers, including rapid loss of righting reflex, coma-like inactivity and spastic uncontrolled limb movement. Following intrathecal (it) administration to mice, S3.2 causes rapid hindlimb paralysis that spreads to include the entire body over a course of 10-20 minutes followed by death, presumably due to respiratory paralysis. However, unlike classic μ-conopeptides, S3.2 has no significant activity following intravenous administration (iv) to mice. Classic μ-conopeptides, such as GIIIA and PIIIA, cause rapid paralysis and death following iv administration, indicating their activity at skeletal muscle sodium channels. To confirm the selectivity of S3.2, 80 nmol was administered iv to rats. The effect of S3.2 was measured on skeletal muscle contraction, blood pressure and heart rate. S3.2 was found to have no effect on any of these parameters. Controls were performed using classical μ-conopeptides, including Sm3.1, Sm3.3 and Bu3.1 described herein, also administered iv at 80 nmol. These control peptides caused a dramatic decrease in skeletal muscle contractility, as well as a significant drop in systemic blood pressure. Thus, μ-conopeptide S3.2 suprisingly is selective for neuronal sodium channels. The most obvious difference between the S3.2 sequence and the sequences of these other peptides is a shortened first loop (the first loop between cysteine residues) which lacks a charged amino acid. [0109]
  • It will be appreciated that the methods and compositions of the instant invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent to the artisan that other embodiments exist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive. [0110]
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  • 1 520 1 280 DNA Conus arentus 1 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttcttga ccatctgtat 60 gcttctgttt ccccttactg ctcttccgct ggatggggat caacctgcag accgacctgc 120 agagcgtatg caggacgact ttataactga gcatcatccc ctgtttgatc ctgtcaaacg 180 gtgttgcgag aggccatgca acataggatg cgtaccttgt tgttaatgac cagctttgtc 240 atcgcggcct catcaagcga ataagtaaaa cgattgcagt 280 2 67 PRT Conus arentus 2 Met Met Ser Lys Leu Gly Val Phe Leu Thr Ile Cys Met Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Phe Ile Thr Glu His His Pro Leu Phe 35 40 45 Asp Pro Val Lys Arg Cys Cys Glu Arg Pro Cys Asn Ile Gly Cys Val 50 55 60 Pro Cys Cys 65 3 14 PRT Conus arentus PEPTIDE (1)..(14) Xaa at residue 3 is Glu or gamma-carboxy Glu; Xaa at residue 5 and 12 is Pro or Hyp 3 Cys Cys Xaa Arg Xaa Cys Asn Ile Gly Cys Val Xaa Cys Cys 1 5 10 4 244 DNA Conus atlanticus 4 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttccactt 60 actgctcttc cgctggatga agatcaaccg gtacaccgac ctgcagagcg tatgcaggac 120 atttcatctg atcaacatct cttctttgat ctcatcaaac ggtgctgcga gttgccatgc 180 gggccaggct tttgcgtccc ttgttgctga catcaataac gtgttgatga ccaactttct 240 cgag 244 5 69 PRT Conus atlanticus 5 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Pro Leu Asp Glu Asp Gln Pro Val His 20 25 30 Arg Pro Ala Glu Arg Met Gln Asp Ile Ser Ser Asp Gln His Leu Phe 35 40 45 Phe Asp Leu Ile Lys Arg Cys Cys Glu Leu Pro Cys Gly Pro Gly Phe 50 55 60 Cys Val Pro Cys Cys 65 6 15 PRT Conus atlanticus PEPTIDE (1)..(15) Xaa at residue 3 is Glu or gamma-carboxy Glu; Xaa at residue 5, 8 and 13 is Pro or Hyp 6 Cys Cys Xaa Leu Xaa Cys Gly Xaa Gly Phe Cys Val Xaa Cys Cys 1 5 10 15 7 310 DNA Conus aurisiacus 7 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgttt 60 gcttctgttt ccccttactg ctcttccgat ggatggagat caatctgtag accgacctga 120 agagcgtatg caggacgaca tttcatctga gcagcatccc ttgtttaatc agaaaagaat 180 gtgttgcggc gaaggccgga aatgccccag ctatttcaga aacagtcaga tttgtcattg 240 ttgttaaatg acaacgtgtc gatgaccaac ttcgttatca cgactaatga ataagtaaaa 300 cgattgcagt 310 8 74 PRT Conus aurisiacus 8 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Ser Val Asp Arg Pro 20 25 30 Glu Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Gln His Pro Leu Phe 35 40 45 Asn Gln Lys Arg Met Cys Cys Gly Glu Gly Arg Lys Cys Pro Ser Tyr 50 55 60 Phe Arg Asn Ser Gln Ile Cys His Cys Cys 65 70 9 22 PRT Conus aurisiacus PEPTIDE (1)..(22) Xaa at residue 5 is Glu or gamma-carboxy Glu; Xaa at residue 10 is Pro or Hyp; Xaa at residue 12 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho- Tyr 9 Met Cys Cys Gly Xaa Gly Arg Lys Cys Xaa Ser Xaa Phe Arg Asn Ser 1 5 10 15 Gln Ile Cys His Cys Cys 20 10 257 DNA Conus aurisiacus 10 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtttgcttct gtttcccctt 60 actgctcttc cgatcgatgg agatcaatct gtagaccgac ctgcagagcg tatgcaggat 120 gacatttcat ctgagcagca tcgcttgttc aatcagaaaa gaaggtgctg ccggtggcca 180 tgcccccgac aaatcgacgg tgaatattgt ggctgttgcc ttggatgata accgtgttga 240 tgaccaactt tctcgag 257 11 75 PRT Conus aurisiacus 11 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Pro Ile Asp Gly Asp Gln Ser Val Asp 20 25 30 Arg Pro Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Gln His Arg 35 40 45 Leu Phe Asn Gln Lys Arg Arg Cys Cys Arg Trp Pro Cys Pro Arg Gln 50 55 60 Ile Asp Gly Glu Tyr Cys Gly Cys Cys Leu Gly 65 70 75 12 19 PRT Conus aurisiacus PEPTIDE (1)..(19) Xaa at residue 13 is Glu or gamma-carboxy Glu; Xaa at residue 5 and 7 is Pro or Hyp; Xaa at residue 4 is Trp or Bromo Trp; Xaa at residue 14 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 12 Cys Cys Arg Xaa Xaa Cys Xaa Arg Gln Ile Asp Gly Xaa Xaa Cys Gly 1 5 10 15 Cys Cys Leu 13 262 DNA Conus aurisiacus 13 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctacttct gtttcccctt 60 actgcttttc cgatggatgg agatcaacct gcagaccaac ctgcagatcg tatgcaggac 120 gacatttcat ctgagcagta tcccttgttt gataagagac aaaagtgttg cactgggaag 180 aaggggtcat gctccggcaa agcatgcaaa aatctcaaat gttgctctgg acgataacgt 240 gttgatgacc aactttctcg ag 262 14 78 PRT Conus aurisiacus 14 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Phe Pro Met Asp Gly Asp Gln Pro Ala Asp 20 25 30 Gln Pro Ala Asp Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Tyr Pro 35 40 45 Leu Phe Asp Lys Arg Gln Lys Cys Cys Thr Gly Lys Lys Gly Ser Cys 50 55 60 Ser Gly Lys Ala Cys Lys Asn Leu Lys Cys Cys Ser Gly Arg 65 70 75 15 23 PRT Conus aurisiacus PEPTIDE (1)..(23) Xaa at residue 1 is Gln or pyro-Glu 15 Xaa Lys Cys Cys Thr Gly Lys Lys Gly Ser Cys Ser Gly Lys Ala Cys 1 5 10 15 Lys Asn Leu Lys Cys Cys Ser 20 16 232 DNA Conus aurisiacus 16 ggatccatga tgtctaaact gggagtcttg ctgaccatct gtctgcttct gtttccactt 60 actgctgttc cgctggatgg agatcaacct ctagaccgac acgcggagcg tatgcatgat 120 ggcatttcac ctaaacgcca tccctggttt gatcccgtca aacggtgttg caaggtgcaa 180 tgcgagtctt gcaccccttg ttgctaacgt gttgatgacc aactttctcg ag 232 17 68 PRT Conus aurisiacus 17 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Leu Asp 20 25 30 Arg His Ala Glu Arg Met His Asp Gly Ile Ser Pro Lys Arg His Pro 35 40 45 Trp Phe Asp Pro Val Lys Arg Cys Cys Lys Val Gln Cys Glu Ser Cys 50 55 60 Thr Pro Cys Cys 65 18 13 PRT Conus aurisiacus PEPTIDE (1)..(13) Xaa at residue 7 is Glu or gamma-carboxy Glu; Xaa at residue 11 is Pro or Hyp 18 Cys Cys Lys Val Gln Cys Xaa Ser Cys Thr Xaa Cys Cys 1 5 10 19 241 DNA Conus bandus 19 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtatgcttct gtttcccctc 60 actgctcttc cgatggatgg agatcaacct gcagaccgac ctgcagagcg tagtcaggac 120 gtttcatctg aacagcatcc cttgtttgat cccgtcaaac ggtgttgcaa ctggccatgc 180 tccatgggat gcatcccttg ttgctactat taataacgtg ttgatgacca actttctcga 240 g 241 20 70 PRT Conus bandus 20 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Met Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp 20 25 30 Arg Pro Ala Glu Arg Ser Gln Asp Val Ser Ser Glu Gln His Pro Leu 35 40 45 Phe Asp Pro Val Lys Arg Cys Cys Asn Trp Pro Cys Ser Met Gly Cys 50 55 60 Ile Pro Cys Cys Tyr Tyr 65 70 21 16 PRT Conus bandus PEPTIDE (1)..(16) Xaa at residue 5 and 12 is Pro or Hyp; Xaa at residue 4 is Trp or bromo-Trp; Xaa at residue 15 and 16 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho- Tyr 21 Cys Cys Asn Xaa Xaa Cys Ser Met Gly Cys Ile Xaa Cys Cys Xaa Xaa 1 5 10 15 22 298 DNA Conus betulinus 22 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccttctgtct 60 gcttctgttt cccctgactg ctcttccgct ggatgaagat caacctgcag accgacctgc 120 agagcgtatg caggacattt catctgaaca gcatcccttg tttgatcccg tcaaacggtg 180 ttgcgaattg ccatgccatg gatgcgtccc ttgttgctgg ccttaataac gtgtggatga 240 ccaactgtgt tatcacggcc acgtcaagtg tctaatgaat aagtaaaatg attgcagt 298 23 67 PRT Conus betulinus 23 Met Met Ser Lys Leu Gly Val Leu Leu Thr Phe Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Glu Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Ile Ser Ser Glu Gln His Pro Leu Phe Asp 35 40 45 Pro Val Lys Arg Cys Cys Glu Leu Pro Cys His Gly Cys Val Pro Cys 50 55 60 Cys Trp Pro 65 24 15 PRT Conus betulinus PEPTIDE (1)..(15) Xaa at residue 3 is Glu or gamma-carboxy Glu; Xaa at residue 5, 11 and 15 is Pro or Hyp; Xaa at residue 14 is Trp or bromo-Trp 24 Cys Cys Xaa Leu Xaa Cys His Gly Cys Val Xaa Cys Cys Xaa Xaa 1 5 10 15 25 298 DNA Conus betulinus 25 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccttctgtct 60 gcttctgttt cccctgactg ctcttccgct ggatgaagat caacctgcag accgacatgc 120 agagcgtatg caggacattt cacctgaaca gcatccctcg tttgatcccg tcaaacggtg 180 ttgcgggctg ccatgcaatg gatgcgtccc ttgttgctgg ccttcataac gtgtggacga 240 ccaactttgt tatcacggcc acgtcaagtg tctgatgaat aagtaaaacg attgcagt 298 26 68 PRT Conus betulinus 26 Met Met Ser Lys Leu Gly Val Leu Leu Thr Phe Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Glu Asp Gln Pro Ala Asp Arg His 20 25 30 Ala Glu Arg Met Gln Asp Ile Ser Pro Glu Gln His Pro Ser Phe Asp 35 40 45 Pro Val Lys Arg Cys Cys Gly Leu Pro Cys Asn Gly Cys Val Pro Cys 50 55 60 Cys Trp Pro Ser 65 27 16 PRT Conus betulinus PEPTIDE (1)..(16) Xaa at residue 5, 11 and 15 is Pro or Hyp; Xaa at residue 14 is Trp or bromo-Trp 27 Cys Cys Gly Leu Xaa Cys Asn Gly Cys Val Xaa Cys Cys Xaa Xaa Ser 1 5 10 15 28 282 DNA Conus betulinus 28 caagagggat cgatagcagt tcatgatgtt taaactggga gtcttgttga ccatctatat 60 gcttctgttt ccctttactg ctcttccgct ggatggagat caacctgcag accaacctct 120 agagcgcatg cagtatgaca tgttacgtgc agtgaatccc tggtttgatc ccgtcaaaag 180 gtgctgctcg aggaactgcg cagtatgcat cccttgttgc ccgaattggc cagcttgatt 240 atcgcggcca agagtctaat gaataagtaa aacgattgca gt 282 29 71 PRT Conus betulinus 29 Met Met Phe Lys Leu Gly Val Leu Leu Thr Ile Tyr Met Leu Leu Phe 1 5 10 15 Pro Phe Thr Ala Leu Pro Leu Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Leu Glu Arg Met Gln Tyr Asp Met Leu Arg Ala Val Asn Pro Trp Phe 35 40 45 Asp Pro Val Lys Arg Cys Cys Ser Arg Asn Cys Ala Val Cys Ile Pro 50 55 60 Cys Cys Pro Asn Trp Pro Ala 65 70 30 18 PRT Conus betulinus PEPTIDE (1)..(18) Xaa at residue 11, 14 and 17 is Pro or Hyp; Xaa at residue 16 is Trp or bromo-Trp 30 Cys Cys Ser Arg Asn Cys Ala Val Cys Ile Xaa Cys Cys Xaa Asn Xaa 1 5 10 15 Xaa Ala 31 325 DNA Conus bullatus 31 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt cccctttttg ctcttccgca ggatggagat caacctgcag accgacctgc 120 agagcgtatg caggacgaca tttcatctga gcagaattcc ttgcttgaga agagagttac 180 tgacaggtgc tgcaaaggga agagggaatg cggcagatgg tgcagagatc actcgcgttg 240 ttgcggtcga cgataagctg ttgatgacca gctttgttat cacggctaca tcaagtgtct 300 agtgaataag taaaatgatt gcagt 325 32 77 PRT Conus bullatus 32 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Phe Ala Leu Pro Gln Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Asn Ser Leu Leu 35 40 45 Glu Lys Arg Val Thr Asp Arg Cys Cys Lys Gly Lys Arg Glu Cys Gly 50 55 60 Arg Trp Cys Arg Asp His Ser Arg Cys Cys Gly Arg Arg 65 70 75 33 23 PRT Conus bullatus PEPTIDE (1)..(23) Xaa at residue 11 is Glu or gamma-carboxy Glu; Xaa at residue 15 is Trp or bromo-Trp 33 Val Thr Asp Arg Cys Cys Lys Gly Lys Arg Xaa Cys Gly Arg Xaa Cys 1 5 10 15 Arg Asp His Ser Arg Cys Cys 20 34 326 DNA Conus bullatus 34 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt cccctttttg ctcttcggca ggatggagat caacctgcag accgacctgc 120 agagcgtatg caggatgaca tttcatctga gcagaatccc ttgcttgaga agagagttgg 180 tgacaggtgc tgcaaaggga agagggggtg cggcagatgg tgcagagatc actcacgttg 240 ttgcggtcga cgataacgtg ttgatgacca gctttgttat cacggctaca tcaagtgtct 300 tagtgattaa gtaaaacgat tgcagt 326 35 77 PRT Conus bullatus 35 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Phe Ala Leu Arg Gln Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Asn Pro Leu Leu 35 40 45 Glu Lys Arg Val Gly Asp Arg Cys Cys Lys Gly Lys Arg Gly Cys Gly 50 55 60 Arg Trp Cys Arg Asp His Ser Arg Cys Cys Gly Arg Arg 65 70 75 36 23 PRT Conus bullatus PEPTIDE (1)..(23) Xaa at residue 15 is Trp or bromo-Trp 36 Val Gly Asp Arg Cys Cys Lys Gly Lys Arg Gly Cys Gly Arg Xaa Cys 1 5 10 15 Arg Asp His Ser Arg Cys Cys 20 37 331 DNA Conus bullatus 37 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt cccctttttg ctcttccgca ggatggagat caacctgcag accgacctgc 120 agagcgtatg caggacgaca tttcatctga gcagaatccc ttgcttgaga agagagttgg 180 tgaaaggtgc tgcaaaaacg ggaagagggg gtgcggcaga tggtgcagag atcactcacg 240 ttgttgcggt cgacgataac gtgttgatga ccgaggcttt cgttatcacg gctacatcaa 300 gtgtctagtg aataagtaaa acgattgcag t 331 38 78 PRT Conus bullatus 38 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Phe Ala Leu Pro Gln Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Asn Pro Leu Leu 35 40 45 Glu Lys Arg Val Gly Glu Arg Cys Cys Lys Asn Gly Lys Arg Gly Cys 50 55 60 Gly Arg Trp Cys Arg Asp His Ser Arg Cys Cys Gly Arg Arg 65 70 75 39 24 PRT Conus bullatus PEPTIDE (1)..(24) Xaa at residue 3 is Glu or gamma-carboxy Glu; Xaa at residue 16 is Trp or bromo-Trp 39 Val Gly Xaa Arg Cys Cys Lys Asn Gly Lys Arg Gly Cys Gly Arg Xaa 1 5 10 15 Cys Arg Asp His Ser Arg Cys Cys 20 40 337 DNA Conus bullatus 40 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt cccctttttg ctcttccgca ggacggagat caacctgcag accgacctgc 120 agagcgtatg caggacgacc tttcatctga gcagcatccc ttgtttgaga agagaattgt 180 tgacaggtgc tgcaacaaag ggaacgggaa gagggggtgc agcagatggt gcagagatca 240 ctcacgttgt tgcggtcgac gatgaactgt tgatgaccga ggctttggtt atcacggcta 300 catcaagtgt ctagtgaata agtaaaacga ttgcagt 337 41 80 PRT Conus bullatus 41 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Phe Ala Leu Pro Gln Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Leu Ser Ser Glu Gln His Pro Leu Phe 35 40 45 Glu Lys Arg Ile Val Asp Arg Cys Cys Asn Lys Gly Asn Gly Lys Arg 50 55 60 Gly Cys Ser Arg Trp Cys Arg Asp His Ser Arg Cys Cys Gly Arg Arg 65 70 75 80 42 26 PRT Conus bullatus PEPTIDE (1)..(26) Xaa at residue 18 is Trp or bromo-Trp 42 Ile Val Asp Arg Cys Cys Asn Lys Gly Asn Gly Lys Arg Gly Cys Ser 1 5 10 15 Arg Xaa Cys Arg Asp His Ser Arg Cys Cys 20 25 43 337 DNA Conus bullatus 43 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt cccctttttg ctcttccgca ggatggagat caacctgcag accgacctgc 120 tgagcgtatg caggacgaca tttcatctga gcggaatccc ttgtttgaga agagcgttgg 180 tttatattgc tgccgaccca aacccaacgg gcagatgatg tgcgacagat ggtgcgaaaa 240 aaactcacgt tgttgcggtc gacgataatg tgttgatgac cagctttgtt atcaaggcta 300 catcaagtat ctagtgaata agtaaaacga ttgcagt 337 44 77 PRT Conus bullatus 44 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Phe Ala Leu Pro Gln Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Asn Pro Leu Phe Glu Lys 35 40 45 Ser Val Gly Cys Cys Arg Pro Lys Pro Asn Gly Gln Met Met Cys Asp 50 55 60 Arg Trp Cys Glu Lys Asn Ser Arg Cys Cys Gly Arg Arg 65 70 75 45 27 PRT Conus bullatus PEPTIDE (1)..(27) Xaa at residue 21 is Glu or gamma-carboxy Glu; Xaa at residue 8 and 10 is Pro or Hyp; Xaa at residue 19 is Trp or bromo-Trp; Xaa at residue 4 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 45 Val Gly Leu Xaa Cys Cys Arg Xaa Lys Xaa Asn Gly Gln Met Met Cys 1 5 10 15 Asp Arg Xaa Cys Xaa Lys Asn Ser Arg Cys Cys 20 25 46 323 DNA Conus bullatus 46 caagaaggat cgatagcagt tcatgatgtc taaactggga gttttgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccgat ggatggagat caatctgtag accgacctgc 120 agaacgtatg caggacgacc tttcatctga gcagcatccc ttgtttgttc agaaaagaag 180 gtgttgcggc gaaggcttga catgccccag atattggaaa aacagtcaga tttgtgcttg 240 ttgttaaatg acaacgtgtc gatgaccaac ttcggtatca cgactacgcc aagtgtctaa 300 tgaataagta aaacgattgc agt 323 47 74 PRT Conus bullatus 47 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Ser Val Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Leu Ser Ser Glu Gln His Pro Leu Phe 35 40 45 Val Gln Lys Arg Arg Cys Cys Gly Glu Gly Leu Thr Cys Pro Arg Tyr 50 55 60 Trp Lys Asn Ser Gln Ile Cys Ala Cys Cys 65 70 48 22 PRT Conus bullatus PEPTIDE (1)..(22) Xaa at residue 5 is Glu or gamma-carboxy Glu; Xaa at residue 10 is Pro or Hyp; Xaa at residue 13 is Trp or bromo-Trp; Xaa at residue 12 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 48 Arg Cys Cys Gly Xaa Gly Leu Thr Cys Xaa Arg Xaa Xaa Lys Asn Ser 1 5 10 15 Gln Ile Cys Ala Cys Cys 20 49 322 DNA Conus bullatus 49 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt cccctttttg ctcttccgca ggatggagat caacctgcag accgacctgc 120 tgagcgtatg caggacgaca tttcatctga gcaggatccc ttgtttgttc agaaaagaag 180 gtgttgcggc gaaggcttga catgccccag atattggaaa aacagtcaga tttgtgcttg 240 ttgttaaatg acaacgtgtg atgaccaact tcggtatcac gactacgcca agtgtctaat 300 gaataagtaa aacgattgca gt 322 50 74 PRT Conus bullatus 50 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Phe Ala Leu Pro Gln Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Asp Pro Leu Phe 35 40 45 Val Gln Lys Arg Arg Cys Cys Gly Glu Gly Leu Thr Cys Pro Arg Tyr 50 55 60 Trp Lys Asn Ser Gln Ile Cys Ala Cys Cys 65 70 51 22 PRT Conus bullatus PEPTIDE (1)..(22) Xaa at residue 5 is Glu or gamma-carboxy Glu; Xaa at residue 10 is Pro or Hyp; Xaa at residue 13 is Trp or bromo-Trp; Xaa at residue 12 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 51 Arg Cys Cys Gly Xaa Gly Leu Thr Cys Xaa Arg Xaa Xaa Lys Asn Ser 1 5 10 15 Gln Ile Cys Ala Cys Cys 20 52 238 DNA Conus capitaneus 52 ggatccatga tgtctaaact gggagtcttg gtgaccatct gcctgcttct gtttcccctt 60 gctgcttttc cactggatgg aaatcaacct gcagaccacc ctgcaaagcg tacgcaagat 120 gacagttcag ctgccctgat caatacctgg attgatcatt cccattcttg ctgcagggac 180 tgcggtgaag attgtgttgg ttgttgccgg taacgtgttg atgaccaact ttctcgag 238 53 70 PRT Conus capitaneus 53 Gly Ser Met Met Ser Lys Leu Gly Val Leu Val Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Ala Ala Phe Pro Leu Asp Gly Asn Gln Pro Ala Asp 20 25 30 His Pro Ala Lys Arg Thr Gln Asp Asp Ser Ser Ala Ala Leu Ile Asn 35 40 45 Thr Trp Ile Asp His Ser His Ser Cys Cys Arg Asp Cys Gly Glu Asp 50 55 60 Cys Val Gly Cys Cys Arg 65 70 54 15 PRT Conus capitaneus PEPTIDE (1)..(15) Xaa at residue 8 is Glu or gamma-carboxy Glu 54 Ser Cys Cys Arg Asp Cys Gly Xaa Asp Cys Val Gly Cys Cys Arg 1 5 10 15 55 323 DNA Conus caracteristicus 55 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccaat ggatggagat caacctgcag accaacctgc 120 agatcgtatg caggacgaca tttcatctga gcagtatccc ttgtttgata tgagaaaaag 180 gtgttgcggc cccggcggtt catgccccgt atatttcaga gacaatttta tttgtggttg 240 ttgttaaatg acaacgtgtc gatgaccaac ttcattatca cgactacgcc aagtgtctaa 300 tgaataagta aaatgattgc agt 323 56 74 PRT Conus caracteristicus 56 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Asp Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Tyr Pro Leu Phe 35 40 45 Asp Met Arg Lys Arg Cys Cys Gly Pro Gly Gly Ser Cys Pro Val Tyr 50 55 60 Phe Arg Asp Asn Phe Ile Cys Gly Cys Cys 65 70 57 21 PRT Conus caracteristicus PEPTIDE (1)..(21) Xaa at residue 4 and 9 is Pro or Hyp; Xaa at residue 11 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 57 Cys Cys Gly Xaa Gly Gly Ser Cys Xaa Val Xaa Phe Arg Asp Asn Phe 1 5 10 15 Ile Cys Gly Cys Cys 20 58 316 DNA Conus caracteristicus 58 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccgat ggatggagat gaacctgcaa accgacctgt 120 cgagcgtatg caggacaaca tttcatctga gcagtatccc ttgtttgaga agagacgaga 180 ttgttgcact ccgccgaaga aatgcaaaga ccgacaatgc aaaccccaga gatgttgcgc 240 tggacgataa cgtgttgatg accaacttta tcacggctac gtcaagtgtt tagtgaataa 300 gtaaaatgat tgcagt 316 59 75 PRT Conus caracteristicus 59 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Glu Pro Ala Asn Arg Pro 20 25 30 Val Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln Tyr Pro Leu Phe 35 40 45 Glu Lys Arg Arg Asp Cys Cys Thr Pro Pro Lys Lys Cys Lys Asp Arg 50 55 60 Gln Cys Lys Pro Gln Arg Cys Cys Ala Gly Arg 65 70 75 60 22 PRT Conus caracteristicus PEPTIDE (1)..(22) Xaa at residue 6, 7 and 17 is Pro or Hyp 60 Arg Asp Cys Cys Thr Xaa Xaa Lys Lys Cys Lys Asp Arg Gln Cys Lys 1 5 10 15 Xaa Gln Arg Cys Cys Ala 20 61 314 DNA Conus caracteristicus 61 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccact ggatggagat caacctgcag atcaatctgc 120 agagcgacct gcagagcgta cgcaggacga cattcagcag catccgttat atgatccgaa 180 aagaaggtgt tgccgttatc catgccccga cagctgccac ggatcttgct gctataagtg 240 ataacatgtt gatggccagc tttgttatca cggccacgtc aagtgtctta atgaataagt 300 aaaacgattg cagt 314 62 72 PRT Conus caracteristicus 62 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Gly Asp Gln Pro Ala Asp Gln Ser 20 25 30 Ala Glu Arg Pro Ala Glu Arg Thr Gln Asp Asp Ile Gln Gln His Pro 35 40 45 Leu Tyr Asp Pro Lys Arg Arg Cys Cys Arg Tyr Pro Cys Pro Asp Ser 50 55 60 Cys His Gly Ser Cys Cys Tyr Lys 65 70 63 18 PRT Conus caracteristicus PEPTIDE (1)..(18) Xaa at residue 6 and 8 is Pro or Hyp; Xaa at residue 5 and 17 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 63 Arg Cys Cys Arg Xaa Xaa Cys Xaa Asp Ser Cys His Gly Ser Cys Cys 1 5 10 15 Xaa Lys 64 292 DNA Conus caracteristicus 64 caagagggat cgatagcagt tcatgatgtc taaactggga gccttgttga ccatctgtct 60 acttctgttt tcccttactg ctgttccgct ggatggagat caacatgcag accaacctgc 120 acagcgtctg caggaccgca ttccaactga agatcatccc ttatttgatc ccaacaaacg 180 gtgttgcccg ccggtggcat gcaacatggg atgcaagcct tgttgtggat gaccagcttt 240 gttatcgcgg tcttcatgaa gtgtcttaat gaataagtaa aatgattgca gt 292 65 69 PRT Conus caracteristicus 65 Met Met Ser Lys Leu Gly Ala Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Gln Arg Leu Gln Asp Arg Ile Pro Thr Glu Asp His Pro Leu Phe 35 40 45 Asp Pro Asn Lys Arg Cys Cys Pro Pro Val Ala Cys Asn Met Gly Cys 50 55 60 Lys Pro Cys Cys Gly 65 66 15 PRT Conus caracteristicus PEPTIDE (1)..(15) Xaa at residue 3, 4 and 13 is Pro or Hyp 66 Cys Cys Xaa Xaa Val Ala Cys Asn Met Gly Cys Lys Xaa Cys Cys 1 5 10 15 67 293 DNA Conus caracteristicus 67 caagagggat cgatagcagt tcatgatgtc taaactggga gccttgttga ccatctgtct 60 acttctgttt tccctaactg ctgttccgct ggatggagat caacatgcag accaacctgc 120 agagcgtctg catgaccgcc ttccaactga aaatcatccc ttatatgatc ccgtcaaacg 180 gtgttgcgat gattcggaat gcgactattc ttgctggcct tgctgtatgt ttggataacc 240 tttgttatcg cggcctcatc aagtgtctaa tgaataagta aaacgattgc agt 293 68 71 PRT Conus caracteristicus 68 Met Met Ser Lys Leu Gly Ala Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu His Asp Arg Leu Pro Thr Glu Asn His Pro Leu Tyr 35 40 45 Asp Pro Val Lys Arg Cys Cys Asp Asp Ser Glu Cys Asp Tyr Ser Cys 50 55 60 Trp Pro Cys Cys Met Phe Gly 65 70 69 17 PRT Conus caracteristicus PEPTIDE (1)..(17) Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 13 is Pro or Hyp; Xaa at residue 12 is Trp or bromo-Trp; Xaa at residue 9 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 69 Cys Cys Asp Asp Ser Xaa Cys Asp Xaa Ser Cys Xaa Xaa Cys Cys Met 1 5 10 15 Phe 70 232 DNA Conus caracteristicus 70 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctgttc cgctggatgg agatcaacct gcagaccgac ctgcagagcg taagcaggac 120 gtttcatctg aacagcatcc cttctttgat cccgtcaaac ggtgttgccg ccggtgttac 180 atgggatgca tcccttgttg cttttaacgt gttgatgacc aactttctcg ag 232 71 68 PRT Conus caracteristicus 71 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp 20 25 30 Arg Pro Ala Glu Arg Lys Gln Asp Val Ser Ser Glu Gln His Pro Phe 35 40 45 Phe Asp Pro Val Lys Arg Cys Cys Arg Arg Cys Tyr Met Gly Cys Ile 50 55 60 Pro Cys Cys Phe 65 72 14 PRT Conus caracteristicus PEPTIDE (1)..(14) Xaa at residue 11 is Pro or Hyp; Xaa at residue 6 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 72 Cys Cys Arg Arg Cys Xaa Met Gly Cys Ile Xaa Cys Cys Phe 1 5 10 73 323 DNA Conus circumcisus 73 caagaaggat cgatagcagt tcatgatgtc taaactgggg gtattgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccaat ggatggagat caacctgcag accaacctgc 120 agatcgtatg caggacgaca tttcatctga gcagtatccc ttgtttgata agagacgaaa 180 gtgttgcggc aaagacgggc catgccccaa atatttcaaa gacaatttta tttgtggttg 240 ttgttaaatg acaacgtgtc gatgaccaac ttcgttatca cgattcgcca agtgtcttaa 300 tgaataagta aaatgattgc agt 323 74 74 PRT Conus circumcisus 74 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Asp Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Tyr Pro Leu Phe 35 40 45 Asp Lys Arg Arg Lys Cys Cys Gly Lys Asp Gly Pro Cys Pro Lys Tyr 50 55 60 Phe Lys Asp Asn Phe Ile Cys Gly Cys Cys 65 70 75 23 PRT Conus circumcisus PEPTIDE (1)..(23) Xaa at residue 9 and 11 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 75 Arg Lys Cys Cys Gly Lys Asp Gly Xaa Cys Xaa Lys Xaa Phe Lys Asp 1 5 10 15 Asn Phe Ile Cys Gly Cys Cys 20 76 293 DNA Conus dalli 76 caagagggat cgatagcagt tcatgatgtc taaactggga gccttgttga ccatctgtct 60 acttctgttt tccctaactg ctgttccgct ggatggagat caacatgcag accaacctgc 120 agagcgtctg caggaccgcc ttccaactga aaatcatccc ttatatgatc ccgtcaaacg 180 gtgttgcgat gattcggaat gcgactattc ttgctggcct tgctgtattt tatcataacc 240 tttgttatcg cggcctcatc aagtgtcaaa tgaataagta aaatgattgc agt 293 77 71 PRT Conus dalli 77 Met Met Ser Lys Leu Gly Ala Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Gln Asp Arg Leu Pro Thr Glu Asn His Pro Leu Tyr 35 40 45 Asp Pro Val Lys Arg Cys Cys Asp Asp Ser Glu Cys Asp Tyr Ser Cys 50 55 60 Trp Pro Cys Cys Ile Leu Ser 65 70 78 18 PRT Conus dalli PEPTIDE (1)..(18) Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 13 is Pro or Hyp; Xaa at residue 12 is Trp or bromo-Trp; Xaa at residue 9 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 78 Cys Cys Asp Asp Ser Xaa Cys Asp Xaa Ser Cys Xaa Xaa Cys Cys Ile 1 5 10 15 Leu Ser 79 299 DNA Conus dalli 79 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatttgtct 60 acttctgttt ccccttactg ctgttccact ggatggagat cagcctgcag accgacctgc 120 agagcgtatg caggacggca tttcatctga acatcatcca ttttttgatt ccgtcaaaaa 180 gaaacaacag tgttgcccgc cggtggcatg caacatggga tgcgagcctt gttgtggatg 240 accagctttg ttatcgcggc tcatgaagtg tcctaatgaa taagtaaaac gattgcagt 299 80 72 PRT Conus dalli 80 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Gly Ile Ser Ser Glu His His Pro Phe Phe 35 40 45 Asp Ser Val Lys Lys Lys Gln Gln Cys Cys Pro Pro Val Ala Cys Asn 50 55 60 Met Gly Cys Glu Pro Cys Cys Gly 65 70 81 17 PRT Conus dalli PEPTIDE (1)..(17) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 14 is Glu or gamma-carboxy Glu; Xaa at residue 5, 6 and 15is Pro or Hyp 81 Xaa Gln Cys Cys Xaa Xaa Val Ala Cys Asn Met Gly Cys Xaa Xaa Cys 1 5 10 15 Cys 82 290 DNA Conus dalli 82 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttgttga tcatatgtct 60 atttctgttt ccccttactg ctgttcagct caatggagat cagcctgcag accaatctgc 120 agagcgtatg caggacaaaa tttcatctga acatcatccc ttttttgatc ccgtcaaacg 180 ttgttgcaac gcggggtttt gccgcttcgg atgcacgcct tgttgttggt gaccagcttt 240 gttatcgcgg cctcatcaag tgtctaatga ataagtaaaa tgattgcagt 290 83 69 PRT Conus dalli 83 Met Met Ser Lys Leu Gly Val Leu Leu Ile Ile Cys Leu Phe Leu Phe 1 5 10 15 Pro Leu Thr Ala Val Gln Leu Asn Gly Asp Gln Pro Ala Asp Gln Ser 20 25 30 Ala Glu Arg Met Gln Asp Lys Ile Ser Ser Glu His His Pro Phe Phe 35 40 45 Asp Pro Val Lys Arg Cys Cys Asn Ala Gly Phe Cys Arg Phe Gly Cys 50 55 60 Thr Pro Cys Cys Trp 65 84 16 PRT Conus dalli PEPTIDE (1)..(16) Xaa at residue 13 is Pro or Hyp; Xaa at residue 16 is Trp or bromo-Trp 84 Cys Cys Asn Ala Gly Phe Cys Arg Phe Gly Cys Thr Xaa Cys Cys Xaa 1 5 10 15 85 288 DNA Conus distans 85 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgctga ccatctttct 60 gcttctgttt ccccttactg ctgttccgct ggatggagat caacccgcag acggacttgc 120 agagcgcatg caggacgaca gttcagctgc actgattaga gactggcttc ttcaaacccg 180 acagtgttgt gtgcatccat gcccatgcac gccttgctgt agatgaccag ctttgtcatc 240 gcggctacgt caagtatcta atgaataagt aagtaaaacg attgcagt 288 86 67 PRT Conus distans 86 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Phe Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Gly Leu 20 25 30 Ala Glu Arg Met Gln Asp Asp Ser Ser Ala Ala Leu Ile Arg Asp Trp 35 40 45 Leu Leu Gln Thr Arg Gln Cys Cys Val His Pro Cys Pro Cys Thr Pro 50 55 60 Cys Cys Arg 65 87 14 PRT Conus distans PEPTIDE (1)..(14) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 6, 8 and 11 is Pro or Hyp 87 Xaa Cys Cys Val His Xaa Cys Xaa Cys Thr Xaa Cys Cys Arg 1 5 10 88 303 DNA Conus ermineus 88 acctcaagag ggatcgatcg cagttcatga tgtctaaact gggagccttg ttgaccatct 60 gtctgcttct gtttcccatt actgctcttc tgatggatgg agatcagcct gcagaccgac 120 ctgcagagcg tacggaggat gacatttcat ctgactacat tccctgttgc agttggccat 180 gcccccgata ctccaacggt aaacttgttt gtttttgttg ccttggatga taatgtgttg 240 atgaccaact ttgttatcac ggctacgtca agtgtctact gaataagtaa aatgattgca 300 gta 303 89 67 PRT Conus ermineus 89 Met Met Ser Lys Leu Gly Ala Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Ile Thr Ala Leu Leu Met Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Thr Glu Asp Asp Ile Ser Ser Asp Tyr Ile Pro Cys Cys 35 40 45 Ser Trp Pro Cys Pro Arg Tyr Ser Asn Gly Lys Leu Val Cys Phe Cys 50 55 60 Cys Leu Gly 65 90 20 PRT Conus ermineus PEPTIDE (1)..(20) Xaa at residue 5 and 7 is Pro or Hyp; Xaa at residue 4 is Trp or bromo-Trp; Xaa at residue 9 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 90 Cys Cys Ser Xaa Xaa Cys Xaa Arg Xaa Ser Asn Gly Lys Leu Val Cys 1 5 10 15 Phe Cys Cys Leu 20 91 241 DNA Conus generalis 91 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctggttct gtttcccctt 60 actgctcttc cactggatgg agaacaacct gtagaccgac atgccgagca tatgcaggat 120 gacaattcag ctgcacagaa cccctgggtt attgccatca gacagtgttg cacgttctgc 180 aactttggat gccaaccttg ttgcctcacc tgataacgtg ttgatgacca actttctcga 240 g 241 92 70 PRT Conus generalis 92 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Val 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Pro Leu Asp Gly Glu Gln Pro Val Asp 20 25 30 Arg His Ala Glu His Met Gln Asp Asp Asn Ser Ala Ala Gln Asn Pro 35 40 45 Trp Val Ile Ala Ile Arg Gln Cys Cys Thr Phe Cys Asn Phe Gly Cys 50 55 60 Gln Pro Cys Cys Leu Thr 65 70 93 16 PRT Conus generalis PEPTIDE (1)..(16) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 12 is Pro or Hyp 93 Xaa Cys Cys Thr Phe Cys Asn Phe Gly Cys Gln Xaa Cys Cys Leu Thr 1 5 10 15 94 241 DNA Conus generalis 94 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctggttct gtttcccctt 60 actgctcttc cactggatgg agaacaacct gtagaccgac atgccgagca tatgcaggat 120 gacaattcag ctgcacagaa cccctgggtt attgccatca gacagtgttg cacgttctgc 180 aactttggat gccagccttg ttgcgtcccc tgataacgtg ttgatgacca actttctcga 240 g 241 95 70 PRT Conus generalis 95 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Val 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Pro Leu Asp Gly Glu Gln Pro Val Asp 20 25 30 Arg His Ala Glu His Met Gln Asp Asp Asn Ser Ala Ala Gln Asn Pro 35 40 45 Trp Val Ile Ala Ile Arg Gln Cys Cys Thr Phe Cys Asn Phe Gly Cys 50 55 60 Gln Pro Cys Cys Val Pro 65 70 96 16 PRT Conus generalis PEPTIDE (1)..(16) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 12 and 16 is Pro or Hyp 96 Xaa Cys Cys Thr Phe Cys Asn Phe Gly Cys Gln Xaa Cys Cys Val Xaa 1 5 10 15 97 862 DNA Conus geographus 97 gtcgactcta gaggatccga caacaaagag tcaaccccac tgccacgtca agagcgaagc 60 gccacagcta agacaagagg gatcgatagc agttcatgat gtctaaactg ggagtcttgt 120 tgaccatctg tctgcttctg tttcccctta ctgctcttcc gatggatgga gatgaacctg 180 caaaccgacc tgtcgagcgt atgcaggaca acatttcatc tgagcagtat cccttgtttg 240 agaagagacg agattgttgc actccgccga agaaatgcaa agaccgacaa tgcaaacccc 300 agagatgttg cgctggacga taacgtgttg atgaccaact ttatcacggc tacgtcaagt 360 gtttagtgaa taagtaaaat gattgcagtc ttgctcagat ttgcttttgt gttttggtct 420 aaagatcaat gaccaaaccg ttgttttgat gcggattgtc atatatttct cgattccaat 480 ccaacactag atgatttaat cacgatagat taattttcta tcaatgcctt gatttttcgt 540 ctgtcatatc agttttgttt atatttattt tttcgtcact gtctacacaa acgcatgcat 600 gcacgcatgc acgcacacac gcacgcacgc tcgcacaaac atgcgcgcgc acgcacacac 660 acacacacac acacaaacac acacacaagc aatcacacaa ttattgacat tatttattta 720 ttcattgatg tatttgttat tcgtttgctt gtttttagaa tagtttgagg ccgtcttttt 780 ggatttattt gaactgcttt attgtatacg agtacttcgt gctttgaaac actgctgaaa 840 ataaaacaaa cactgacgta gc 862 98 75 PRT Conus geographus 98 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Glu Pro Ala Asn Arg Pro 20 25 30 Val Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln Tyr Pro Leu Phe 35 40 45 Glu Lys Arg Arg Asp Cys Cys Thr Pro Pro Lys Lys Cys Lys Asp Arg 50 55 60 Gln Cys Lys Pro Gln Arg Cys Cys Ala Gly Arg 65 70 75 99 22 PRT Conus geographus PEPTIDE (1)..(22) Xaa at residue 6, 7 and 17 is Pro or Hyp 99 Arg Asp Cys Cys Thr Xaa Xaa Lys Lys Cys Lys Asp Arg Gln Cys Lys 1 5 10 15 Xaa Gln Arg Cys Cys Ala 20 100 860 DNA Conus geographus 100 ggccagacga caacaaagag tcaaccccac tgccacgtca agagcgaagc gccacagcta 60 agacaagagg gatcgatagc agttcatgat gtctaaactg ggagtcttgt tgaccatctg 120 tctgcttctg tttcccctta ctgctcttcc gatggatgga gatgaacctg caaaccgacc 180 tgtcgagcgt atgcaggaca acatttcatc tgagcagtat cccttgtttg agaagagacg 240 agattgttgc actccgccga ggaaatgcaa agaccgacga tgcaaaccca tgaaatgttg 300 cgctggacga taacgtgttg atgaccaact ttatcacggc tagctcagtg tttagtgaat 360 aagtaaaatg attgcagtct tgctcagatt gcttttgtgt tttggtctaa gatcaatgac 420 caaaccgttg ttttgatgcg gattgtcata tatttctcga ttccaatcca acactagatg 480 atttaatcac gatagattaa ttttctatca atgccttgat ttttcgtctg tcatatcagt 540 tttgtttata tttatttttt cgtcactgtc tacacaaacg catgcatgca cgcatgcacg 600 cacacacgca cgcacgctcg cacaaacatg cgcgcgcacg cacacacaca cacacacaca 660 aacacacaca cgaagcaatc acacaattag ttgacattat ttatttattc attgatgtat 720 ttgttattcg tttgcttgtt tttagaatag tttgaggccg tctttttgga tttatttgaa 780 ctgctttatt gtatacgagt acttcgtgct ttgaaacact gctgaaaata aaacaaacac 840 tgacgtagca aaaaaaaaaa 860 101 75 PRT Conus geographus 101 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Glu Pro Ala Asn Arg Pro 20 25 30 Val Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln Tyr Pro Leu Phe 35 40 45 Glu Lys Arg Arg Asp Cys Cys Thr Pro Pro Arg Lys Cys Lys Asp Arg 50 55 60 Arg Cys Lys Pro Met Lys Cys Cys Ala Gly Arg 65 70 75 102 22 PRT Conus geographus PEPTIDE (1)..(22) Xaa at residue 6, 7 and 17 is Pro or Hyp 102 Arg Asp Cys Cys Thr Xaa Xaa Arg Lys Cys Lys Asp Arg Arg Cys Lys 1 5 10 15 Xaa Met Lys Cys Cys Ala 20 103 22 PRT Conus geographus PEPTIDE (1)..(22) Xaa at residue 6, 7 and 17 is Pro or Hyp 103 Arg Asp Cys Cys Thr Xaa Xaa Lys Lys Cys Lys Asp Arg Arg Cys Lys 1 5 10 15 Xaa Leu Lys Cys Cys Ala 20 104 321 DNA Conus gloriamaris 104 ctcactatag gaattcgagc tcggtacacg ggatcgatag cagttcatga tgtctaaact 60 gggagccttg ttgaccatct gtctacttct gttttcccta actgctgttc cgctggatgg 120 agatcaacat gcagaccaac ctgcagagcg tctgcatgac cgccttccaa ctgaaaatca 180 tcccttatat gatcccgtca aacggtgttg cgatgattcg gaatgcgact attcttgctg 240 gccttgctgt atgtttggat aacctttgtt atcgcggcct cgataagtgt ctaatgaata 300 agtaaaacga ttgcagtagg c 321 105 71 PRT Conus gloriamaris 105 Met Met Ser Lys Leu Gly Ala Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu His Asp Arg Leu Pro Thr Glu Asn His Pro Leu Tyr 35 40 45 Asp Pro Val Lys Arg Cys Cys Asp Asp Ser Glu Cys Asp Tyr Ser Cys 50 55 60 Trp Pro Cys Cys Met Phe Gly 65 70 106 17 PRT Conus gloriamaris PEPTIDE (1)..(17) Xaa at residue is 6 Glu or gamma-carboxy Glu; Xaa at residue 13 is Pro or Hyp; Xaa at residue 12 is Trp or bromo-Trp; Xaa at residue 9 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 106 Cys Cys Asp Asp Ser Xaa Cys Asp Xaa Ser Cys Xaa Xaa Cys Cys Met 1 5 10 15 Phe 107 257 DNA Conus gloriamaris 107 gttcatgatg tctaaactgg gagtcttgtt gatcatctgt ctacttctgt ttccccttac 60 tgctgttccg ctggatggag atcaacctgc agaccgatat gcagagcgta tgcaggacga 120 catttcatct gaacatcatc ccatgtttga tgccgtcaga gggtgttgcc atctgttggc 180 atgccgcttc ggatgctcgc cttgttgttg gtgatcagct ttgttatcgc ggcctcatca 240 agtgactcta atgcaaa 257 108 69 PRT Conus gloriamaris 108 Met Met Ser Lys Leu Gly Val Leu Leu Ile Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Arg Tyr 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu His His Pro Met Phe 35 40 45 Asp Ala Val Arg Gly Cys Cys His Leu Leu Ala Cys Arg Phe Gly Cys 50 55 60 Ser Pro Cys Cys Trp 65 109 17 PRT Conus gloriamaris PEPTIDE (1)..(17) Xaa at residue 14 is Pro or Hyp; Xaa at residue 17 is Trp or bromo-Trp 109 Gly Cys Cys His Leu Leu Ala Cys Arg Phe Gly Cys Ser Xaa Cys Cys 1 5 10 15 Xaa 110 471 DNA Conus gloriamaris 110 gagacgacaa ggaacagtca accccacagc cacgccaaga gcagacagcc acagctacgt 60 gaagaagggt ggagagaggt tcgtgatgtt gaaaatggga gtggtgctat tcatcttcct 120 ggtactgttt cccctggcaa cgctccagct ggatgcagat caacctgtag aacgatatgc 180 ggagaacaaa cagctcctca acccagatga aaggagggaa atcatattgc atgctctggg 240 gacgcgatgc tgttcttggg atgtgtgcga ccacccgagt tgtacttgct gcggcggtta 300 gcgccgaaca tccatggcgc tgtgctgggc ggttttatcc aacaacgaca gcgtttgttg 360 atttcatgta tcattgcgcc cacgtctctt gtctaagaat gacgaacatg attgcactct 420 ggttcagatt tcgtgttctt ttctgacaat aaatgacaaa actccaaaaa a 471 111 71 PRT Conus gloriamaris 111 Met Leu Lys Met Gly Val Val Leu Phe Ile Phe Leu Val Leu Phe Pro 1 5 10 15 Leu Ala Thr Leu Gln Leu Asp Ala Asp Gln Pro Val Glu Arg Tyr Ala 20 25 30 Glu Asn Lys Gln Leu Leu Asn Pro Asp Glu Arg Arg Glu Ile Ile Leu 35 40 45 His Ala Leu Gly Thr Arg Cys Cys Ser Trp Asp Val Cys Asp His Pro 50 55 60 Ser Cys Thr Cys Cys Gly Gly 65 70 112 16 PRT Conus gloriamaris PEPTIDE (1)..(16) Xaa at residue 10 is Pro or Hyp; Xaa at residue 4 is Trp or bromo-Trp 112 Cys Cys Ser Xaa Asp Val Cys Asp His Xaa Ser Cys Thr Cys Cys Gly 1 5 10 15 113 304 DNA Conus laterculatus 113 cgacctcaag aaggatcgat agcagttcat gatgtctaaa ctgggagtct tgttgaccat 60 ctgtctgctt ctgtttcccc ttactgctct tccgatggat ggagatcaac ctgcagaccg 120 acctgcagag cgtatgcagg acgtttcatc tgaacagcat cccttgtatg atcccgtcaa 180 acggtgttgc gactggccat gcagcggatg catcccttgt tgctaatagt aacaacgtgt 240 tgataaccaa ctttcttacc acgactacgt caagtgtcta atgaataagt aaaatgattg 300 cagt 304 114 65 PRT Conus laterculatus 114 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Val Ser Ser Glu Gln His Pro Leu Tyr Asp 35 40 45 Pro Val Lys Arg Cys Cys Asp Trp Pro Cys Ser Gly Cys Ile Pro Cys 50 55 60 Cys 65 115 13 PRT Conus laterculatus PEPTIDE (1)..(13) Xaa at residue 5 and 11 is Pro or Hyp; Xaa at residue 4 is Trp or bromo-Trp 115 Cys Cys Asp Xaa Xaa Cys Ser Gly Cys Ile Xaa Cys Cys 1 5 10 116 313 DNA Conus laterculatus 116 cgacctcaag aaggatcgat agcagttcat gatgtctaaa ctgggagtct tgttgaccat 60 ctgtctgctt ctgtttcccc ttactgctct ggatggagat caacctgcag accgacttgc 120 agagcgtatg caggacgaca tttcatctga gcagcatccc tttgaaaaga gacgagactg 180 ttgcacacct ccgaagaaat gcagagaccg acaatgcaaa cctgcacgtt gttgcggagg 240 ataacgtgtt gatgaccaac tttgttatca cggctacgtc aagtgtctag tgaataagta 300 aaacgattgc agt 313 117 71 PRT Conus laterculatus 117 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Asp Gly Asp Gln Pro Ala Asp Arg Leu Ala Glu 20 25 30 Arg Met Gln Asp Asp Ile Ser Ser Glu Gln His Pro Phe Glu Lys Arg 35 40 45 Arg Asp Cys Cys Thr Pro Pro Lys Lys Cys Arg Asp Arg Gln Cys Lys 50 55 60 Pro Ala Arg Cys Cys Gly Gly 65 70 118 22 PRT Conus laterculatus PEPTIDE (1)..(22) Xaa at residue 6, 17 and 17 is Pro or Hyp 118 Arg Asp Cys Cys Thr Xaa Xaa Lys Lys Cys Arg Asp Arg Gln Cys Lys 1 5 10 15 Xaa Ala Arg Cys Cys Gly 20 119 314 DNA Conus laterculatus 119 gggatcgata gcagttcatg atgtctaaac tgggagtctt gttgaccatc tgtctgcttc 60 tgtttcccct tactgctctt ccgatggatg gagatcaact tgcacgccga tctgcagagc 120 gtatgcagga caacatttca tctgagcagc atcacctctt tgaaaagaga cgaccaccat 180 gttgcaccta tgacgggagt tgcctaaaag aatcatgcat gcgtaaagct tgttgcggat 240 gataacgtgt tgatgaccaa ctttgttatc acggctactc aagtgtctaa tgaataagta 300 aaatgattgc agta 314 120 74 PRT Conus laterculatus 120 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Leu Ala Arg Arg Ser 20 25 30 Ala Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His His Leu Phe 35 40 45 Glu Lys Arg Arg Pro Pro Cys Cys Thr Tyr Asp Gly Ser Cys Leu Lys 50 55 60 Glu Ser Cys Met Arg Lys Ala Cys Cys Gly 65 70 121 22 PRT Conus laterculatus PEPTIDE (1)..(22) Xaa at residue 14 is Glu or gamma-carboxy Glu; Xaa at residue 2 and 3 is Pro or Hyp; Xaa at residue 7 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho- Tyr 121 Arg Xaa Xaa Cys Cys Thr Xaa Asp Gly Ser Cys Leu Lys Xaa Ser Cys 1 5 10 15 Met Arg Lys Ala Cys Cys 20 122 314 DNA Conus laterculatus 122 gggatcgata gcagttcatg atgtctaaac tgggagtctt gttgaccacc tgtctgcttc 60 tgtttcccct tactgctctt ccgatggatg gagatcaact tgcacgccga cctgcagagc 120 gtatgcagga caacatttca tctgagcagc atcccttctt tgaaaggaga cgaccaccat 180 gttgcaccta tgacgggagt tgcctaaaag aatcatgcaa gcgtaaagct tgttgcggat 240 aataacgtgt tgatgaccaa ctttgttatc acggctactc aagtgtctaa tgaataagta 300 aaatgattgc agta 314 123 74 PRT Conus laterculatus 123 Met Met Ser Lys Leu Gly Val Leu Leu Thr Thr Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Leu Ala Arg Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His Pro Phe Phe 35 40 45 Glu Arg Arg Arg Pro Pro Cys Cys Thr Tyr Asp Gly Ser Cys Leu Lys 50 55 60 Glu Ser Cys Lys Arg Lys Ala Cys Cys Gly 65 70 124 22 PRT Conus laterculatus PEPTIDE (1)..(22) Xaa at residue 14 is Glu or gamma-carboxy Glu; Xaa at residue 2 and 3 is Pro or Hyp; Xaa at residue 7 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho- Tyr 124 Arg Xaa Xaa Cys Cys Thr Xaa Asp Gly Ser Cys Leu Lys Xaa Ser Cys 1 5 10 15 Lys Arg Lys Ala Cys Cys 20 125 247 DNA Conus leopardus 125 ggatccatga tgtctaaact gggagtcttg ttgaccgtct gtctgcttct gtttcccctt 60 actgctcttc ggctggttgg agatcaacct gcagagcgac ctgcaaagcg tacgcaggac 120 gacattccag atggacagca tccgttaaat gataggcaga taaactgttg cccgtggcca 180 tgccctagta catgccgcca tcaatgctgc cattaatgat aacgtgttga tgaccaactt 240 tctcgag 247 126 71 PRT Conus leopardus 126 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Val Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Arg Leu Val Gly Asp Gln Pro Ala Glu 20 25 30 Arg Pro Ala Lys Arg Thr Gln Asp Asp Ile Pro Asp Gly Gln His Pro 35 40 45 Leu Asn Asp Arg Gln Ile Asn Cys Cys Pro Trp Pro Cys Pro Ser Thr 50 55 60 Cys Arg His Gln Cys Cys His 65 70 127 19 PRT Conus leopardus PEPTIDE (1)..(19) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 6, 8 and 10 is Pro or Hyp; Xaa at residue 7 is Trp or bromo-Trp 127 Xaa Ile Asn Cys Cys Xaa Xaa Xaa Cys Xaa Ser Thr Cys Arg His Gln 1 5 10 15 Cys Cys His 128 244 DNA Conus lividus 128 ggatccatga tgtctaaact gggagtcttg ttgaccgtct gtctgcttct gtttcccctt 60 actgctcttc ggctggttag agatcaacct gcagagcgac ctgcaaagcg tacgcaggac 120 gacattccaa atggacagga tccgttaatt gataggcaga taaattgttg cccttggcca 180 tgccctgatt catgccacta tcaatgctgc cactgataac gtgttgatga ccaactttct 240 cgag 244 129 71 PRT Conus lividus 129 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Val Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Arg Leu Val Arg Asp Gln Pro Ala Glu 20 25 30 Arg Pro Ala Lys Arg Thr Gln Asp Asp Ile Pro Asn Gly Gln Asp Pro 35 40 45 Leu Ile Asp Arg Gln Ile Asn Cys Cys Pro Trp Pro Cys Pro Asp Ser 50 55 60 Cys His Tyr Gln Cys Cys His 65 70 130 19 PRT Conus lividus PEPTIDE (1)..(19) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 6, 8 and 10 is Pro or Hyp; Xaa at residue 7 is Trp or bromo-Trp; Xaa at residue 15 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 130 Xaa Ile Asn Cys Cys Xaa Xaa Xaa Cys Xaa Asp Ser Cys His Xaa Gln 1 5 10 15 Cys Cys His 131 275 DNA Conus lynceus 131 aaggatcgat agcagttcat gatgtctaaa ctgggagtct tgttgaccat ctgtctgctt 60 ctgtttcccc ttactgctct tccgatggat ggagatcaat ctgcagaccg acttgcagag 120 cgtatgcagg acaacatttc atctgagcag catcccttct ttgaaaagag aggacgagac 180 tgttgcacac ctccgaggaa atgcagagac cgagcctgca aacctcaacg ttgttgcgga 240 ggataagctg ttgatgacca actttgttat acggc 275 132 75 PRT Conus lynceus 132 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Ser Ala Asp Arg Leu 20 25 30 Ala Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His Pro Phe Phe 35 40 45 Glu Lys Arg Gly Arg Asp Cys Cys Thr Pro Pro Arg Lys Cys Arg Asp 50 55 60 Arg Ala Cys Lys Pro Gln Arg Cys Cys Gly Gly 65 70 75 133 23 PRT Conus lynceus PEPTIDE (1)..(23) Xaa at residue 7, 8 and 18 is Pro or Hyp 133 Gly Arg Asp Cys Cys Thr Xaa Xaa Arg Lys Cys Arg Asp Arg Ala Cys 1 5 10 15 Lys Xaa Gln Arg Cys Cys Gly 20 134 803 DNA Conus magus 134 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccgat ggatggagat gaacctgcaa accgacctgt 120 cgagcgtatg caggacaaca tttcatctga gcagtatccc ttgtttgaga agagacgaga 180 ttgttgcact ccgccgaaga aatgcaaaga ccgacaatgc aaaccccaga gatgttgcgc 240 tggacgataa cgtgttgatg accaacttta tcacggctac gtcaagtgtt tagtgaataa 300 gtaaaatgat tgcagtcttg ctcagatttg cttttgtgtt ttggtctaaa gatcaatgac 360 caaaccgttg ttttgatgcg gattgtcata tatttctcga ttccaatcca acactagatg 420 atttaatcac gatagattaa ttttctatca atgccttgat ttttcgtctg tcatatcagt 480 tttgtttata tttatttttt cgtcactgtc tacacaaacg catgcatgca cgcatgcacg 540 cacacacgca cgcacgctcg cacaaacatg cgcgcgcacg cacacacaca cacacacaca 600 caaacacaca cacgaagcaa tcacacaatt agttgacatt atttatttat tcattgatgt 660 atttgttatt cgtttgcttg tttttagaat agtttgaggc cgtctttttg gatttatttg 720 aactgcttta ttgtatacga gtacttcgtg cggggaaaca ctgctgaaaa taaaacaaac 780 actgacgtag caaaaaaaaa aaa 803 135 75 PRT Conus magus 135 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Glu Pro Ala Asn Arg Pro 20 25 30 Val Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln Tyr Pro Leu Phe 35 40 45 Glu Lys Arg Arg Asp Cys Cys Thr Pro Pro Lys Lys Cys Lys Asp Arg 50 55 60 Gln Cys Lys Pro Gln Arg Cys Cys Ala Gly Arg 65 70 75 136 22 PRT Conus magus PEPTIDE (1)..(22) Xaa at residue 6 and 7 is Pro or Hyp 136 Arg Asp Cys Cys Thr Xaa Xaa Lys Lys Cys Lys Asp Arg Gln Cys Lys 1 5 10 15 Xaa Gln Arg Cys Cys Ala 20 137 656 DNA Conus magus 137 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccaat ggatggagat caacctgcag accaacctgc 120 agatcgtatg caggacgaca tttcatctga gcagtatccc ttgtttgata tgagaaaaag 180 gtgttgcggc cccggcggtt catgccccgt atatttcaga gacaatttta tttgtggttg 240 ttgttaaatg acaacgtgtc gatgaccaac ttcattatca cgactacgcc aagtgtctaa 300 tgaataaata aaatgattgc agtctcgctc agatttgctt ttgtattttg gtctaaagat 360 caatgaccaa accgttgttt tggtgtggat tttcatatat ttctcgagtc ctatccaaca 420 ctagatgatt taatcacgat agatctgatt tttttatcaa aggcttggtt tttcgtctgt 480 cacatcagtt ttgtttatat ttaatttttc gtcactgatt acacacacgc atgaacgcac 540 agagtactaa cacatacaca cacacacaca cacacacaca cacacacaca cacacacaca 600 cacacacaca cacgcgcgcg cgcggcgcca tctagtagcg ccgcgacgac acacac 656 138 74 PRT Conus magus 138 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Asp Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Tyr Pro Leu Phe 35 40 45 Asp Met Arg Lys Arg Cys Cys Gly Pro Gly Gly Ser Cys Pro Val Tyr 50 55 60 Phe Arg Asp Asn Phe Ile Cys Gly Cys Cys 65 70 139 21 PRT Conus magus PEPTIDE (1)..(21) Xaa at residue 4 and 9 is Pro or Hyp; Xaa at residue is 11 Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 139 Cys Cys Gly Xaa Gly Gly Ser Cys Xaa Val Xaa Phe Arg Asp Asn Phe 1 5 10 15 Ile Cys Gly Cys Cys 20 140 594 DNA Conus magus 140 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgttt 60 gcttctgttt ccccttactg ctcttccgag ggatggagat caatctgtag accgacctgc 120 agagcgtatg caggacgaca tttcatctga gctgcatccc ttgtcaatca gaaaaagaat 180 gtgttgcggc gagagtgcgc catgccccag ctatttcaga aacagtcaga tttgtcattg 240 ttgttaaatg acaacgtgtc gatgaccacc ttcgttatca cgactaatga taagtaaaat 300 gattgcagtc tcgctcagat ttgcttttgt attttggtct aaagatcaat gaccaaaccg 360 ttgttttgat gtggattttc atatatttct cgagtcctat ccaacactag atgatttaat 420 cacgatagat ctgatttttt tatcaaagcc ttggtttttc gtctgtcaca tcagttttgt 480 ttatatttaa tttttcgtca ctgattacac acacgcatga acgcacagac gtactaacac 540 atacacacac acacacacac acacacacac acacacacac acacacacac acac 594 141 74 PRT Conus magus 141 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Arg Asp Gly Asp Gln Ser Val Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Leu His Pro Leu Ser 35 40 45 Ile Arg Lys Arg Met Cys Cys Gly Glu Ser Ala Pro Cys Pro Ser Tyr 50 55 60 Phe Arg Asn Ser Gln Ile Cys His Cys Cys 65 70 142 22 PRT Conus magus PEPTIDE (1)..(22) Xaa at residue 5 is Glu or gamma-carboxy Glu; Xaa at residue 8 and 10 is Pro or Hyp; Xaa at residue 12 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 142 Met Cys Cys Gly Xaa Ser Ala Xaa Cys Xaa Ser Xaa Phe Arg Asn Ser 1 5 10 15 Gln Ile Cys His Cys Cys 20 143 501 DNA Conus magus 143 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccaat ggatggagat caacctgcag accaacctgc 120 agatcgtatg caggacgaca tttcatctga gcagtatccc ttgtttgata agagacaaaa 180 gtgttgcggc cccggcggtt catgccccgt atatttcaca gacaatttta tttgtggttg 240 ttgttaaatg acaacgtgtc gatgaccaac ttcattatca cgactacgcc aagtgtctaa 300 tgaataaata aaatgattgc agtctcgctc agatttgctt ttgtatttgg tctaaagatc 360 aatgaccaaa ccgttgtttt ggtgctggat tttcatatat ttctcgattc ctatccaaca 420 ctagatgatt taatcacgat agatctgatt tttttatcaa tgccttaatt ttttgctctg 480 tcatatcagt tttgtttata t 501 144 74 PRT Conus magus 144 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Asp Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Tyr Pro Leu Phe 35 40 45 Asp Lys Arg Gln Lys Cys Cys Gly Pro Gly Gly Ser Cys Pro Val Tyr 50 55 60 Phe Thr Asp Asn Phe Ile Cys Gly Cys Cys 65 70 145 23 PRT Conus magus PEPTIDE (1)..(23) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 6 and 11 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 145 Xaa Lys Cys Cys Gly Xaa Gly Gly Ser Cys Xaa Val Xaa Phe Thr Asp 1 5 10 15 Asn Phe Ile Cys Gly Cys Cys 20 146 454 DNA Conus magus 146 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccaat ggatggagat caacctgcag accaacctgc 120 agatcgtatg caggacgaca tttcatctga gcagtatccc ttgtttgata agagacaaaa 180 gtgttgcggc cccggcggtt catgccccgt atatttcaga gacaatttta tttgtggttg 240 ttgttaaatg acaacgtgtc gatgaccatc ttcattatca cgactacgcc aagtgtctaa 300 tgaataaata aaatgattgc agtctcgctc agatttgctt ttgtattttg gtctaaagat 360 caatgaccaa accgttgttt tggtgtggat tttcatatat ttctcgattc ctatccaaca 420 ctagatgatt taatcacgat agatctgatt tttt 454 147 74 PRT Conus magus 147 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Asp Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Tyr Pro Leu Phe 35 40 45 Asp Lys Arg Gln Lys Cys Cys Gly Pro Gly Gly Ser Cys Pro Val Tyr 50 55 60 Phe Arg Asp Asn Phe Ile Cys Gly Cys Cys 65 70 148 23 PRT Conus magus PEPTIDE (1)..(23) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 6 and 11 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 148 Xaa Lys Cys Cys Gly Xaa Gly Gly Ser Cys Xaa Val Xaa Phe Arg Asp 1 5 10 15 Asn Phe Ile Cys Gly Cys Cys 20 149 22 PRT Conus magus PEPTIDE (1)..(22) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 10 and 20 is Pro or Hyp; Xaa at residue 12 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 149 Xaa Lys Cys Cys Ser Gly Gly Ser Cys Xaa Leu Xaa Phe Arg Asp Arg 1 5 10 15 Leu Ile Cys Xaa Cys Cys 20 150 19 PRT Conus marmoreus PEPTIDE (1)..(19) Xaa at residue 16 is Pro or Hyp 150 Ser Lys Gln Cys Cys His Leu Ala Ala Cys Arg Phe Gly Cys Thr Xaa 1 5 10 15 Cys Cys Asn 151 321 DNA Conus marmoreus 151 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt cccgttactg ctcttccgat ggatggtgat caacctgcag accgacttgt 120 agagcgtatg caggacaaca tttcatctga gcagcatccc ttctttgaaa agagaagagg 180 aggctgttgc acacctccga ggaaatgcaa agaccgagcc tgcaaacctg cacgttgctg 240 cggcccagga taacgtgttg atgaccaact ttgttatcac ggctacgtca agtgtctagt 300 gaataagtaa aacgattgca g 321 152 76 PRT Conus marmoreus 152 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Val Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Arg Leu 20 25 30 Val Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His Pro Phe Phe 35 40 45 Glu Lys Arg Arg Gly Gly Cys Cys Thr Pro Pro Arg Lys Cys Lys Asp 50 55 60 Arg Ala Cys Lys Pro Ala Arg Cys Cys Gly Pro Gly 65 70 75 153 24 PRT Conus marmoreus PEPTIDE (1)..(24) Xaa at residue 3, 8, 18 and 24 is Pro or Hyp 153 Arg Gly Gly Cys Cys Thr Xaa Xaa Arg Lys Cys Lys Asp Arg Ala Cys 1 5 10 15 Lys Xaa Ala Arg Cys Cys Gly Xaa 20 154 296 DNA Conus marmoreus 154 gagctcggta ccccgacctc aagagggatc gatagcagtt catgatgtct aaactgggaa 60 tcttgttgac catctgtcta cttctatttc cccttactgc tgttccgctg gatggagatc 120 aacctgcaga ccgacctgca gagcgtatgc aggacgacat ttcatctgaa catcatccct 180 tttttgatcc cgtcaaacgg tgttgcaggt tatcatgcgg cctgggatgc cacccttgtt 240 gtggatgacc agctttgtta tcgcggcctc atcaagtgtc taatgaataa gtaaaa 296 155 68 PRT Conus marmoreus 155 Met Met Ser Lys Leu Gly Ile Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu His His Pro Phe Phe 35 40 45 Asp Pro Val Lys Arg Cys Cys Arg Leu Ser Cys Gly Leu Gly Cys His 50 55 60 Pro Cys Cys Gly 65 156 14 PRT Conus marmoreus PEPTIDE (1)..(14) Xaa at residue 12 is Pro or Hyp 156 Cys Cys Arg Leu Ser Cys Gly Leu Gly Cys His Xaa Cys Cys 1 5 10 157 355 DNA Conus marmoreus 157 ggcctacacc aagcttgcat gcctgcaggt cgactctaga ggatccccga tcgatagcag 60 ttcatgatgt ctagactggg agtcttgttg accatctgtc tacttctgtt tccccttact 120 gctgttccgc tggatggaga tcaacctgcg gaccgacctg cagagcgcct gcaggacgac 180 atttcatctg aacatcatcc ccattttgat tccggcagag agtgttgcgg ttcgttcgca 240 tgccgctttg gatgcgtgcc ttgttgtgta tgaccagctt tgttatcacg gcctcatcga 300 gtgtctaatg aataagtaaa acgattgcag taggcgggta ccgagctcga attcc 355 158 69 PRT Conus marmoreus 158 Met Met Ser Arg Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Leu Gln Asp Asp Ile Ser Ser Glu His His Pro His Phe 35 40 45 Asp Ser Gly Arg Glu Cys Cys Gly Ser Phe Ala Cys Arg Phe Gly Cys 50 55 60 Val Pro Cys Cys Val 65 159 17 PRT Conus marmoreus PEPTIDE (1)..(17) Xaa at residue 1 is Glu or gamma-carboxy Glu; Xaa at residue 14 is Pro or Hyp 159 Xaa Cys Cys Gly Ser Phe Ala Cys Arg Phe Gly Cys Val Xaa Cys Cys 1 5 10 15 Val 160 295 DNA Conus marmoreus 160 cgacctcaag agggatcgat agcagttcat gatgtctaaa ctgggagtct tgttgaccat 60 ctgtctactt ctatttcccc ttactgctgt tccgctggat ggagaccaac ctgcagaccg 120 acctgcagag cgtatgcagg acgacatttc atctgaacgt catccttttt ttgatcgcag 180 caaacagtgt tgccatctgc cggcatgccg cttcggatgt acgccttgtt gttggtgatc 240 agctttgtta tcgcgtcctc atcaagtgtc taatgaataa gtaaaatgat tgcag 295 161 67 PRT Conus marmoreus 161 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser His Pro Phe Phe Asp Arg 35 40 45 Ser Lys Gln Cys Cys His Leu Pro Ala Cys Arg Phe Gly Cys Thr Pro 50 55 60 Cys Cys Trp 65 162 19 PRT Conus marmoreus PEPTIDE (1)..(19) Xaa at residue 8 and 16 is Pro or Hyp; Xaa at residue 19 is Trp or bromo-Trp 162 Ser Lys Gln Cys Cys His Leu Xaa Ala Cys Arg Phe Gly Cys Thr Xaa 1 5 10 15 Cys Cys Xaa 163 235 DNA Conus marmoreus 163 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctcttc cgctggatgg agatcaacct gcagaccaac gtgcagagcg tacgcaggcc 120 gagaagcatt ccttgcctga tccgagaatg ggctgttgcc cgtttccatg caaaaccagt 180 tgcactactt tgtgttgcgg gtgatgataa cgtgttgatg accaactttc tcgag 235 164 67 PRT Conus marmoreus 164 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Pro Leu Asp Gly Asp Gln Pro Ala Asp 20 25 30 Gln Arg Ala Glu Arg Thr Gln Ala Glu Lys His Ser Leu Pro Asp Pro 35 40 45 Arg Met Gly Cys Cys Pro Phe Pro Cys Lys Thr Ser Cys Thr Thr Leu 50 55 60 Cys Cys Gly 65 165 17 PRT Conus marmoreus PEPTIDE (1)..(17) Xaa at residue 5 and 7 is Pro or Hyp 165 Met Gly Cys Cys Xaa Phe Xaa Cys Lys Thr Ser Cys Thr Thr Leu Cys 1 5 10 15 Cys 166 16 PRT Conus marmoreus PEPTIDE (1)..(16) Xaa at residue 4 and 6 is Trp or bromo-Trp 166 Cys Cys His Xaa Asn Xaa Cys Asp His Leu Cys Ser Cys Cys Gly Ser 1 5 10 15 167 357 DNA Conus marmoreus 167 gccaagcttg catgcctgca ggatgactct agaggatccc cacctcaaga gggatcgata 60 gcagttcatg atgtctaaac tgggagtctt gttgaccatc tgtctacttc tgtttgccct 120 tactgctgtt ccgctggatg gagatcaacc tgcagaccga cctgcagaac gtatgcagga 180 cgacatttca tctgaacgtc atcccatgtt tgatgccgtc agagattgtt gcccgttgcc 240 ggcatgcccc tttggatgca acccttgttg tggatgacca gctttgttat cgggacctca 300 tcaagtgtct aatgaataag taaaaaacga ttcgagtggg taccgagctc gaattcc 357 168 67 PRT Conus marmoreus 168 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ala Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser His Pro Met Phe Asp Ala 35 40 45 Val Arg Asp Cys Cys Pro Leu Pro Ala Cys Pro Phe Gly Cys Asn Pro 50 55 60 Cys Cys Gly 65 169 16 PRT Conus marmoreus PEPTIDE (1)..(16) Xaa at residue 4, 6, 9 and 14 is Pro or Hyp 169 Asp Cys Cys Xaa Leu Xaa Ala Cys Xaa Phe Gly Cys Asn Xaa Cys Cys 1 5 10 15 170 16 PRT Conus marmoreus PEPTIDE (1)..(16) Xaa at residue 4 and 13 is Pro or Hyp 170 Cys Cys Ala Xaa Ser Ala Cys Arg Leu Gly Cys Arg Xaa Cys Cys Arg 1 5 10 15 171 16 PRT Conus marmoreus PEPTIDE (1)..(16) Xaa at residue 4 and 13 is Pro or Hyp 171 Cys Cys Ala Xaa Ser Ala Cys Arg Leu Gly Cys Arg Xaa Cys Cys Arg 1 5 10 15 172 16 PRT Conus marmoreus PEPTIDE (1)..(16) Xaa at residue 4 and 13 is Pro or Hyp 172 Cys Cys Ala Xaa Ser Ala Cys Arg Leu Gly Cys Arg Xaa Cys Cys Arg 1 5 10 15 173 17 PRT Conus marmoreus PEPTIDE (1)..(17) Xaa at residue 14 is Pro or Hyp 173 Gly Cys Cys Gly Ser Phe Ala Cys Arg Phe Gly Cys Val Xaa Cys Cys 1 5 10 15 Val 174 244 DNA Conus nobilis 174 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctacttct gtttcccctt 60 actgctcttc cgctggatga agatcaaccg gtacaccgac ctgcagagcg tatgcaggac 120 atttcatctg atcaacatct cttctttgat ctcatcaaac ggtgctgcga gttgccatgc 180 gggccaggct tttgcgtccc ttgttgctga catcaataac gtgttgatga ccaactttct 240 cgag 244 175 69 PRT Conus nobilis 175 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Pro Leu Asp Glu Asp Gln Pro Val His 20 25 30 Arg Pro Ala Glu Arg Met Gln Asp Ile Ser Ser Asp Gln His Leu Phe 35 40 45 Phe Asp Leu Ile Lys Arg Cys Cys Glu Leu Pro Cys Gly Pro Gly Phe 50 55 60 Cys Val Pro Cys Cys 65 176 15 PRT Conus nobilis PEPTIDE (1)..(15) Xaa at residue 3 is Glu or gamma-carboxy Glu; Xaa at residue 5, 8 adn 13 is Pro or Hyp 176 Cys Cys Xaa Leu Xaa Cys Gly Xaa Gly Phe Cys Val Xaa Cys Cys 1 5 10 15 177 262 DNA Conus nobilis 177 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctacttct gtttcccctt 60 actgcttttc cgatggatgg agatcaacct gcagaccaac ctgcagatcg tatgcaggac 120 gacatttcat ctgagcagta tcccttgttt gataagagac aaaagtgttg cactgggaag 180 aaggggtcat gctccggcaa agcatgcaaa aatctcaaat gttgctctgg acgataacgt 240 gttgatgacc aactttctcg ag 262 178 78 PRT Conus nobilis 178 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Phe Pro Met Asp Gly Asp Gln Pro Ala Asp 20 25 30 Gln Pro Ala Asp Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Tyr Pro 35 40 45 Leu Phe Asp Lys Arg Gln Lys Cys Cys Thr Gly Lys Lys Gly Ser Cys 50 55 60 Ser Gly Lys Ala Cys Lys Asn Leu Lys Cys Cys Ser Gly Arg 65 70 75 179 23 PRT Conus nobilis PEPTIDE (1)..(23) Xaa at residue 1 is Gln or pyro-Glu 179 Xaa Lys Cys Cys Thr Gly Lys Lys Gly Ser Cys Ser Gly Lys Ala Cys 1 5 10 15 Lys Asn Leu Lys Cys Cys Ser 20 180 238 DNA Conus pulicarius 180 ggatccatga tgtctaaact gggagttttg ttgaccatct gtctgcttct gtttcccctt 60 actgctgttc cgctggatgg agatcaacct gcagaccgac ctgcagagcg tatgcaggac 120 attgcaactg aacagcatcc cttctttgat cccgtcaaac ggtgttgcaa cagctgttac 180 atgggatgca tcccttgttg cttctagtaa taacgtgttg atgaccaact ttctcgag 238 181 68 PRT Conus pulicarius 181 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp 20 25 30 Arg Pro Ala Glu Arg Met Gln Asp Ile Ala Thr Glu Gln His Pro Phe 35 40 45 Phe Asp Pro Val Lys Arg Cys Cys Asn Ser Cys Tyr Met Gly Cys Ile 50 55 60 Pro Cys Cys Phe 65 182 14 PRT Conus pulicarius PEPTIDE (1)..(14) Xaa at residue 11 is Pro or Hyp; Xaa at residue 5 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 182 Cys Cys Asn Ser Cys Xaa Met Gly Cys Ile Xaa Cys Cys Phe 1 5 10 183 238 DNA Conus quercinus 183 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 acagctcttc agctggatgg agatcaacct gcagaccgac ctgcagagcg tacgcaggac 120 attgcatctg aacagtatcg aaagtttgat cagagacaga ggtgttgcca gtggccatgc 180 cccggtagtt gcagatgctg ccgtactggt taacgtgttg atgaccaact ttctcgag 238 184 70 PRT Conus quercinus 184 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Gln Leu Asp Gly Asp Gln Pro Ala Asp 20 25 30 Arg Pro Ala Glu Arg Thr Gln Asp Ile Ala Ser Glu Gln Tyr Arg Lys 35 40 45 Phe Asp Gln Arg Gln Arg Cys Cys Gln Trp Pro Cys Pro Gly Ser Cys 50 55 60 Arg Cys Cys Arg Thr Gly 65 70 185 17 PRT Conus quercinus PEPTIDE (1)..(17) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 7 and 9 is Pro or Hyp; Xaa at residue 6 is Trp or bromo-Trp 185 Xaa Arg Cys Cys Gln Xaa Xaa Cys Xaa Gly Ser Cys Arg Cys Cys Arg 1 5 10 15 Thr 186 15 PRT Conus quercinus PEPTIDE (1)..(15) Xaa at residue 11 and 14 is Pro or Hyp 186 Cys Cys Ser Gln Asp Cys Leu Val Cys Ile Xaa Cys Cys Xaa Asn 1 5 10 15 187 15 PRT Conus quercinus PEPTIDE (1)..(15) Xaa at residue 11 14 is Pro or Hyp; Xaa at residue 7 is Trp or bromo-Trp 187 Cys Cys Ser Arg His Cys Xaa Val Cys Ile Xaa Cys Cys Xaa Asn 1 5 10 15 188 323 DNA Conus radiatus 188 tcaagaagga tcgatagcag ttcatgatgt ctaaactggg agtcttgttg accatctgtc 60 tgcttctgtt tccccttact gctcttccga tggatggaga tcaacctgta gaccgacttg 120 cagagcgtat gcaggacaac atttcatctg agcagcatac cttctttgaa aagagactac 180 catcgtgttg ctcccttaac ttgcggcttt gcccagtacc agcatgcaaa cgtaaccctt 240 gttgcacagg ataacgtgtt gatgaccaac tttgttatca cggctacgtc aagtgtctag 300 tgaataagta aaacgattgc agt 323 189 76 PRT Conus radiatus 189 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Val Asp Arg Leu 20 25 30 Ala Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His Thr Phe Phe 35 40 45 Glu Lys Arg Leu Pro Ser Cys Cys Ser Leu Asn Leu Arg Leu Cys Pro 50 55 60 Val Pro Ala Cys Lys Arg Asn Pro Cys Cys Thr Gly 65 70 75 190 24 PRT Conus radiatus PEPTIDE (1)..(24) Xaa at residue 2, 13, 15 and 21 is Pro or Hyp 190 Leu Xaa Ser Cys Cys Ser Leu Asn Leu Arg Leu Cys Xaa Val Xaa Ala 1 5 10 15 Cys Lys Arg Asn Xaa Cys Cys Thr 20 191 336 DNA Conus radiatus 191 aggtcgactc tagaggatcc ccaaggatcg atagcagttc atgatgtcta aactgggagt 60 cttgttgacc atctgtctgc ttctgtttcc ccttactgct cttccgatgg atggagatca 120 acctgcagac cgacttgcag agcgtatgca ggacgacatt tcatctgagc agcatccctt 180 ctttaaaaag agacaacaaa gatgttgcac cgttaagagg atttgtccag taccagcatg 240 cagaagtaaa ccttgttgca aatcataacg tattgatgac caactttgtt atcacggcta 300 cgtcaagtgt ctagtgaata agtaaaatga ttgcag 336 192 75 PRT Conus radiatus 192 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Arg Leu 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Gln His Pro Phe Phe 35 40 45 Lys Lys Arg Gln Gln Arg Cys Cys Thr Val Lys Arg Ile Cys Pro Val 50 55 60 Pro Ala Cys Arg Ser Lys Pro Cys Cys Lys Ser 65 70 75 193 24 PRT Conus radiatus PEPTIDE (1)..(24) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 12, 14 and 20 is Pro or Hyp 193 Xaa Gln Arg Cys Cys Thr Val Lys Arg Ile Cys Xaa Val Xaa Ala Cys 1 5 10 15 Arg Ser Lys Xaa Cys Cys Lys Ser 20 194 326 DNA Conus radiatus 194 acctcaagaa ggatcgatag cagttcatga tgtctaaact gggagtcttg ttgaccatct 60 gtctgcttct gtttcccgtt actgctcttc cgatggatgg tgatcaacct gcagaccgac 120 ttgtagagcg tatgcaggac aacatttcat ctgagcagca tcccttcttt gaaaagagaa 180 gaggaggctg ttgcacacct ccgaggaaat gcaaagaccg agcctgcaaa cctgcacgtt 240 gctgcggccc aggataacgt gttgatgacc aactttgtta tcacggctac gtcaagtgtc 300 tagtgaataa gtaaaacgat tgcagt 326 195 76 PRT Conus radiatus 195 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Val Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Arg Leu 20 25 30 Val Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His Pro Phe Phe 35 40 45 Glu Lys Arg Arg Gly Gly Cys Cys Thr Pro Pro Arg Lys Cys Lys Asp 50 55 60 Arg Ala Cys Lys Pro Ala Arg Cys Cys Gly Pro Gly 65 70 75 196 24 PRT Conus radiatus PEPTIDE (1)..(24) Xaa at residue 7, 8, 18 and 24 is Pro or Hyp 196 Arg Gly Gly Cys Cys Thr Xaa Xaa Arg Lys Cys Lys Asp Arg Ala Cys 1 5 10 15 Lys Xaa Ala Arg Cys Cys Gly Xaa 20 197 238 DNA Conus rattus 197 ggatccatga tgtctaaact gggagtcttg gtgaccatct gcctgcttct gttccctctt 60 gctgcttttc cactggatgg agatcaacct gcagaccacc ctgcaaagcg tacgcaagat 120 gacagttcag ctgccctgat caatgcctgg cttgatgaat cccagacttg ctgcagtaac 180 tgcggtgaag attgtgatgg ttgttgccag taacgtgttg atgaccaact ttctcgag 238 198 70 PRT Conus rattus 198 Gly Ser Met Met Ser Lys Leu Gly Val Leu Val Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Ala Ala Phe Pro Leu Asp Gly Asp Gln Pro Ala Asp 20 25 30 His Pro Ala Lys Arg Thr Gln Asp Asp Ser Ser Ala Ala Leu Ile Asn 35 40 45 Ala Trp Leu Asp Glu Ser Gln Thr Cys Cys Ser Asn Cys Gly Glu Asp 50 55 60 Cys Asp Gly Cys Cys Gln 65 70 199 16 PRT Conus rattus PEPTIDE (1)..(16) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 9 is Glu or gamma-carboxy Glu 199 Xaa Thr Cys Cys Ser Asn Cys Gly Xaa Asp Cys Asp Gly Cys Cys Gln 1 5 10 15 200 327 DNA Conus stercusmuscarum 200 gacctcaaga gggatcgata gcagttcgtg atgtctaaac tgggagtctt gttgaccatc 60 tgtctgcttc tgtttcctct tactgctctt ccgatggatg gagatcaacc tgcagaccaa 120 cctgcagatc gtatgcagga cgacatttca tctgagcagt atcccttgtt tgataagaga 180 caaaagtgtt gcactgggaa gaaggggtca tgctccggca aagcatgcaa aaatctcaaa 240 tgttgctctg gacgataacg tgttgatgac caactttgtt atcacggcta cgtcaagtgt 300 ctaatgaata agtaaaacga ttgcagt 327 201 75 PRT Conus stercusmuscarum 201 Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe Pro 1 5 10 15 Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Gln Pro Ala 20 25 30 Asp Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Tyr Pro Leu Phe Asp 35 40 45 Lys Arg Gln Lys Cys Cys Thr Gly Lys Lys Gly Ser Cys Ser Gly Lys 50 55 60 Ala Cys Lys Asn Leu Lys Cys Cys Ser Gly Arg 65 70 75 202 23 PRT Conus stercusmuscarum PEPTIDE (1)..(23) Xaa at residue 1 is Gln or pyro-Glu 202 Xaa Lys Cys Cys Thr Gly Lys Lys Gly Ser Cys Ser Gly Lys Ala Cys 1 5 10 15 Lys Asn Leu Lys Cys Cys Ser 20 203 316 DNA Conus stercusmuscarum 203 gatcgatagc agttcgtgat gtctaaactg ggagtcttgt tgaccatctg tctgcttctg 60 tttcccctta ctgctcttcc gatggatgga gatcaacctg cagaccaacc tgcagatcgt 120 atgcagaacg acatttcatc tgagcagtat cccttgtttg ataagagaca aaagtgttgc 180 ggccccggcg cgtcatgccc cagatatttc aaagacaatt ttatttgtgg ttgttgttaa 240 atgacaacgt gtcgatgacc aacttcgtta tcacgacttc gccaagtgtc taatgaataa 300 gtaaaacgat tgcagt 316 204 73 PRT Conus stercusmuscarum 204 Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe Pro 1 5 10 15 Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Gln Pro Ala 20 25 30 Asp Arg Met Gln Asn Asp Ile Ser Ser Glu Gln Tyr Pro Leu Phe Asp 35 40 45 Lys Arg Gln Lys Cys Cys Gly Pro Gly Ala Ser Cys Pro Arg Tyr Phe 50 55 60 Lys Asp Asn Phe Ile Cys Gly Cys Cys 65 70 205 23 PRT Conus stercusmuscarum PEPTIDE (1)..(23) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 6 and 11 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho- Tyr 205 Xaa Lys Cys Cys Gly Xaa Gly Ala Ser Cys Xaa Arg Xaa Phe Lys Asp 1 5 10 15 Asn Phe Ile Cys Gly Cys Cys 20 206 331 DNA Conus striatus 206 cgacctttca agagggatcg atagcagttc gcgatgtcta aactgggggt attgttgacc 60 atctgtctgc ttctgtttcc ccttactgct cttccgatgg atgaagatca acctgcagac 120 caacttgaag atcgtatgca ggacgacatt tcatctgagc agtatccctc gtttgttagg 180 agacaaaagt gttgcggcga aggctcgtca tgccccaaat atttcaaaaa caattttatt 240 tgtggttgtt gttaaatgac aacgtgtcga tgaccaactt cgttatcacg actacgccaa 300 gtgtcttgtc taatgataat aaaatgattc c 331 207 73 PRT Conus striatus 207 Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe Pro 1 5 10 15 Leu Thr Ala Leu Pro Met Asp Glu Asp Gln Pro Ala Asp Gln Leu Glu 20 25 30 Asp Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Tyr Pro Ser Phe Val 35 40 45 Arg Arg Gln Lys Cys Cys Gly Glu Gly Ser Ser Cys Pro Lys Tyr Phe 50 55 60 Lys Asn Asn Phe Ile Cys Gly Cys Cys 65 70 208 23 PRT Conus striatus PEPTIDE (1)..(23) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 11 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 208 Xaa Lys Cys Cys Gly Xaa Gly Ser Ser Cys Xaa Lys Xaa Phe Lys Asn 1 5 10 15 Asn Phe Ile Cys Gly Cys Cys 20 209 256 DNA Conus striatus 209 ggatccatga tgtctaaact gggagtcttg ttgaccgtct gtctgcttct gtttcccctt 60 actgctcttc cgctggatgg agatcaacct gcagaccgac ctgcagagcg tatgcaggac 120 gacatttcat ctgacgagca tcccttgttt gataagagac aaaactgttg caatggggga 180 tgctccagca aatggtgcag agatcacgca cgttgttgcg gtcgatgata acgtgttgat 240 gaccaacttt ctcgag 256 210 75 PRT Conus striatus 210 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Val Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Pro Leu Asp Gly Asp Gln Pro Ala Asp 20 25 30 Arg Pro Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Asp Glu His Pro 35 40 45 Leu Phe Asp Lys Arg Gln Asn Cys Cys Asn Gly Gly Cys Ser Ser Lys 50 55 60 Trp Cys Arg Asp His Ala Arg Cys Cys Gly Arg 65 70 75 211 20 PRT Conus striatus PEPTIDE (1)..(20) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 12 is Trp or bromo-Trp 211 Xaa Asn Cys Cys Asn Gly Gly Cys Ser Ser Lys Xaa Cys Arg Asp His 1 5 10 15 Ala Arg Cys Cys 20 212 235 DNA Conus tessulatus 212 ggatccatga tgtctaaact gggagtcttg ttgaccatgt gtctgcttct gtttcccctt 60 actgctgttc cgctggatgg agatcaacct gcagaccgac ctgcagagcg taggcaggac 120 attgcaactg acgatcatcc tttgtttgat cccgtcaaac ggtgctgcca caaatgctat 180 atgggatgca tcccttgttg catttagtaa cgtgttgatg accaactttc tcgag 235 213 68 PRT Conus tessulatus 213 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Met Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp 20 25 30 Arg Pro Ala Glu Arg Arg Gln Asp Ile Ala Thr Asp Asp His Pro Leu 35 40 45 Phe Asp Pro Val Lys Arg Cys Cys His Lys Cys Tyr Met Gly Cys Ile 50 55 60 Pro Cys Cys Ile 65 214 14 PRT Conus tessulatus PEPTIDE (1)..(14) Xaa at residue 11 is Pro or Hyp; Xaa at residue 6 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 214 Cys Cys His Lys Cys Xaa Met Gly Cys Ile Xaa Cys Cys Ile 1 5 10 215 238 DNA Conus tessulatus 215 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtgtgcttct gtttcccctt 60 actgctgttc cgctggatgg agatcaacct gcagaccaac ctgcagagcg tacgcagaac 120 gagcagcatc ccttgtatga tcagaaaaga aagtgttgcc ggccgccatg cgccatgagc 180 tgcggcatgg ctaggtgttg ctattaatga taacgtgttg atgaccaact ttctcgag 238 216 68 PRT Conus tessulatus 216 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Val Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp 20 25 30 Gln Pro Ala Glu Arg Thr Gln Asn Glu Gln His Pro Leu Tyr Asp Gln 35 40 45 Lys Arg Lys Cys Cys Arg Pro Pro Cys Ala Met Ser Cys Gly Met Ala 50 55 60 Arg Cys Cys Tyr 65 217 18 PRT Conus tessulatus PEPTIDE (1)..(18) Xaa at residue 5 and 6 is Pro or Hyp; Xaa at residue 18 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 217 Lys Cys Cys Arg Xaa Xaa Cys Ala Met Ser Cys Gly Met Ala Arg Cys 1 5 10 15 Cys Xaa 218 564 DNA Conus textile 218 gagtcaaccc actgtcacgc caagagcgga cgccacagct aaggcaagaa ggatcgatag 60 cagttcatga tgtctaaact gggagccttg ttgaccatct gtctacttct gttttccctt 120 actgctgttc cgctggatgg agatcaacat gcagaccaac ctgcacagcg tctgcaggac 180 cgcattccaa ctgaagatca tcccttattt gatcccaaca aacggtgttg cccgccggtg 240 gcatgcaaca tgggatgcaa gccttgttgt ggatgaccag ctttgttatc gcggtctcat 300 gaagtgtcta atgaataagt aaaacgattg cagtttcgtt cagatttgct gttgtatttt 360 ggtctaaaga ttaatgacca aactgttctt ttgatccgga ttttcacgta tttctcgatt 420 219 69 PRT Conus textile 219 Met Met Ser Lys Leu Gly Ala Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Gln Arg Leu Gln Asp Arg Ile Pro Thr Glu Asp His Pro Leu Phe 35 40 45 Asp Pro Asn Lys Arg Cys Cys Pro Pro Val Ala Cys Asn Met Gly Cys 50 55 60 Lys Pro Cys Cys Gly 65 220 16 PRT Conus textile PEPTIDE (1)..(16) Xaa at residue 3, 4 and 13 is Pro or Hyp 220 Cys Cys Xaa Xaa Val Ala Cys Asn Met Gly Cys Lys Xaa Cys Cys Gly 1 5 10 15 221 780 DNA Conus textile 221 ggatccagac gacaaagaag agtcaaccca ctgccacgtc aagagcagag cccacagcta 60 agacaagaag gatcgatagc agttcatgat gtttaaactg ggagtcttgt tgaccatctg 120 tctccttctg ttttccctta atgctgttcc gttggatgga gatcaacctg cagaccaacc 180 tgcagagcgt ctgctggacg acatttcatt tgaaaataat cccttttatg atcccgccaa 240 acggtgttgc aggacttgct tcggttgcac accttgttgt ggatgaccag cctcatcaag 300 tgtctaacga ataagtaaag cgattgcagt ctcgttcaga tttacttttg tattctggtc 360 taaagattaa tgaccaaact cttcttttga tccggatgta catatatttc tcgattccta 420 tccaacgcta gataagctaa tcacgacaga tctgattttc tgtcaatgcc ttgctttttg 480 gtctctcata tcactcttgt ttatatttaa tttctcgtca ctatatatat atatacacac 540 acacacacac ggaattccga ttgtccagta ccgttcttgg gatcgaggta ttgctgcgat 600 ggcttattct gtactctttt cttctgcgct tgatagtgat gtcttctact cccatctgtg 660 ctacccctgg cttgatcttt gataggcgtg tgcccttcac tggttataaa cccctctgat 720 cctactctct ggacgcctcg ggggcccaac ctccaaataa agcgacatcc aatgaaaaaa 780 222 66 PRT Conus textile 222 Met Met Phe Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Asn Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Leu Asp Asp Ile Ser Phe Glu Asn Asn Pro Phe Tyr 35 40 45 Asp Pro Ala Lys Arg Cys Cys Arg Thr Cys Phe Gly Cys Thr Pro Cys 50 55 60 Cys Gly 65 223 12 PRT Conus textile PEPTIDE (1)..(12) Xaa at residue 10 is Pro or Hyp 223 Cys Cys Arg Thr Cys Phe Gly Cys Thr Xaa Cys Cys 1 5 10 224 456 DNA Conus textile 224 ggaacagtca accccacagc cacgccaaga gcagacagcc acagctacgt gaagaagggt 60 ggagagaggt tcatgatgtt gaaaatggga gtggtgctat tcatctttct ggtactgttt 120 cccctggcaa cgctccagct ggatgcagat caacctgtag aacgatatgc ggagaacaaa 180 cagctcctca acccagatga aaggagggaa atcctattgc ctgctctgag gaagttctgc 240 tgtgattcga attggtgcca catttcggat tgtgagtgct gctacggtta gcgccgaaca 300 tccatggcac tgtgctgggc ggtttcatcc caacaacgac agcgtttgtt gatttcatgt 360 atcattgcgc ccacgtctct tgtctaagaa tgacgaacat gattgcactc tggttcagat 420 ttcgtgttct tttctgacaa taaatgacaa acctcc 456 225 70 PRT Conus textile 225 Met Met Leu Lys Met Gly Val Val Leu Phe Ile Phe Leu Val Leu Phe 1 5 10 15 Pro Leu Ala Thr Leu Gln Leu Asp Ala Asp Gln Pro Val Glu Arg Tyr 20 25 30 Ala Glu Asn Lys Gln Leu Leu Asn Pro Asp Glu Arg Arg Glu Ile Leu 35 40 45 Leu Pro Ala Leu Arg Lys Phe Cys Cys Asp Ser Asn Trp Cys His Asp 50 55 60 Cys Glu Cys Cys Tyr Gly 65 70 226 17 PRT Conus textile PEPTIDE (1)..(17) Xaa at residue 14 is Glu or gamma-carboxy Glu; Xaa at residue 7 is Trp or bromo-Trp; Xaa at residue 17 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho- Tyr 226 Phe Cys Cys Asp Ser Asn Xaa Cys His Ile Ser Asp Cys Xaa Cys Cys 1 5 10 15 Xaa 227 456 DNA Conus textile misc_feature (1)..(456) n may be any nucleotide 227 caaggaacag tcaaccccac agccacgcca agagcagaca gccacagcta cgtgaagaag 60 ggtggagaga ggttcgtgat gttgaaaatg ggagtggtgc tattcatctt cctggtactg 120 tttcccctgg caacgctcca gctggatgca gatcaacctg tagaacgata tgcggagaac 180 aaacagctcc tcagcccaga tgaaaggagg gaaatcatat tgcatgctct ggggacgcga 240 tgctgttctt gggatgtgtg cgaccacccg agttgtactt gctgcggtta gcgccgaaca 300 tccatggcgc tgtgctgggc ggttttatcc caacaacgac agcgtttgtt gatttcatgt 360 atcattgcgc ccacgtctct tgtctaagaa tgacgaacat gattgcactc tggttcagat 420 ttcgtgttct tttctgacaa taaatgacaa aacncc 456 228 70 PRT Conus textile 228 Met Leu Lys Met Gly Val Val Leu Phe Ile Phe Leu Val Leu Phe Pro 1 5 10 15 Leu Ala Thr Leu Gln Leu Asp Ala Asp Gln Pro Val Glu Arg Tyr Ala 20 25 30 Glu Asn Lys Gln Leu Leu Ser Pro Asp Glu Arg Arg Glu Ile Ile Leu 35 40 45 His Ala Leu Gly Thr Arg Cys Cys Ser Trp Asp Val Cys Asp His Pro 50 55 60 Ser Cys Thr Cys Cys Gly 65 70 229 15 PRT Conus textile PEPTIDE (1)..(15) Xaa at residue 10 is Pro or Hyp; Xaa at residue 4 is Trp or bromo-Trp 229 Cys Cys Ser Xaa Asp Val Cys Asp His Xaa Ser Cys Thr Cys Cys 1 5 10 15 230 235 DNA Conus textile 230 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctcttc cgctggatgg agatcaaccc gcagaccaag ctgcagagcg tatgcaggcc 120 gagcagcatc ccttgtttga tcagaaaaga cggtgctgca agtttccatg ccccgatagt 180 tgcagatatt tgtgttgcgg gtgatgataa cgtgttgatg accaactttc tcgag 235 231 67 PRT Conus textile 231 Gly Ser Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu 1 5 10 15 Leu Phe Pro Leu Thr Ala Leu Pro Leu Asp Gly Asp Gln Pro Ala Asp 20 25 30 Gln Ala Ala Glu Arg Met Gln Ala Glu Gln His Pro Leu Phe Asp Gln 35 40 45 Lys Arg Arg Cys Cys Lys Phe Pro Cys Pro Asp Ser Cys Arg Tyr Leu 50 55 60 Cys Cys Gly 65 232 16 PRT Conus textile PEPTIDE (1)..(16) Xaa at residue 3 and 8 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 232 Arg Cys Cys Lys Phe Xaa Cys Xaa Asp Ser Cys Arg Xaa Leu Cys Cys 1 5 10 15 233 321 DNA Conus tulipa 233 cgacctcaag agggatcgat agcagttcat gtctaaactg ggagtcttgt tgacaatctg 60 tctgcttctg tttcccctta ctgctctgcc gatggatgga gatgaacctg cagaccgacc 120 tgcagagcgt atgcaggaca acatttcatc tgagcagcat cccttgtttg aggagagaca 180 cggatgttgc aaggggcccg aaggatgctc ctccagagaa tgcagacccc aacattgttg 240 cggtcgacga taacgtgttg agggccaact ttgttatcac ggctacgtca agtgtttagt 300 gaataagtaa aatgattgca g 321 234 74 PRT Conus tulipa 234 Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe Pro 1 5 10 15 Leu Thr Ala Leu Pro Met Asp Gly Asp Glu Pro Ala Asp Arg Pro Ala 20 25 30 Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His Pro Leu Phe Glu 35 40 45 Glu Arg His Gly Cys Cys Lys Gly Pro Glu Gly Cys Ser Ser Arg Glu 50 55 60 Cys Arg Pro Gln His Cys Cys Gly Arg Arg 65 70 235 21 PRT Conus tulipa PEPTIDE (1)..(21) Xaa at residue 8 and 14 is Glu or gamma-carboxy Glu; Xaa at residue 7 and 17 is Pro or Hyp 235 His Gly Cys Cys Lys Gly Xaa Xaa Gly Cys Ser Ser Arg Xaa Cys Arg 1 5 10 15 Xaa Gln His Cys Cys 20 236 287 DNA Conus figulinus 236 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttgctga ccatctgtct 60 gcttctgatt ccccttactg ctctttcgct ggatggagat caacctgcag accgacctgc 120 agagcgtatg caggatggaa tttcatctga acagcatccc atgtttgatc ccgtcagacg 180 gtgttgcccg tggccatgca acataggatg cgtaccttgt tgttgatgac cagttttgtt 240 atcgcggcct catcaaatgt ctaatgaata agtaaaacga ttgcagt 287 237 67 PRT Conus figulinus 237 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Ile 1 5 10 15 Pro Leu Thr Ala Leu Ser Leu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Gly Ile Ser Ser Glu Gln His Pro Met Phe 35 40 45 Asp Pro Val Arg Arg Cys Cys Pro Trp Pro Cys Asn Ile Gly Cys Val 50 55 60 Pro Cys Cys 65 238 14 PRT Conus figulinus PEPTIDE (1)..(14) Xaa at residue 3, 5 and 12 is Pro or Hyp; Xaa at residue 4 is Trp or bromo-Trp 238 Cys Cys Xaa Xaa Xaa Cys Asn Ile Gly Cys Val Xaa Cys Cys 1 5 10 239 283 DNA Conus figulinus 239 caagagggat cgatagcagt tcatgatgtt taaactggga gtcctgttga ccatctgtat 60 gcttctgttt ccctttactg ctcttccgct ggatggagag caacctgcag accaacctgc 120 agagcgcatg cagtatgaca tgttacgtgc aatgaatccc tggtttgatc ccgtcaaaag 180 gtgctgctcg aagaactgcg cagtatgcat cccttgttgc ccgtaactga ccagcttgat 240 tatcgcggcc aaggctctaa tgaataagta aaacgattgc agt 283 240 67 PRT Conus figulinus 240 Met Met Phe Lys Leu Gly Val Leu Leu Thr Ile Cys Met Leu Leu Phe 1 5 10 15 Pro Phe Thr Ala Leu Pro Leu Asp Gly Glu Gln Pro Ala Asp Gln Pro 20 25 30 Ala Glu Arg Met Gln Tyr Asp Met Leu Arg Ala Met Asn Pro Trp Phe 35 40 45 Asp Pro Val Lys Arg Cys Cys Ser Lys Asn Cys Ala Val Cys Ile Pro 50 55 60 Cys Cys Pro 65 241 14 PRT Conus figulinus PEPTIDE (1)..(14) Xaa at residue 11 and 14 is Pro or Hyp 241 Cys Cys Ser Lys Asn Cys Ala Val Cys Ile Xaa Cys Cys Xaa 1 5 10 242 286 DNA Conus figulinus 242 caagagggat cgatagcagt tcatgatgtc taaactgaga gtcttgttga ccttatgtct 60 gcttctgttt ccccttactg ctcttccgct gaatgaagat caacctgcag agcgtatgca 120 ggacgacaat tcatctgagc agcacccctt gtatgaccac aaacgaaagt gttgccggtg 180 gccatgcccc gcaagatgcg gctcttgttg cctgtaataa cgtgttggcc aactttgtta 240 tcacggccac gtcaaatgtt taatgaataa gtaaaacgat tgcagt 286 243 64 PRT Conus figulinus 243 Met Met Ser Lys Leu Arg Val Leu Leu Thr Leu Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asn Glu Asp Gln Pro Ala Glu Arg Met 20 25 30 Gln Asp Asp Asn Ser Ser Glu Gln His Pro Leu Tyr Asp His Lys Arg 35 40 45 Lys Cys Cys Arg Trp Pro Cys Pro Ala Arg Cys Gly Ser Cys Cys Leu 50 55 60 244 15 PRT Conus figulinus PEPTIDE (1)..(15) Xaa at residue 5 and 7 is Pro or Hyp; Xaa at residue 4 is Trp or bromo-Trp 244 Cys Cys Arg Xaa Xaa Cys Xaa Ala Arg Cys Gly Ser Cys Cys Leu 1 5 10 15 245 301 DNA Conus figulinus 245 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccttatgtct 60 gcttctgttt cccctgactg ctcttccgct ggatgaagat caagctgcag accgacctgc 120 agagcgtatg cagggcatgt catctgaaca gcatcccttc tttgatcccg tcaaacggtg 180 ttgcgagttg tcacgctgcc ttggatgcgt cccttgttgc acatcttaat aacgtgtgga 240 tgaccaactg tgttatcacg gccacgtcaa gtgtctaatg aataagtaaa atgattgcag 300 t 301 246 68 PRT Conus figulinus 246 Met Met Ser Lys Leu Gly Val Leu Leu Thr Leu Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Glu Asp Gln Ala Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Gly Met Ser Ser Glu Gln His Pro Phe Phe Asp 35 40 45 Pro Val Lys Arg Cys Cys Glu Leu Ser Arg Cys Leu Gly Cys Val Pro 50 55 60 Cys Cys Thr Ser 65 247 16 PRT Conus figulinus PEPTIDE (1)..(16) Xaa at residue 3 and 12 is Pro or Hyp 247 Cys Cys Xaa Leu Ser Arg Cys Leu Gly Cys Val Xaa Cys Cys Thr Ser 1 5 10 15 248 301 DNA Conus figulinus 248 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccttatgtct 60 gcttctgttt cccctgactg ctcttccgct ggatgaagat caacctgcag accgacctgc 120 agagcgtatg cagggcatgt catctgaaca gcatcccttc tttgatcccg tcaaacggtg 180 ttgcgagttg tcaaaatgcc atggatgcgt cccttgttgc ataccttaat aacgtgcgga 240 tgaccaactg tgttatcacg gccacgtcaa gtgtctaatg aataagtaaa atgattgcag 300 t 301 249 68 PRT Conus figulinus 249 Met Met Ser Lys Leu Gly Val Leu Leu Thr Leu Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Glu Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Gly Met Ser Ser Glu Gln His Pro Phe Phe Asp 35 40 45 Pro Val Lys Arg Cys Cys Glu Leu Ser Lys Cys His Gly Cys Val Pro 50 55 60 Cys Cys Ile Pro 65 250 16 PRT Conus figulinus PEPTIDE (1)..(16) Xaa at residue 3 is Glu or gamma-carboxy Glu; Xaa at residue 12 and 16 is Pro or Hyp 250 Cys Cys Xaa Leu Ser Lys Cys His Gly Cys Val Xaa Cys Cys Ile Xaa 1 5 10 15 251 298 DNA Conus quercinus 251 caagagggat cgatagcagt tcatgatgtc taaactcgga gtcttgttga ccatctgtct 60 ggttctgttt ccccttacag ctcttcagct ggatggagat caacctgcag accgacctgc 120 agagcgtacg caggacattt catctgaaca gtatcgaaag tttgatcaga gacagaggtg 180 ttgccggtgg ccatgccccg gtagttgcag atgctgccgt tatcgttaac gtgttggtga 240 ccagctttgt tatcacgacc acgccaagtg tctaacgaat aagtaaaatg attgcagt 298 252 68 PRT Conus quercinus 252 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Val Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Gln Leu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Thr Gln Asp Ile Ser Ser Glu Gln Tyr Arg Lys Phe Asp 35 40 45 Gln Arg Gln Arg Cys Cys Arg Trp Pro Cys Pro Gly Ser Cys Arg Cys 50 55 60 Cys Arg Tyr Arg 65 253 18 PRT Conus quercinus PEPTIDE (1)..(18) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 7 and 9 is Pro or Hyp; Xaa at residue 6 is Trp or bromo-Trp; Xaa at residue 17 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 253 Xaa Arg Cys Cys Arg Xaa Xaa Cys Xaa Gly Ser Cys Arg Cys Cys Arg 1 5 10 15 Xaa Arg 254 313 DNA Conus quercinus 254 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccact ggatggagat caacctgcag atcaatctgc 120 agagcgacct gcagagcgta cgcaggacga cattcagcag catccgttat atgatccgaa 180 aagaaggtgt tgccgttatc catgccccga cagctgccac ggatcttgct gctataagtg 240 ataacatgtt gatggccagc tttgttatca cggccacgtc aagtgtctaa tgaataagta 300 aaacgattgc agt 313 255 72 PRT Conus quercinus 255 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Gly Asp Gln Pro Ala Asp Gln Ser 20 25 30 Ala Glu Arg Pro Ala Glu Arg Thr Gln Asp Asp Ile Gln Gln His Pro 35 40 45 Leu Tyr Asp Pro Lys Arg Arg Cys Cys Arg Tyr Pro Cys Pro Asp Ser 50 55 60 Cys His Gly Ser Cys Cys Tyr Lys 65 70 256 18 PRT Conus quercinus PEPTIDE (1)..(18) Xaa at residue 6 and 8 is Pro or Hyp; Xaa at residue 5 and 17 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 256 Arg Cys Cys Arg Xaa Xaa Cys Xaa Asp Ser Cys His Gly Ser Cys Cys 1 5 10 15 Xaa Lys 257 256 DNA Conus wittigi 257 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccatt 60 actgctcttc cggtgggtgg agatcagcct gcagaccgac ttgcagagcg tatgcaggac 120 gacacttcat ctgagcagca tccctttgaa aagagactac catcatgttg cgactttgag 180 aggctttgcg tagtaccagc atgcatacgt catcagtgtt gcacaggata acgtgttgat 240 gaccaacttt ctcgag 256 258 74 PRT Conus wittigi 258 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Ile Thr Ala Leu Pro Val Gly Gly Asp Gln Pro Ala Asp Arg Leu 20 25 30 Ala Glu Arg Met Gln Asp Asp Thr Ser Ser Glu Gln His Pro Phe Glu 35 40 45 Lys Arg Leu Pro Ser Cys Cys Asp Phe Glu Arg Leu Cys Val Val Pro 50 55 60 Ala Cys Ile Arg His Gln Cys Cys Thr Gly 65 70 259 23 PRT Conus wittigi PEPTIDE (1)..(23) Xaa at residue 8 is Glu or gamma-carboxy Glu; Xaa at residue 2 and 14 is Pro or Hyp 259 Leu Xaa Ser Cys Cys Asp Phe Xaa Arg Leu Cys Val Val Xaa Ala Cys 1 5 10 15 Ile Arg His Gln Cys Cys Thr 20 260 14 PRT Conus betulinus PEPTIDE (1)..(14) Xaa at residue 11 is Pro or Hyp; Xaa at residue 14 is Trp or bromo-Trp 260 Cys Cys Lys Gln Ser Cys Thr Thr Cys Met Xaa Cys Cys Xaa 1 5 10 261 259 DNA Conus tulipa misc_feature (1)..(259) n may be any nucleotide 261 ggatccatga tgtctaaact gggagtcttg ttgacaatct gtctgcttct gtttcccctt 60 actgctctgc cgatggatgg agatgaacct gcagaccgac ctgcagagcg tatgcaggac 120 aacatttcat ctgagcagca tcccttgttt gaggagagac acggatgttg cgaggggccg 180 aagggatgct cctccagaga atgcagaccc caacattgtt gcggtcgacg ataacgtgtt 240 gatgaccaac tntctcgag 259 262 75 PRT Conus tulipa 262 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Glu Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His Pro Leu Phe 35 40 45 Glu Glu Arg His Gly Cys Cys Glu Gly Pro Lys Gly Cys Ser Ser Arg 50 55 60 Glu Cys Arg Pro Gln His Cys Cys Gly Arg Arg 65 70 75 263 21 PRT Conus tulipa PEPTIDE (1)..(21) Xaa at residue 5 and 14 is Glu or gamma-carboxy Glu; Xaa at residue 7 and 17 is Pro or Hyp 263 His Gly Cys Cys Xaa Gly Xaa Lys Gly Cys Ser Ser Arg Xaa Cys Arg 1 5 10 15 Xaa Gln His Cys Cys 20 264 262 DNA Conus aurisiacus misc_feature (1)..(262) n may be any nucleotide 264 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctacttct gtttcccctt 60 actgcttttc cgatggatgg agatcaacct gcagaccaac ctgcagatcg tatgcaggac 120 gacatttcat ctgagcagta tcccttgttt gataagagac aaaagtgttg cactgggagg 180 aaggggtcat gctccggcaa agcatgcaaa aatctcaaat gttgctctgg acgataacgt 240 gttgatgacc aactttctcg an 262 265 76 PRT Conus aurisiacus 265 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Phe Pro Met Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Asp Arg Met Gln Asp Asp Ile Ser Ser Glu Gln Tyr Pro Leu Phe 35 40 45 Asp Lys Arg Gln Lys Cys Cys Thr Gly Arg Lys Gly Ser Cys Ser Gly 50 55 60 Lys Ala Cys Lys Asn Leu Lys Cys Cys Ser Gly Arg 65 70 75 266 23 PRT Conus aurisiacus PEPTIDE (1)..(23) Xaa at residue 1 is Gln or pyro-Glu 266 Xaa Lys Cys Cys Thr Gly Arg Lys Gly Ser Cys Ser Gly Lys Ala Cys 1 5 10 15 Lys Asn Leu Lys Cys Cys Ser 20 267 239 DNA Conus betulinus 267 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctgttc cgttggatgg agatcaacct gcagaccaac ctgcagagcg tatgcagaac 120 gagcagcatc cctcgtttga tcagaaaaga aggtgctgcc ggtggccatg ccccagtata 180 tgcggcatgg ctaggtgttg cttcgtcatg ataacgtgtt gatgaccaac tttctcgag 239 268 71 PRT Conus betulinus 268 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Glu Arg Met Gln Asn Glu Gln His Pro Ser Phe Asp Gln Lys Arg 35 40 45 Arg Cys Cys Arg Trp Pro Cys Pro Ser Ile Cys Gly Met Ala Arg Cys 50 55 60 Cys Phe Val Met Ile Thr Cys 65 70 269 23 PRT Conus betulinus PEPTIDE (1)..(23) Xaa at residue 6 and 8 is Pro or Hyp; Xaa at residue 5 is Trp or bromo-Trp 269 Arg Cys Cys Arg Xaa Xaa Cys Xaa Ser Ile Cys Gly Met Ala Arg Cys 1 5 10 15 Cys Phe Val Met Ile Thr Cys 20 270 226 DNA Conus betulinus misc_feature (1)..(226) n may be any nucleotide 270 ggatccatga tgtctaaact gggagtcttg ttgatcatct gtctgcttct gtttcccctt 60 actgctgttc cgctggatgg agatcagcct gcagagcgta cgcagatcga gcagcatccc 120 ttgtttgacc agaaaagaag gtgttgccgg tggccatgcc ccagtagatg cggcatggct 180 aggtgttgct tcgtcatgat aacgtgttga tgancgacct ctcnag 226 271 67 PRT Conus betulinus 271 Met Met Ser Lys Leu Gly Val Leu Leu Ile Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Glu Arg Thr 20 25 30 Gln Ile Glu Gln His Pro Leu Phe Asp Gln Lys Arg Arg Cys Cys Arg 35 40 45 Trp Pro Cys Pro Ser Arg Cys Gly Met Ala Arg Cys Cys Phe Val Met 50 55 60 Ile Thr Cys 65 272 23 PRT Conus betulinus PEPTIDE (1)..(23) Xaa at residue 6 and 8 is Pro or Hyp; Xaa at residue 5 is Trp or bromo-Trp 272 Arg Cys Cys Arg Xaa Xaa Cys Xaa Ser Arg Cys Gly Met Ala Arg Cys 1 5 10 15 Cys Phe Val Met Ile Thr Cys 20 273 262 DNA Conus parius 273 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctcttc cgatggatgg tgatcaacct gcagaccgac ttgtagagcg tatgcaggac 120 aacatttcat ctgagcagca tcccttcttt gaaaagagaa gaggaggctg ttgcacacct 180 ccgaagaaat gcaaagaccg agcctgcaaa cctgcacgtt gctgcggccc aggataacgt 240 gttgatgacc aactttctcg cc 262 274 76 PRT Conus parius 274 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Arg Leu 20 25 30 Val Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His Pro Phe Phe 35 40 45 Glu Lys Arg Arg Gly Gly Cys Cys Thr Pro Pro Lys Lys Cys Lys Asp 50 55 60 Arg Ala Cys Lys Pro Ala Arg Cys Cys Gly Pro Gly 65 70 75 275 24 PRT Conus parius PEPTIDE (1)..(24) Xaa at residue 7, 8, 18 and 24 is Pro or Hyp 275 Arg Gly Gly Cys Cys Thr Xaa Xaa Lys Lys Cys Lys Asp Arg Ala Cys 1 5 10 15 Lys Xaa Ala Arg Cys Cys Gly Xaa 20 276 259 DNA Conus parius 276 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctcttc cgatggatgg tgatcaacct gcagaccgac ttgtagagcg tatgcaggac 120 aacatttcat ctgagcagca tcccttcttt gaaaagagaa gaggctgttg cacacctccg 180 aggaaatgca aagaccgagc ctgcaaacct gcacgttgtt gcggcccagg ataacgtgtt 240 gatgaccaac tttctcgag 259 277 75 PRT Conus parius 277 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Arg Leu 20 25 30 Val Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His Pro Phe Phe 35 40 45 Glu Lys Arg Arg Gly Cys Cys Thr Pro Pro Arg Lys Cys Lys Asp Arg 50 55 60 Ala Cys Lys Pro Ala Arg Cys Cys Gly Pro Gly 65 70 75 278 23 PRT Conus parius PEPTIDE (1)..(23) Xaa at residue 6, 7, 17 and 23 is Pro or Hyp 278 Arg Gly Cys Cys Thr Xaa Xaa Arg Lys Cys Lys Asp Arg Ala Cys Lys 1 5 10 15 Xaa Ala Arg Cys Cys Gly Xaa 20 279 241 DNA Conus coronatus 279 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttccaatt 60 actgcccttc cgctggatga agatcaacct gcagaccgac ctgcagagcg tatgcaggac 120 attgcaactg aacagcatcc cttgtttgat cccgtcaaac ggtgctgcga ttggccatgc 180 atcccaggat gcaccccttg ttgcttgcct tgataacgtg ttgatgacca actttctcga 240 g 241 280 68 PRT Conus coronatus 280 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Ile Thr Ala Leu Pro Leu Asp Glu Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Ile Ala Thr Glu Gln His Pro Leu Phe Asp 35 40 45 Pro Val Lys Arg Cys Cys Asp Trp Pro Cys Ile Pro Gly Cys Thr Pro 50 55 60 Cys Cys Leu Pro 65 281 16 PRT Conus coronatus PEPTIDE (1)..(16) Xaa at residue 5, 8, 12 and 16 is Pro or Hyp; Xaa at residue 4 is Trp or bromo-Trp 281 Cys Cys Asp Xaa Xaa Cys Ile Xaa Gly Cys Thr Xaa Cys Cys Leu Xaa 1 5 10 15 282 244 DNA Conus musicus 282 ggatccatga tgtctaaact gggagtcctg ttgaccatct gtctgcttct gtttcctctt 60 tctgctcttc cgatggatga agatcaactt gcagacctac ctgcagagcg tatgcgggac 120 actgcaactg tagatcatcc ctcctatgat cctgacaaag cgtgctgcga gcagagctgt 180 acaacatgct ttccgtgctg ctagccttga acacagtaac gtgttgatga ccaactttct 240 cgag 244 283 65 PRT Conus musicus 283 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Ser Ala Leu Pro Met Asp Glu Asp Gln Leu Ala Asp Leu Pro 20 25 30 Ala Glu Arg Met Arg Asp Thr Ala Thr Val Asp His Pro Ser Tyr Asp 35 40 45 Pro Asp Lys Ala Cys Cys Glu Gln Ser Cys Thr Thr Cys Phe Pro Cys 50 55 60 Cys 65 284 14 PRT Conus musicus PEPTIDE (1)..(14) Xaa at residue4 is Glu or gamma-carboxy Glu; Xaa at residue 12 is Pro or Hyp 284 Ala Cys Cys Xaa Gln Ser Cys Thr Thr Cys Phe Xaa Cys Cys 1 5 10 285 14 PRT Conus betulinus PEPTIDE (1)..(14) Xaa at residue 4 is Glu or gamma-carboxy Glu; Xaa at residue 12 is Pro or Hyp 285 Ala Cys Cys Xaa Gln Ser Cys Thr Thr Cys Met Xaa Cys Cys 1 5 10 286 14 PRT Conus betulinus PEPTIDE (1)..(14) Xaa at residue 3 is Glu or gamma-carboxy Glu; Xaa at residue 11 is Pro or Hyp; Xaa at residue 14 is Trp or bromo-Trp 286 Cys Cys Xaa Gln Ser Cys Thr Thr Cys Met Xaa Cys Cys Xaa 1 5 10 287 235 DNA Conus pennaceus 287 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctcttc cgctggatgg agatcaacct gcataccaag ctgcagagcg tatgcaggcc 120 gagcatcatc ccttgtttga tcagaaaaga cggtgctgca agtttccatg ccccgatagt 180 tgcaaatatt tgtgttgcgg gtgatgataa catgttgatg accaactttc ttgag 235 288 65 PRT Conus pennaceus 288 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Gly Asp Gln Pro Ala Tyr Gln Ala 20 25 30 Ala Glu Arg Met Gln Ala Glu His His Pro Leu Phe Asp Gln Lys Arg 35 40 45 Arg Cys Cys Lys Phe Pro Cys Pro Asp Ser Cys Lys Tyr Leu Cys Cys 50 55 60 Gly 65 289 16 PRT Conus pennaceus PEPTIDE (1)..(16) Xaa at residue 6 and 8 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 289 Arg Cys Cys Lys Phe Xaa Cys Xaa Asp Ser Cys Lys Xaa Leu Cys Cys 1 5 10 15 290 241 DNA Conus pulicarius 290 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctcttc cgatggatgg tgatcaactt gcagaccgac ttgtagagcg tatgcaggac 120 aacatttcat ctgagcagca tcccttcttt gatcccgtca aacggtgttg cgtcagctgt 180 tacatgggat gcatcccttg ttgcttctag taataacgtg ttgatgacca actttctcga 240 g 241 291 67 PRT Conus pulicarius 291 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Leu Ala Asp Arg Leu 20 25 30 Val Glu Arg Met Gln Asp Asn Ile Ser Ser Glu Gln His Pro Phe Phe 35 40 45 Asp Pro Val Lys Arg Cys Cys Val Ser Cys Tyr Met Gly Cys Ile Pro 50 55 60 Cys Cys Phe 65 292 14 PRT Conus pulicarius PEPTIDE (1)..(14) Xaa at residue 11 is Pro or Hyp; Xaa at residue 6 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 292 Cys Cys Val Ser Cys Xaa Met Gly Cys Ile Xaa Cys Cys Phe 1 5 10 293 244 DNA Conus pulicarius 293 ggatccatga tgtctaaact gggagtcttg ttgaccgtct gtctgcttct gtgtcccctt 60 actgctcttc cactggatga agatcaactt gcagaccgac ctgcagagcg tatgcaggat 120 gacacttcag ctgcacagat tttcgggttt gatcccgtca aacggtgctg caaattgcta 180 tgctactcgg gatgcactcc ttgttgccat atttgataac gtgttgatga ccaactttct 240 cgag 244 294 67 PRT Conus pulicarius 294 Met Met Ser Lys Leu Gly Val Leu Leu Thr Val Cys Leu Leu Leu Cys 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Glu Asp Gln Leu Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Thr Ser Ala Ala Gln Ile Phe Gly Phe 35 40 45 Asp Pro Val Lys Arg Cys Cys Lys Leu Leu Cys Gly Cys Thr Pro Cys 50 55 60 Cys His Ile 65 295 16 PRT Conus pulicarius PEPTIDE (1)..(16) Xaa at residue 12 is Pro or Hyp; Xaa at residue 7 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 295 Cys Cys Lys Leu Leu Cys Xaa Ser Gly Cys Thr Xaa Cys Cys His Ile 1 5 10 15 296 259 DNA Conus rattus 296 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttgt gtttccgctt 60 actgctcttc cgatggatgg tgatcaacct gcagaccgac ttgtagagcg tatacaggac 120 aacatttcat ctgagcagca tcccttcttt gaaaagagaa gaggctgttg cgcacctccg 180 aggaaatgca aagaccgagc ctgcaaacct gcacgttgct gcggcccagg ataacgtgtt 240 gatgaccaac tttctcgag 259 297 75 PRT Conus rattus 297 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Val Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Arg Leu 20 25 30 Val Glu Arg Ile Gln Asp Asn Ile Ser Ser Glu Gln His Pro Phe Phe 35 40 45 Glu Lys Arg Arg Gly Cys Cys Ala Pro Pro Arg Lys Cys Lys Asp Arg 50 55 60 Ala Cys Lys Pro Ala Arg Cys Cys Gly Pro Gly 65 70 75 298 23 PRT Conus rattus PEPTIDE (1)..(23) Xaa at residue 6, 7, 17 and 23 is Pro or Hyp 298 Arg Gly Cys Cys Ala Xaa Xaa Arg Lys Cys Lys Asp Arg Ala Cys Lys 1 5 10 15 Xaa Ala Arg Cys Cys Gly Xaa 20 299 262 DNA Conus stercusmuscarum 299 ggatccatga tgtctaaact gggagtcttg ttgacaatct gtctgcttct gtttcccctt 60 attgctcttc cgctggatgg agatcaacct gcagaccgac ctgcagagcg tatgcaggac 120 gacatttcat ctgagaagca tcccttgttt gataagagac aacggtgttg caatgggcgg 180 aggggatgct ccagcagatg gtgcagagat cactcacgtt gttgcggtcg acgataacgt 240 gttgatgacc aactttctcg ag 262 300 76 PRT Conus stercusmuscarum 300 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Ile Ala Leu Pro Leu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Lys His Pro Leu Phe 35 40 45 Asp Lys Arg Gln Arg Cys Cys Asn Gly Arg Arg Gly Cys Ser Ser Arg 50 55 60 Trp Cys Arg Asp His Ser Arg Cys Cys Gly Arg Arg 65 70 75 301 22 PRT Conus stercusmuscarum PEPTIDE (1)..(22) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 14 is Trp or bromo-Trp 301 Xaa Arg Cys Cys Asn Gly Arg Arg Gly Cys Ser Ser Arg Xaa Cys Arg 1 5 10 15 Asp His Ser Arg Cys Cys 20 302 241 DNA Conus ebraceus 302 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctcttc cactggatga aggtcaacct gcagacctac ctgcagagcg tatgcaggac 120 attgcaactg aacagcatcc cttgtttgat cctgtcaaac ggtgttgcga gcagccatgc 180 tacatgggat gcatcccttg ttgcttctaa taataacgtg ttgatgacca actttctcga 240 g 241 303 67 PRT Conus ebraceus 303 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Glu Gly Gln Pro Ala Asp Leu Pro 20 25 30 Ala Glu Arg Met Gln Asp Ile Ala Thr Glu Gln His Pro Leu Phe Asp 35 40 45 Pro Val Lys Arg Cys Cys Glu Gln Pro Cys Tyr Met Gly Cys Ile Pro 50 55 60 Cys Cys Phe 65 304 15 PRT Conus ebraceus PEPTIDE (1)..(15) Xaa at residue 3 is Glu or gamma-carboxy Glu; Xaa at residue 5 and 12 is Pro or Hyp; Xaa at residue 7 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho- Tyr 304 Cys Cys Xaa Gln Xaa Cys Xaa Met Gly Cys Ile Xaa Cys Cys Phe 1 5 10 15 305 241 DNA Conus ebraceus 305 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctcttc cactggatga agatcaacct gcagacctac ctgcagagcg tatgcaggac 120 attgcaactg aacagcatcc cttgtttgat cctgtcaaac ggtgctgcgc gcagccatgc 180 tacatgggat gcatcccttg ttgcttctaa taataacgtg ttgatgacca actttctcga 240 g 241 306 67 PRT Conus ebraceus 306 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Glu Asp Gln Pro Ala Asp Leu Pro 20 25 30 Ala Glu Arg Met Gln Asp Ile Ala Thr Glu Gln His Pro Leu Phe Asp 35 40 45 Pro Val Lys Arg Cys Cys Ala Gln Pro Cys Tyr Met Gly Cys Ile Pro 50 55 60 Cys Cys Phe 65 307 15 PRT Conus ebraceus PEPTIDE (1)..(15) Xaa at residue 5 and 12 is Pro or Hyp; Xaa at residue 7 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho- Tyr or O-phospho-Tyr 307 Cys Cys Ala Gln Xaa Cys Xaa Met Gly Cys Ile Xaa Cys Cys Phe 1 5 10 15 308 238 DNA Conus flavidus 308 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttcccctt 60 actgctgttc cgttggatgg agatcaacct gcagaccagc ctgcagagcg tatgcagaac 120 gagcagcatc ccttgtttga tcagaaaaga aggtgctgcc ggtggccatg ccccagtata 180 tgcggcatgg ctaggtgttg ctcgtcatga taacgtgttg atgaccaact ttctcgag 238 309 67 PRT Conus flavidus 309 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Glu Arg Met Gln Asn Glu Gln His Pro Leu Phe Asp Gln Lys Arg 35 40 45 Arg Cys Cys Arg Trp Pro Cys Pro Ser Ile Cys Gly Met Ala Arg Cys 50 55 60 Cys Ser Ser 65 310 19 PRT Conus flavidus PEPTIDE (1)..(19) Xaa at residue 6 and 8 is Pro or Hyp; Xaa at residue 5 is Trp or bromo-Trp 310 Arg Cys Cys Arg Xaa Xaa Cys Xaa Ser Ile Cys Gly Met Ala Arg Cys 1 5 10 15 Cys Ser Ser 311 245 DNA Conus miliaris misc_feature (1)..(245) n may be any nucleotide 311 ggatccatga tgtctaaact gggagtcttg ttgaccatct gtctgcttct gtttccaatt 60 actgcccttc cactggatga agatcaacct gcagaccgac ctgcagagcg tatgcaggac 120 attgcaactg aacagcatcc cttgtttgat cccgtcaaac ggtgttgcga ttggccatgc 180 agcgcaggat gctacccttg ttgcttccct taataacgtg ttgatgacca actnangnaa 240 aaaaa 245 312 68 PRT Conus miliaris 312 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Ile Thr Ala Leu Pro Leu Asp Glu Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Ile Ala Thr Glu Gln His Pro Leu Phe Asp 35 40 45 Pro Val Lys Arg Cys Cys Asp Trp Pro Cys Ser Ala Gly Cys Tyr Pro 50 55 60 Cys Cys Phe Pro 65 313 16 PRT Conus miliaris PEPTIDE (1)..(16) Xaa at residue 5, 12 and 16 is Pro or Hyp; Xaa at residue 4 is Trp or bromo-Trp; Xaa at residue 11 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho -Tyr 313 Cys Cys Asp Xaa Xaa Cys Ser Ala Gly Cys Xaa Xaa Cys Cys Phe Xaa 1 5 10 15 314 230 DNA Conus miliaris misc_feature (1)..(230) n may be any nucleotide 314 ggatccatga tgtctaaact gggagtggtg ccattcgtct ttctggtcct gtttcccctg 60 gcaacactcc aactggatgc agatcaacct gcagaccgac ctgcgcgtaa aaagggcatt 120 gcaactaaac ggcatccctt gtctgatcct gtcagagggt gttgccctcc aatgtgcaca 180 ccatgcttcc cttgctgttt tcgttaataa cgtgttgatg natgatgnan 230 315 66 PRT Conus miliaris 315 Met Met Ser Lys Leu Gly Val Val Pro Phe Val Phe Leu Val Leu Phe 1 5 10 15 Pro Leu Ala Thr Leu Gln Leu Asp Ala Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Arg Lys Lys Gly Ile Ala Thr Lys Arg His Pro Leu Ser Asp Pro 35 40 45 Val Arg Gly Cys Cys Pro Pro Met Cys Thr Pro Cys Phe Pro Cys Cys 50 55 60 Phe Arg 65 316 16 PRT Conus miliaris PEPTIDE (1)..(16) Xaa at residue 4, 9 and 12 is Pro or Hyp; Xaa at residue 5 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 316 Gly Cys Cys Xaa Xaa Met Cys Thr Xaa Cys Phe Xaa Cys Cys Phe Arg 1 5 10 15 317 295 DNA Conus ammiralis 317 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt ccccttactg ctcttccgct ggatggagat caacctgcag accaagctgc 120 agagcgtatg caggccgagc agcatccctt gtttgatcag aaaagacggt gttgcaggtt 180 tccatgcccc gatacttgca gacatttgtg ttgcgggtga tgataacgtg ctgatgaccc 240 actttgtcat cacggctacg tcaagtgtct aatgaataag taaaatgatt gcagt 295 318 65 PRT Conus ammiralis 318 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Leu Asp Gly Asp Gln Pro Ala Asp Gln Ala 20 25 30 Ala Glu Arg Met Gln Ala Glu Gln His Pro Leu Phe Asp Gln Lys Arg 35 40 45 Arg Cys Cys Arg Phe Pro Cys Pro Asp Thr Cys Arg His Leu Cys Cys 50 55 60 Gly 65 319 16 PRT Conus ammiralis PEPTIDE (1)..(16) Xaa at residue 6 and 8 is Pro or Hyp 319 Arg Cys Cys Arg Phe Xaa Cys Xaa Asp Thr Cys Arg His Leu Cys Cys 1 5 10 15 320 267 DNA Conus ammiralis 320 caagagggat cgatagcagt tcatgatgtt taaactggga gtcttgctga ccatctgtct 60 acttctgttt tcccttaatg ctgttccgct ggatggagat caacctgcag accaacctgc 120 agagcgtctg ctggacgaca tttcatctga aaataatccc ttttatgatc ccgccaaacg 180 gtgttgcatg acttgcttcg gttgcacacc ttgttgtgga tgaccagcct catcaagtgt 240 ctaacgaata agtaaaacga ttgcagt 267 321 66 PRT Conus ammiralis 321 Met Met Phe Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Asn Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Leu Asp Asp Ile Ser Ser Glu Asn Asn Pro Phe Tyr 35 40 45 Asp Pro Ala Lys Arg Cys Cys Met Thr Cys Phe Gly Cys Thr Pro Cys 50 55 60 Cys Gly 65 322 12 PRT Conus ammiralis PEPTIDE (1)..(12) Xaa at residue 10 is Pro or Hyp 322 Cys Cys Met Thr Cys Phe Gly Cys Thr Xaa Cys Cys 1 5 10 323 294 DNA Conus ammiralis 323 caagaaggat cgatagcagt tcatgatgtc taaactggga gccttgttga ccatctgtct 60 acttctgttt tcccttactg ctgttccgct ggatggagat caacatgcag accaacctgc 120 agagcgtctg caggaccgcc ttccaactga aaatcatccc ttatatgatc ccgtcaaacg 180 gtgttgcgat gattcggaat gcgactattc ttgctggcct tgctgtattt tttcataacc 240 tttgttatcg cggcctcatc ctagtgtcaa atgaataagt aaaacgattg cagt 294 324 71 PRT Conus ammiralis 324 Met Met Ser Lys Leu Gly Ala Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Gln Asp Arg Leu Pro Thr Glu Asn His Pro Leu Tyr 35 40 45 Asp Pro Val Lys Arg Cys Cys Asp Asp Ser Glu Cys Asp Tyr Ser Cys 50 55 60 Trp Pro Cys Cys Ile Phe Ser 65 70 325 18 PRT Conus ammiralis PEPTIDE (1)..(18) Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 13 is Pro or Hyp; Xaa at residue 12 is Trp or bromo-Trp; Xaa at residue 9 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 325 Cys Cys Asp Asp Ser Xaa Cys Asp Xaa Ser Cys Xaa Xaa Cys Cys Ile 1 5 10 15 Phe Ser 326 284 DNA Conus ammiralis 326 caagagggat cgatagcagt tcatgatgtt taaactcgga gtcttgctga ccatctgtct 60 acttctgttt tccctaattg ctgttccgct ggatggagat caacatgcag accaacctgc 120 agagcgtctg caggaccgcc ttccaactga aaatcatccc ttatatgatc ccgtcaaacg 180 gtgttgcagg ttgttatgcc tcagttgcaa cccttgttgt ggatgaccag ctttgttatc 240 acggcctcat caagtgtcta atgaataagt aaaacgattg cagt 284 327 67 PRT Conus ammiralis 327 Met Met Phe Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Ile Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Gln Asp Arg Leu Pro Thr Glu Asn His Pro Leu Tyr 35 40 45 Asp Pro Val Lys Arg Cys Cys Arg Leu Leu Cys Leu Ser Cys Asn Pro 50 55 60 Cys Cys Gly 65 328 13 PRT Conus ammiralis PEPTIDE (1)..(13) Xaa at residue 11 is Pro or Hyp 328 Cys Cys Arg Leu Leu Cys Leu Ser Cys Asn Xaa Cys Cys 1 5 10 329 289 DNA Conus ammiralis 329 caagaaggat cgatagcagt tcatgatgtc taaactggga gccttgttga ccatctgtct 60 acttctgttt tcccttactg ctgttccgct ggatggagat caacatgcag accaacctgc 120 agagcgtctg caggaccgca ttccaactga agatcatccc ttatttgatc ccaacaaacg 180 gtgttgcgat gattcggaat gcggctattc atgctggcct tgctgttatg gataagcttt 240 gttatcgcgg cctcatccag tgtcaacgaa taagtaaaac gattgcagt 289 330 70 PRT Conus ammiralis 330 Met Met Ser Lys Leu Gly Ala Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Gln Asp Arg Ile Pro Thr Glu Asp His Pro Leu Phe 35 40 45 Asp Pro Asn Lys Arg Cys Cys Asp Asp Ser Glu Cys Gly Tyr Ser Cys 50 55 60 Trp Pro Cys Cys Tyr Gly 65 70 331 16 PRT Conus ammiralis PEPTIDE (1)..(16) Xaa at residue6 is Glu or gamma-carboxy Glu; Xaa at residue 13 is Pro or Hyp; Xaa at residue 12 is Trp or bromo-Trp; Xaa at residue 9 and 16 is Tyr, 125I-Tyr, mono- iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 331 Cys Cys Asp Asp Ser Xaa Cys Gly Xaa Ser Cys Xaa Xaa Cys Cys Xaa 1 5 10 15 332 272 DNA Conus spurius 332 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttgctga ccatctgtct 60 gcttctgttt ccacgtactt ctcttccgct ggatggagat caacctgcag tccgatctgc 120 aaagcgtatg cattcatcta tacagcgtcg tttctttgat cccgtcaaac ggtgttgccc 180 tagatgcagc gagtgcaacc cttgttgtgg atgaccagct ttgtcatcgc ggcctcatta 240 agtgtctaat gaataagtaa aatgattgca gt 272 333 63 PRT Conus spurius 333 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Arg Thr Ser Leu Pro Leu Asp Gly Asp Gln Pro Ala Val Arg Ser 20 25 30 Ala Lys Arg Met His Ser Ser Ile Gln Arg Arg Phe Phe Asp Pro Val 35 40 45 Lys Arg Cys Cys Pro Arg Cys Ser Glu Cys Asn Pro Cys Cys Gly 50 55 60 334 12 PRT Conus spurius PEPTIDE (1)..(12) Xaa at residue 7 is Glu or gamma-carboxy Glu; Xaa at residue 3 and 10 is Pro or Hyp 334 Cys Cys Xaa Arg Cys Ser Xaa Cys Asn Xaa Cys Cys 1 5 10 335 293 DNA Conus omaria 335 caagagggat cgatagcagt tcatgatgtc taaactggga gtctcgttga ccatctgtct 60 acttctattt tcccttactg ctgttccgct tgatggagat caacatgcag accaacctgc 120 agagcgtctg cagggcgaca ttttatctga aaagcatccc ttatttaatc ccgtcaaacg 180 gtgttgcgat gaggaagaat gcagcagtgc atgctggcct tgttgttggg ggtgatcagc 240 tttgttatcg cggcctcatc aagtgtctaa tgaataagta aaatgattgc agt 293 336 70 PRT Conus omaria 336 Met Met Ser Lys Leu Gly Val Ser Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Gln Gly Asp Ile Leu Ser Glu Lys His Pro Leu Phe 35 40 45 Asn Pro Val Lys Arg Cys Cys Asp Glu Glu Glu Cys Ser Ser Ala Cys 50 55 60 Trp Pro Cys Cys Trp Gly 65 70 337 16 PRT Conus omaria PEPTIDE (1)..(16) Xaa at residue 4, 5 and 6 is Glu or gamma- carboxy Glu; Xaa at residue 13 is Pro or Hyp; Xaa at residue 12 and 16 is Trp or bromo-Trp 337 Cys Cys Asp Xaa Xaa Xaa Cys Ser Ser Ala Cys Xaa Xaa Cys Cys Xaa 1 5 10 15 338 293 DNA Conus omaria 338 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttgttga tcatctgtct 60 acttctgtgt ccccttactg ctgttctgga ggatggagat caacctgcag accgacctgc 120 agagcgtatg caggacgaca tttcaactga gcatcatccc ttttatgatc ccgtcaaacg 180 gtgttgcaag tacgggtgga catgcttgct aggatgcact ccttgtgatt gttgaccagt 240 tttgttatcg cggcctcgtc aagtgtctaa tgaataagta aaacgattgc agt 293 339 70 PRT Conus omaria 339 Met Met Ser Lys Leu Gly Val Leu Leu Ile Ile Cys Leu Leu Leu Cys 1 5 10 15 Pro Leu Thr Ala Val Leu Glu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Thr Glu His His Pro Phe Tyr 35 40 45 Asp Pro Val Lys Arg Cys Cys Lys Tyr Gly Trp Thr Cys Leu Leu Gly 50 55 60 Cys Thr Pro Cys Asp Cys 65 70 340 17 PRT Conus omaria PEPTIDE (1)..(17) Xaa at residue is 14 Pro or Hyp; Xaa at residue 6 is Trp or bromo-Trp; Xaa at residue 4 is Tyr, 125I-Tyr, mono- iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 340 Cys Cys Lys Xaa Gly Xaa Thr Cys Leu Leu Gly Cys Thr Xaa Cys Asp 1 5 10 15 Cys 341 290 DNA Conus omaria 341 caagagggat cgatagcagt tcatgatgtc tatactggga gtcttgttga tcatctgtct 60 acttctgtgt ccccttactg ctgttctgga ggatggagat caacctgcag accgacctgc 120 agagcgtatg caggacggca tttcatctga acatcatccc tttttggatc ccgtcaaacg 180 gtgttgccat ctattggcat gccgctttgg atgctcgcct tgttgttggt gaccagcttt 240 gttatcgcgg cctcatcaag tgtctaatga ataagtaaaa cgattgcagt 290 342 69 PRT Conus omaria 342 Met Met Ser Ile Leu Gly Val Leu Leu Ile Ile Cys Leu Leu Leu Cys 1 5 10 15 Pro Leu Thr Ala Val Leu Glu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Gly Ile Ser Ser Glu His His Pro Phe Leu 35 40 45 Asp Pro Val Lys Arg Cys Cys His Leu Leu Ala Cys Arg Phe Gly Cys 50 55 60 Ser Pro Cys Cys Trp 65 343 16 PRT Conus omaria PEPTIDE (1)..(16) Xaa at residue 13 is Pro or Hyp; Xaa at residue 16 is Trp or bromo-Trp 343 Cys Cys His Leu Leu Ala Cys Arg Phe Gly Cys Ser Xaa Cys Cys Xaa 1 5 10 15 344 293 DNA Conus omaria 344 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttgttga tcatctgtct 60 acttctttgt ccccttactg ctgttccgca ggatggagat caacctgcag accgacctgc 120 agagcgtatg cagggcggca tttcatctga acatcatccc ttttttgatc ccgtcaaacg 180 gtgttgcagg tacgggtgga catgctggct aggatgcact ccctgtggtt gttgaccagc 240 tttgttatcg cggcctcatc aagtgtctaa tgaataagta aaacgattgc agt 293 345 70 PRT Conus omaria 345 Met Met Ser Lys Leu Gly Val Leu Leu Ile Ile Cys Leu Leu Leu Cys 1 5 10 15 Pro Leu Thr Ala Val Pro Gln Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Gly Gly Ile Ser Ser Glu His His Pro Phe Phe 35 40 45 Asp Pro Val Lys Arg Cys Cys Arg Tyr Gly Trp Thr Cys Trp Leu Gly 50 55 60 Cys Thr Pro Cys Gly Cys 65 70 346 17 PRT Conus omaria PEPTIDE (1)..(17) Xaa at residue 14 is Pro or Hyp; Xaa at residue 6 and 9 is Trp or bromo-Trp; Xaa at residue 4 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 346 Cys Cys Arg Xaa Gly Xaa Thr Cys Xaa Leu Gly Cys Thr Xaa Cys Gly 1 5 10 15 Cys 347 293 DNA Conus episcopatus 347 caagaaggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 acttctgttt tcccttattg ctgttccgct tgatggagat caacatgcag accaacctgc 120 agagcgtctg cagggcgaca ttttatctga aaagcatccc ttatttatgc ctgtcaaacg 180 gtgttgcgat gaggacgaat gcaacagttc atgctggcct tgttgttggg ggtgatcagc 240 tttgttatcg cggcctgatc aagtgtataa tgaataagta aaacgattgc agt 293 348 70 PRT Conus episcopatus 348 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Ile Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Gln Gly Asp Ile Leu Ser Glu Lys His Pro Leu Phe 35 40 45 Met Pro Val Lys Arg Cys Cys Asp Glu Asp Glu Cys Asn Ser Ser Cys 50 55 60 Trp Pro Cys Cys Trp Gly 65 70 349 16 PRT Conus episcopatus PEPTIDE (1)..(16) Xaa at residue 4 and 6 is Glu or gamma-carboxy Glu; Xaa at residue 13 is Pro or Hyp; Xaa at residue 12 and 16 is Trp or bromo-Trp 349 Cys Cys Asp Xaa Asp Xaa Cys Asn Ser Ser Cys Xaa Xaa Cys Cys Xaa 1 5 10 15 350 293 DNA Conus episcopatus 350 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 acttctgttt tcccttattg ctgttccgct tgatggagat caacatgcag accaacctgc 120 agagcgtctg cagggcgaca ttttatctga aaagcatccc ttatttatgc ctgtcaaacg 180 gtgttgcgat gaggacgaat gcagcagttc atgctggcct tgttgttggg gatgagcagc 240 tttgttatcg cggcctcatc aagtgtctaa tgaataagta aaacgattgc agt 293 351 70 PRT Conus episcopatus 351 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Ile Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Gln Gly Asp Ile Leu Ser Glu Lys His Pro Leu Phe 35 40 45 Met Pro Val Lys Arg Cys Cys Asp Glu Asp Glu Cys Ser Ser Ser Cys 50 55 60 Trp Pro Cys Cys Trp Gly 65 70 352 16 PRT Conus episcopatus PEPTIDE (1)..(16) Xaa at residue4 and 6 is Glu or gamma-carboxy Glu; Xaa at residue 13 is Pro or Hyp; Xaa at residue 12 and 16 is Trp or bromo-Trp 352 Cys Cys Asp Xaa Asp Xaa Cys Ser Ser Ser Cys Xaa Xaa Cys Cys Xaa 1 5 10 15 353 290 DNA Conus episcopatus 353 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 acttctgttt tcccttactg ctgttccgct tgatggagat caacatgcag accaacctgc 120 agagcgtctg cagggcgaca ttttatctga aaagcatccc ttatttaatc ccgtcaaacg 180 gtgttgcccg gcggcggcat gtgccatggg atgcaagcct tgttgtggat gagcagcttt 240 gttatcgtgg cctcatcaag tgtctaatga ataagtaaaa cgattgcagt 290 354 69 PRT Conus episcopatus 354 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Gln Gly Asp Ile Leu Ser Glu Lys His Pro Leu Phe 35 40 45 Asn Pro Val Lys Arg Cys Cys Pro Ala Ala Ala Cys Ala Met Gly Cys 50 55 60 Lys Pro Cys Cys Gly 65 355 15 PRT Conus episcopatus PEPTIDE (1)..(15) Xaa at residue 3 and 13 is Pro or Hyp 355 Cys Cys Xaa Ala Ala Ala Cys Ala Met Gly Cys Lys Xaa Cys Cys 1 5 10 15 356 295 DNA Conus aulicus 356 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt tccgttactg ctcttccgcc ggatggagat caacctgcag accgagctgc 120 agagcgtagg caggtcgagc agcatcccgt gtttgatcat gaaagagggt gttgctcgcc 180 accatgccac agtatttgcg ctgctttctg ttgcgggtga tgataacgtg ttgatgaccc 240 actttgtcat cacggctgcg tcaagtgtct aatgaataag taaaatgatt gcagt 295 357 65 PRT Conus aulicus 357 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Val Thr Ala Leu Pro Pro Asp Gly Asp Gln Pro Ala Asp Arg Ala 20 25 30 Ala Glu Arg Arg Gln Val Glu Gln His Pro Val Phe Asp His Glu Arg 35 40 45 Gly Cys Cys Ser Pro Pro Cys His Ser Ile Cys Ala Ala Phe Cys Cys 50 55 60 Gly 65 358 16 PRT Conus aulicus PEPTIDE (1)..(16) Xaa at residue 5 and 6 is Pro or Hyp 358 Gly Cys Cys Ser Xaa Xaa Cys His Ser Ile Cys Ala Ala Phe Cys Cys 1 5 10 15 359 290 DNA Conus aulicus 359 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 acttctgttt tcccttactg ctgttccgct tgatggagat caacatgcag accaacctgc 120 agagcgtctg cagggcgaca ttttatctga aaagcatccc ttatttaatc ccgtcaaacg 180 gtgttgccga ccggtggcat gtgccatggg atgcaagcct tgttgtggat gagcagcttt 240 gttatcgtgg cctcatcaag tgtctaatga ataagtaaaa tgattgcagt 290 360 69 PRT Conus aulicus 360 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Gln Gly Asp Ile Leu Ser Glu Lys His Pro Leu Phe 35 40 45 Asn Pro Val Lys Arg Cys Cys Arg Pro Val Ala Cys Ala Met Gly Cys 50 55 60 Lys Pro Cys Cys Gly 65 361 15 PRT Conus aulicus PEPTIDE (1)..(15) Xaa at residue 4 and 13 is Pro or Hyp 361 Cys Cys Arg Xaa Val Ala Cys Ala Met Gly Cys Lys Xaa Cys Cys 1 5 10 15 362 290 DNA Conus aulicus 362 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga tcatctgtct 60 acttctgtct ccccttactg ctgttccgct ggatggagat caacctgcag accgacctgc 120 agagcgtatg caggacgaca tttcatctga acatcaaccc atgtttgatg ccatcagaca 180 gtgttgcccg gcggtggcat gcgccatggg atgcgagcct tgttgtggat gaccagcttt 240 gttatcgcgg cctcatcaag tgtctaatga ataagtaaaa tgattgcagt 290 363 69 PRT Conus aulicus 363 Met Met Ser Lys Leu Gly Val Leu Leu Ile Ile Cys Leu Leu Leu Ser 1 5 10 15 Pro Leu Thr Ala Val Pro Leu Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu His Gln Pro Met Phe 35 40 45 Asp Ala Ile Arg Gln Cys Cys Pro Ala Val Ala Cys Ala Met Gly Cys 50 55 60 Glu Pro Cys Cys Gly 65 364 16 PRT Conus aulicus PEPTIDE (1)..(16) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 13 is Glu or gamma-carboxy Glu; Xaa at residue 4 and 14 is Pro or Hyp 364 Xaa Cys Cys Xaa Ala Val Ala Cys Ala Met Gly Cys Xaa Xaa Cys Cys 1 5 10 15 365 293 DNA Conus aureus 365 caagaaggat cgatagcagt tcatgatgtc taaactggga gccttgttga ccatctgtct 60 acttctgttt tcccttactg ctgttccgct ggatggagat caacatgcag accaacatgc 120 agagcgtctg catgaccgcc ttccaactga aaatcatccc ttatatgatc ccgtcaaacg 180 gtgttgcgat gattcggaat gcgactattc ttgctggcct tgctgtattt ttggataacc 240 tttgttatcg cggcctcatc aagtgtcaaa tgaataagta aaacgattgc agt 293 366 71 PRT Conus aureus 366 Met Met Ser Lys Leu Gly Ala Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln His 20 25 30 Ala Glu Arg Leu His Asp Arg Leu Pro Thr Glu Asn His Pro Leu Tyr 35 40 45 Asp Pro Val Lys Arg Cys Cys Asp Asp Ser Glu Cys Asp Tyr Ser Cys 50 55 60 Trp Pro Cys Cys Ile Phe Gly 65 70 367 17 PRT Conus aureus PEPTIDE (1)..(17) Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 13 is Pro or Hyp; Xaa at residue 12 is Trp or bromo -Trp; Xaa at residue 9 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo- Tyr, O-sulpho-Tyr or O-phospho-Tyr 367 Cys Cys Asp Asp Ser Xaa Cys Asp Xaa Ser Cys Xaa Xaa Cys Cys Ile 1 5 10 15 Phe 368 290 DNA Conus aureus 368 caagagggat cgatagcagt tcatgatgtc taaactggga gccttgttga ccatctgtct 60 acttctgttt tccctaactg ctgttccgct ggatggagat caacatgcag accaacctgc 120 agagcgtctg caggaccgca ttccaactga aaatcatccc ttatttgatc cgaacaaacg 180 gtgttgcaat gattgggaat gcgacgattc atgctggcct tgctgttatg gataaccttt 240 gttatcgcgg cctcatcaag tgtcaaatga ataagtaaaa cgattgcagt 290 369 70 PRT Conus aureus 369 Met Met Ser Lys Leu Gly Ala Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Ser Leu Thr Ala Val Pro Leu Asp Gly Asp Gln His Ala Asp Gln Pro 20 25 30 Ala Glu Arg Leu Gln Asp Arg Ile Pro Thr Glu Asn His Pro Leu Phe 35 40 45 Asp Pro Asn Lys Arg Cys Cys Asn Asp Trp Glu Cys Asp Asp Ser Cys 50 55 60 Trp Pro Cys Cys Tyr Gly 65 70 370 16 PRT Conus aureus PEPTIDE (1)..(16) Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 13 is Pro or Hyp; Xaa at residue 5 and 12 is Trp or bromo-Trp; Xaa at residue 16 is Tyr, 125I-Tyr, mono-iodo- Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 370 Cys Cys Asn Asp Xaa Xaa Cys Asp Asp Ser Cys Xaa Xaa Cys Cys Xaa 1 5 10 15 371 310 DNA Conus consors 371 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgttt 60 gcttctgttt ccccttactg ctcttccaat ggatggagat caatctgtag accgacctgc 120 agagcgtatg caggacgaca tttcatctga gctgcatccc ttgttcaatc agaaaagaat 180 gtgttgcggc gaaggtgcgc catgccccag ctatttcaga aacagtcaga tttgtcattg 240 ttgttaaatg acaacgtgtc gatgaccaac ttcgttatca cgactaatga ataagtaaaa 300 tgattgcagt 310 372 74 PRT Conus consors 372 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Ser Val Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Leu His Pro Leu Phe 35 40 45 Asn Gln Lys Arg Met Cys Cys Gly Glu Gly Ala Pro Cys Pro Ser Tyr 50 55 60 Phe Arg Asn Ser Gln Ile Cys His Cys Cys 65 70 373 22 PRT Conus consors PEPTIDE (1)..(22) Xaa at residue 5 is Glu or gamma-carboxy Glu; Xaa at residue 8 and 10 is Pro or Hyp; Xaa at residue 12 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 373 Met Cys Cys Gly Xaa Gly Ala Xaa Cys Xaa Ser Xaa Phe Arg Asn Ser 1 5 10 15 Gln Ile Cys His Cys Cys 20 374 315 DNA Conus consors 374 taagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ccatctgtct 60 gcttctgttt ccccttattg ctcttccaat ggatggagat caacctgcag accgacctgc 120 agagcgtatg caggacgaca tttcatctca gcagcatccc ttgtttgata agagaggccg 180 ctgttgcgat gtgccgaacg catgctccgg cagatggtgc agagatcacg cacaatgttg 240 cggatgacga taacgtgttg atgaccaact ttgtgatcac ggctacatca agtgaataag 300 taaaacgatt gcagt 315 375 74 PRT Conus consors 375 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Ile Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Arg Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Gln Gln His Pro Leu Phe 35 40 45 Asp Lys Arg Gly Arg Cys Cys Asp Val Pro Asn Ala Cys Ser Gly Arg 50 55 60 Trp Cys Arg Asp His Ala Gln Cys Cys Gly 65 70 376 22 PRT Conus consors PEPTIDE (1)..(22) Xaa at residue 7 is Pro or Hyp; Xaa at residue 14 is Trp or bromo -Trp 376 Gly Arg Cys Cys Asp Val Xaa Asn Ala Cys Ser Gly Arg Xaa Cys Arg 1 5 10 15 Asp His Ala Gln Cys Cys 20 377 322 DNA Conus consors 377 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgttga ctgtctgttt 60 gcttctgttt ccccttactg ctcttccgat ggatggagat caacctgcag accaacctgc 120 agagcgtatg caggacgaca tttcatctga gcagcatccc ttgtttgata agagacaaag 180 gtgttgcact gggaagaagg ggtcatgctc cggtaaagca tgcaaaagtc tcaaatgttg 240 ctctggacga taacgtgttg atgaccaact ttgttatcac ggctacgtca agtgtctagt 300 gaataagtaa aacgattgca gt 322 378 76 PRT Conus consors 378 Met Met Ser Lys Leu Gly Val Leu Leu Thr Val Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Ala Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Gln Pro 20 25 30 Ala Glu Arg Met Gln Asp Asp Ile Ser Ser Glu Gln His Pro Leu Phe 35 40 45 Asp Lys Arg Gln Arg Cys Cys Thr Gly Lys Lys Gly Ser Cys Ser Gly 50 55 60 Lys Ala Cys Lys Ser Leu Lys Cys Cys Ser Gly Arg 65 70 75 379 23 PRT Conus consors PEPTIDE (1)..(23) Xaa at residue 1 is Gln or pyro-Glu 379 Xaa Arg Cys Cys Thr Gly Lys Lys Gly Ser Cys Ser Gly Lys Ala Cys 1 5 10 15 Lys Ser Leu Lys Cys Cys Ser 20 380 284 DNA Conus emaciatus 380 caagagggat cgatagcagt tcatgatgtc taaactggga gtcttgctga ccatctgtct 60 gcttctgttt ccccttactg ttcttccgat ggatggagat caacctgcag acctacctgc 120 attgcgtgcg cagttctttg cacctgaaca tagtccccgg tttgaccccg tcaaacggtg 180 ctgctcgcgg gattgcagtg tttgcatccc ttgttgcccg tatggatcac cttgattatt 240 gcggccacgt caagtgtcta atgaataagt aaaatgattg cagt 284 381 70 PRT Conus emaciatus 381 Met Met Ser Lys Leu Gly Val Leu Leu Thr Ile Cys Leu Leu Leu Phe 1 5 10 15 Pro Leu Thr Val Leu Pro Met Asp Gly Asp Gln Pro Ala Asp Leu Pro 20 25 30 Ala Leu Arg Ala Gln Phe Phe Ala Pro Glu His Ser Pro Arg Phe Asp 35 40 45 Pro Val Lys Arg Cys Cys Ser Arg Asp Cys Ser Val Cys Ile Pro Cys 50 55 60 Cys Pro Tyr Gly Ser Pro 65 70 382 18 PRT Conus emaciatus PEPTIDE (1)..(18) Xaa at residue 11, 14 and 18 is Pro or Hyp; Xaa at residue 15 is Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 382 Cys Cys Ser Arg Asp Cys Ser Val Cys Ile Xaa Cys Cys Xaa Xaa Gly 1 5 10 15 Ser Xaa 383 13 PRT Conus aurisiacus 383 Cys Cys Lys Val Gln Cys Glu Ser Cys Thr Pro Cys Cys 1 5 10 384 15 PRT Conus atlanticus 384 Cys Cys Glu Leu Pro Cys Gly Pro Gly Phe Cys Val Pro Cys Cys 1 5 10 15 385 14 PRT Conus arentus 385 Cys Cys Glu Arg Pro Cys Asn Ile Gly Cys Val Pro Cys Cys 1 5 10 386 16 PRT Conus bandus 386 Cys Cys Asn Trp Pro Cys Ser Met Gly Cys Ile Pro Cys Cys Tyr Tyr 1 5 10 15 387 15 PRT Conus betulinus 387 Cys Cys Glu Leu Pro Cys His Gly Cys Val Pro Cys Cys Trp Pro 1 5 10 15 388 16 PRT Conus betulinus 388 Cys Cys Gly Leu Pro Cys Asn Gly Cys Val Pro Cys Cys Trp Pro Ser 1 5 10 15 389 18 PRT Conus betulinus 389 Cys Cys Ser Arg Asn Cys Ala Val Cys Ile Pro Cys Cys Pro Asn Trp 1 5 10 15 Pro Ala 390 14 PRT Conus betulinus 390 Cys Cys Lys Gln Ser Cys Thr Thr Cys Met Pro Cys Cys Trp 1 5 10 391 14 PRT Conus betulinus PEPTIDE (1)..(14) Xaa is Glu or gamma-carboxy Glu 391 Ala Cys Cys Xaa Gln Ser Cys Thr Thr Cys Met Pro Cys Cys 1 5 10 392 14 PRT Conus betulinus 392 Cys Cys Glu Gln Ser Cys Thr Thr Cys Met Pro Cys Cys Trp 1 5 10 393 18 PRT Conus caracteristicus 393 Arg Cys Cys Arg Tyr Pro Cys Pro Asp Ser Cys His Gly Ser Cys Cys 1 5 10 15 Tyr Lys 394 15 PRT Conus caracteristicus 394 Cys Cys Pro Pro Val Ala Cys Asn Met Gly Cys Lys Pro Cys Cys 1 5 10 15 395 17 PRT Conus caracteristicus 395 Cys Cys Asp Asp Ser Glu Cys Asp Tyr Ser Cys Trp Pro Cys Cys Met 1 5 10 15 Phe 396 14 PRT Conus caracteristicus 396 Cys Cys Arg Arg Cys Tyr Met Gly Cys Ile Pro Cys Cys Phe 1 5 10 397 16 PRT Conus textile 397 Cys Cys Pro Pro Val Ala Cys Asn Met Gly Cys Lys Pro Cys Cys Gly 1 5 10 15 398 19 PRT Conus marmoreus PEPTIDE (1)..(19) Xaa is Hyp 398 Ser Lys Gln Cys Cys His Leu Ala Ala Cys Arg Phe Gly Cys Thr Xaa 1 5 10 15 Cys Cys Asn 399 15 PRT Conus capitaneus 399 Ser Cys Cys Arg Asp Cys Gly Glu Asp Cys Val Gly Cys Cys Arg 1 5 10 15 400 16 PRT Conus coronatus 400 Cys Cys Asp Trp Pro Cys Ile Pro Gly Cys Thr Pro Cys Cys Leu Pro 1 5 10 15 401 18 PRT Conus dalli 401 Cys Cys Asp Asp Ser Glu Cys Asp Tyr Ser Cys Trp Pro Cys Cys Ile 1 5 10 15 Leu Ser 402 17 PRT Conus dalli 402 Glx Gln Cys Cys Pro Pro Val Ala Cys Asn Met Gly Cys Glu Pro Cys 1 5 10 15 Cys 403 16 PRT Conus dalli 403 Cys Cys Asn Ala Gly Phe Cys Arg Phe Gly Cys Thr Pro Cys Cys Trp 1 5 10 15 404 14 PRT Conus distans 404 Glx Cys Cys Val His Pro Cys Pro Cys Thr Pro Cys Cys Arg 1 5 10 405 14 PRT Conus figulinus 405 Cys Cys Pro Trp Pro Cys Asn Ile Gly Cys Val Pro Cys Cys 1 5 10 406 14 PRT Conus figulinus 406 Cys Cys Ser Lys Asn Cys Ala Val Cys Ile Pro Cys Cys Pro 1 5 10 407 15 PRT Conus figulinus 407 Cys Cys Arg Trp Pro Cys Pro Ala Arg Cys Gly Ser Cys Cys Leu 1 5 10 15 408 16 PRT Conus figulinus 408 Cys Cys Glu Leu Ser Arg Cys Leu Gly Cys Val Pro Cys Cys Thr Ser 1 5 10 15 409 16 PRT Conus figulinus 409 Cys Cys Glu Leu Ser Lys Cys His Gly Cys Val Pro Cys Cys Ile Pro 1 5 10 15 410 16 PRT Conus generalis 410 Glx Cys Cys Thr Phe Cys Asn Phe Gly Cys Gln Pro Cys Cys Val Pro 1 5 10 15 411 16 PRT Conus generalis 411 Glx Cys Cys Thr Phe Cys Asn Phe Gly Cys Gln Pro Cys Cys Leu Thr 1 5 10 15 412 16 PRT Conus generalis 412 Glx Cys Cys Thr Phe Cys Asn Phe Gly Cys Gln Pro Cys Cys Val Pro 1 5 10 15 413 17 PRT Conus gloriamaris 413 Cys Cys Asp Asp Ser Glu Cys Asp Tyr Ser Cys Trp Pro Cys Cys Met 1 5 10 15 Phe 414 17 PRT Conus gloriamaris 414 Gly Cys Cys His Leu Leu Ala Cys Arg Phe Gly Cys Ser Pro Cys Cys 1 5 10 15 Trp 415 16 PRT Conus gloriamaris 415 Cys Cys Ser Trp Asp Val Cys Asp His Pro Ser Cys Thr Cys Cys Gly 1 5 10 15 416 13 PRT Conus laterculatus 416 Cys Cys Asp Trp Pro Cys Ser Gly Cys Ile Pro Cys Cys 1 5 10 417 19 PRT Conus leopardus 417 Glx Ile Asn Cys Cys Pro Trp Pro Cys Pro Ser Thr Cys Arg His Gln 1 5 10 15 Cys Cys His 418 19 PRT Conus lividus 418 Glx Ile Asn Cys Cys Pro Trp Pro Cys Pro Asp Ser Cys His Tyr Gln 1 5 10 15 Cys Cys His 419 14 PRT Conus marmoreus 419 Cys Cys Arg Leu Ser Cys Gly Leu Gly Cys His Pro Cys Cys 1 5 10 420 17 PRT Conus marmoreus 420 Glu Cys Cys Gly Ser Phe Ala Cys Arg Phe Gly Cys Val Pro Cys Cys 1 5 10 15 Val 421 19 PRT Conus marmoreus 421 Ser Lys Gln Cys Cys His Leu Pro Ala Cys Arg Phe Gly Cys Thr Pro 1 5 10 15 Cys Cys Trp 422 17 PRT Conus marmoreus 422 Met Gly Cys Cys Pro Phe Pro Cys Lys Thr Ser Cys Thr Thr Leu Cys 1 5 10 15 Cys 423 14 PRT Conus musicus 423 Ala Cys Cys Glu Gln Ser Cys Thr Thr Cys Phe Pro Cys Cys 1 5 10 424 15 PRT Conus nobilis 424 Cys Cys Glu Leu Pro Cys Gly Pro Gly Phe Cys Val Pro Cys Cys 1 5 10 15 425 14 PRT Conus pulicarius 425 Cys Cys Asn Ser Cys Tyr Met Gly Cys Ile Pro Cys Cys Phe 1 5 10 426 17 PRT Conus quercinus 426 Glx Arg Cys Cys Gln Trp Pro Cys Pro Gly Ser Cys Arg Cys Cys Arg 1 5 10 15 Thr 427 18 PRT Conus quercinus 427 Glx Arg Cys Cys Arg Trp Pro Cys Pro Gly Ser Cys Arg Cys Cys Arg 1 5 10 15 Tyr Arg 428 18 PRT Conus quercinus 428 Arg Cys Cys Arg Tyr Pro Cys Pro Asp Ser Cys His Gly Ser Cys Cys 1 5 10 15 Tyr Lys 429 15 PRT Conus quercinus PEPTIDE (1)..(15) Xaa is Hyp 429 Cys Cys Ser Gln Asp Cys Leu Val Cys Ile Xaa Cys Cys Pro Asn 1 5 10 15 430 15 PRT Conus quercinus PEPTIDE (1)..(15) Xaa is Hyp 430 Cys Cys Ser Arg His Cys Trp Val Cys Ile Xaa Cys Cys Pro Asn 1 5 10 15 431 16 PRT Conus rattus 431 Glx Thr Cys Cys Ser Asn Cys Gly Glu Asp Cys Asp Gly Cys Cys Gln 1 5 10 15 432 20 PRT Conus striatus 432 Glx Asn Cys Cys Asn Gly Gly Cys Ser Ser Lys Trp Cys Arg Asp His 1 5 10 15 Ala Arg Cys Cys 20 433 12 PRT Conus textile PEPTIDE (1)..(12) Xaa is Hyp 433 Cys Cys Arg Thr Cys Phe Gly Cys Thr Xaa Cys Cys 1 5 10 434 14 PRT Conus tessulatus 434 Cys Cys His Lys Cys Tyr Met Gly Cys Ile Pro Cys Cys Ile 1 5 10 435 18 PRT Conus tessulatus 435 Lys Cys Cys Arg Pro Pro Cys Ala Met Ser Cys Gly Met Ala Arg Cys 1 5 10 15 Cys Tyr 436 23 PRT Conus betulinus 436 Arg Cys Cys Arg Trp Pro Cys Pro Ser Ile Cys Gly Met Ala Arg Cys 1 5 10 15 Cys Phe Val Met Ile Thr Cys 20 437 23 PRT Conus betulinus 437 Arg Cys Cys Arg Trp Pro Cys Pro Ser Arg Cys Gly Met Ala Arg Cys 1 5 10 15 Cys Phe Val Met Ile Thr Cys 20 438 15 PRT Conus textile 438 Phe Cys Cys Asp Ser Asn Trp Cys His Asp Cys Glu Cys Cys Tyr 1 5 10 15 439 16 PRT Conus marmoreus 439 Cys Cys His Trp Asn Trp Cys Asp His Leu Cys Ser Cys Cys Gly Ser 1 5 10 15 440 16 PRT Conus marmoreus PEPTIDE (1)..(16) Xaa is Hyp 440 Asp Cys Cys Xaa Leu Pro Ala Cys Pro Phe Gly Cys Asn Xaa Cys Cys 1 5 10 15 441 16 PRT Conus marmoreus PEPTIDE (1)..(16) Xaa is Hyp 441 Cys Cys Ala Pro Ser Ala Cys Arg Leu Gly Cys Arg Xaa Cys Cys Arg 1 5 10 15 442 16 PRT Conus marmoreus PEPTIDE (1)..(16) Xaa is Hyp 442 Cys Cys Ala Xaa Ser Ala Cys Arg Leu Gly Cys Arg Xaa Cys Cys Arg 1 5 10 15 443 16 PRT Conus marmoreus 443 Cys Cys Ala Pro Ser Ala Cys Arg Leu Gly Cys Arg Pro Cys Cys Arg 1 5 10 15 444 17 PRT Conus marmoreus PEPTIDE (1)..(17) Xaa is Hyp 444 Gly Cys Cys Gly Ser Phe Ala Cys Arg Phe Gly Cys Val Xaa Cys Cys 1 5 10 15 Val 445 15 PRT Conus textile 445 Cys Cys Ser Trp Asp Val Cys Asp His Pro Ser Cys Thr Cys Cys 1 5 10 15 446 16 PRT Conus textile 446 Arg Cys Cys Lys Phe Pro Cys Pro Asp Ser Cys Arg Tyr Leu Cys Cys 1 5 10 15 447 17 PRT Conus aureus 447 Cys Cys Asp Asp Ser Glu Cys Asp Tyr Ser Cys Trp Pro Cys Cys Ile 1 5 10 15 Phe 448 16 PRT Conus aureus 448 Cys Cys Asn Asp Trp Glu Cys Asp Asp Ser Cys Trp Pro Cys Cys Tyr 1 5 10 15 449 16 PRT Conus ammiralis 449 Arg Cys Cys Arg Phe Pro Cys Pro Asp Thr Cys Arg His Leu Cys Cys 1 5 10 15 450 12 PRT Conus ammiralis 450 Cys Cys Met Thr Cys Phe Gly Cys Thr Pro Cys Cys 1 5 10 451 18 PRT Conus ammiralis 451 Cys Cys Asp Asp Ser Glu Cys Asp Tyr Ser Cys Trp Pro Cys Cys Ile 1 5 10 15 Phe Ser 452 13 PRT Conus ammiralis 452 Cys Cys Arg Leu Leu Cys Leu Ser Cys Asn Pro Cys Cys 1 5 10 453 16 PRT Conus ammiralis 453 Cys Cys Asp Asp Ser Glu Cys Gly Tyr Ser Cys Trp Pro Cys Cys Tyr 1 5 10 15 454 16 PRT Conus aulicus 454 Gly Cys Cys Ser Pro Pro Cys His Ser Ile Cys Ala Ala Phe Cys Cys 1 5 10 15 455 15 PRT Conus aulicus 455 Cys Cys Arg Pro Val Ala Cys Ala Met Gly Cys Lys Pro Cys Cys 1 5 10 15 456 16 PRT Conus aulicus 456 Glx Cys Cys Pro Ala Val Ala Cys Ala Met Gly Cys Glu Pro Cys Cys 1 5 10 15 457 18 PRT Conus emaciatus 457 Cys Cys Ser Arg Asp Cys Ser Val Cys Ile Pro Cys Cys Pro Tyr Gly 1 5 10 15 Ser Pro 458 16 PRT Conus episcopatus 458 Cys Cys Asp Glu Asp Glu Cys Asn Ser Ser Cys Trp Pro Cys Cys Trp 1 5 10 15 459 16 PRT Conus episcopatus 459 Cys Cys Asp Glu Asp Glu Cys Ser Ser Ser Cys Trp Pro Cys Cys Trp 1 5 10 15 460 15 PRT Conus episcopatus 460 Cys Cys Pro Ala Ala Ala Cys Ala Met Gly Cys Lys Pro Cys Cys 1 5 10 15 461 16 PRT Conus omaria 461 Cys Cys Asp Glu Glu Glu Cys Ser Ser Ala Cys Trp Pro Cys Cys Trp 1 5 10 15 462 16 PRT Conus omaria 462 Cys Cys His Leu Leu Ala Cys Arg Phe Gly Cys Ser Pro Cys Cys Trp 1 5 10 15 463 12 PRT Conus spurius 463 Cys Cys Pro Arg Cys Ser Glu Cys Asn Pro Cys Cys 1 5 10 464 16 PRT Conus pennaceus 464 Arg Cys Cys Lys Phe Pro Cys Pro Asp Ser Cys Lys Tyr Leu Cys Cys 1 5 10 15 465 19 PRT Conus flavidus 465 Arg Cys Cys Arg Trp Pro Cys Pro Ser Ile Cys Gly Met Ala Arg Cys 1 5 10 15 Cys Ser Ser 466 14 PRT Conus pulicarius 466 Cys Cys Lys Leu Leu Cys Gly Cys Thr Pro Cys Cys His Ile 1 5 10 467 15 PRT Conus ebraceus 467 Cys Cys Glu Gln Pro Cys Tyr Met Gly Cys Ile Pro Cys Cys Phe 1 5 10 15 468 15 PRT Conus ebraceus 468 Cys Cys Ala Gln Pro Cys Tyr Met Gly Cys Ile Pro Cys Cys Phe 1 5 10 15 469 14 PRT Conus pulicarius 469 Cys Cys Val Ser Cys Tyr Met Gly Cys Ile Pro Cys Cys Phe 1 5 10 470 16 PRT Conus miliaris 470 Cys Cys Asp Trp Pro Cys Ser Ala Gly Cys Tyr Pro Cys Cys Phe Pro 1 5 10 15 471 16 PRT Conus miliaris 471 Gly Cys Cys Pro Pro Met Cys Thr Pro Cys Phe Pro Cys Cys Phe Arg 1 5 10 15 472 23 PRT Conus rattus 472 Arg Gly Cys Cys Ala Pro Pro Arg Lys Cys Lys Asp Arg Ala Cys Lys 1 5 10 15 Pro Ala Arg Cys Cys Gly Pro 20 473 22 PRT Conus stercusmuscarum 473 Glx Arg Cys Cys Asn Gly Arg Arg Gly Cys Ser Ser Arg Trp Cys Arg 1 5 10 15 Asp His Ser Arg Cys Cys 20 474 22 PRT Conus consors 474 Gly Arg Cys Cys Asp Val Pro Asn Ala Cys Ser Gly Arg Trp Cys Arg 1 5 10 15 Asp His Ala Gln Cys Cys 20 475 23 PRT Conus consors 475 Glx Arg Cys Cys Thr Gly Lys Lys Gly Ser Cys Ser Gly Lys Ala Cys 1 5 10 15 Lys Ser Leu Lys Cys Cys Ser 20 476 22 PRT Conus aurisiacus 476 Met Cys Cys Gly Glu Gly Arg Lys Cys Pro Ser Tyr Phe Arg Asn Ser 1 5 10 15 Gln Ile Cys His Cys Cys 20 477 19 PRT Conus aurisiacus 477 Cys Cys Arg Trp Pro Cys Pro Arg Gln Ile Asp Gly Glu Tyr Cys Gly 1 5 10 15 Cys Cys Leu 478 22 PRT Conus bullatus 478 Arg Cys Cys Gly Glu Gly Leu Thr Cys Pro Arg Tyr Trp Lys Asn Ser 1 5 10 15 Gln Ile Cys Ala Cys Cys 20 479 21 PRT Conus caracteristicus 479 Cys Cys Gly Pro Gly Gly Ser Cys Pro Val Tyr Phe Arg Asp Asn Phe 1 5 10 15 Ile Cys Gly Cys Cys 20 480 23 PRT Conus circumcisus 480 Arg Lys Cys Cys Gly Lys Asp Gly Pro Cys Pro Lys Tyr Phe Lys Asp 1 5 10 15 Asn Phe Ile Cys Gly Cys Cys 20 481 20 PRT Conus ermineus 481 Cys Cys Ser Trp Pro Cys Pro Arg Tyr Ser Asn Gly Lys Leu Val Cys 1 5 10 15 Phe Cys Cys Leu 20 482 21 PRT Conus magus 482 Cys Cys Gly Pro Gly Gly Ser Cys Pro Val Tyr Phe Arg Asp Asn Phe 1 5 10 15 Ile Cys Gly Cys Cys 20 483 22 PRT Conus magus 483 Met Cys Cys Gly Glu Ser Ala Pro Cys Pro Ser Tyr Phe Arg Asn Ser 1 5 10 15 Gln Ile Cys His Cys Cys 20 484 22 PRT Conus magus 484 Glx Lys Cys Cys Gly Pro Gly Gly Ser Cys Pro Val Tyr Phe Thr Asp 1 5 10 15 Asn Phe Ile Cys Gly Cys 20 485 23 PRT Conus magus 485 Glx Lys Cys Cys Gly Pro Gly Gly Ser Cys Pro Val Tyr Phe Arg Asp 1 5 10 15 Asn Phe Ile Cys Gly Cys Cys 20 486 23 PRT Conus striatus 486 Glx Lys Cys Cys Gly Glu Gly Ser Ser Cys Pro Lys Tyr Phe Lys Asn 1 5 10 15 Asn Phe Ile Cys Gly Cys Cys 20 487 22 PRT Conus magus 487 Glx Lys Cys Cys Ser Gly Gly Ser Cys Pro Leu Tyr Phe Arg Asp Arg 1 5 10 15 Leu Ile Cys Pro Cys Cys 20 488 23 PRT Conus stercusmuscarum 488 Glx Lys Cys Cys Gly Pro Gly Ala Ser Cys Pro Arg Tyr Phe Lys Asp 1 5 10 15 Asn Phe Ile Cys Gly Cys Cys 20 489 22 PRT Conus consors 489 Met Cys Cys Gly Glu Gly Ala Pro Cys Pro Ser Tyr Phe Arg Asn Ser 1 5 10 15 Gln Ile Cys His Cys Cys 20 490 23 PRT Conus aurisiacus 490 Glx Lys Cys Cys Thr Gly Lys Lys Gly Ser Cys Ser Gly Lys Ala Cys 1 5 10 15 Lys Asn Leu Lys Cys Cys Ser 20 491 23 PRT Conus aurisiacus 491 Glx Lys Cys Cys Thr Gly Arg Lys Gly Ser Cys Ser Gly Lys Ala Cys 1 5 10 15 Lys Asn Leu Lys Cys Cys Ser 20 492 23 PRT Conus bullatus 492 Val Thr Asp Arg Cys Cys Lys Gly Lys Arg Glu Cys Gly Arg Trp Cys 1 5 10 15 Arg Asp His Ser Arg Cys Cys 20 493 23 PRT Conus bullatus 493 Val Gly Asp Arg Cys Cys Lys Gly Lys Arg Gly Cys Gly Arg Trp Cys 1 5 10 15 Arg Asp His Ser Arg Cys Cys 20 494 24 PRT Conus bullatus 494 Val Gly Glu Arg Cys Cys Lys Asn Gly Lys Arg Gly Cys Gly Arg Trp 1 5 10 15 Cys Arg Asp His Ser Arg Cys Cys 20 495 26 PRT Conus bullatus 495 Ile Val Asp Arg Cys Cys Asn Lys Gly Asn Gly Lys Arg Gly Cys Ser 1 5 10 15 Arg Trp Cys Arg Asp His Ser Arg Cys Cys 20 25 496 25 PRT Conus bullatus 496 Val Gly Cys Cys Arg Pro Lys Pro Asn Gly Gln Met Met Cys Asp Arg 1 5 10 15 Trp Cys Glu Lys Asn Ser Arg Cys Cys 20 25 497 22 PRT Conus caracteristicus 497 Arg Asp Cys Cys Thr Pro Pro Lys Lys Cys Lys Asp Arg Gln Cys Lys 1 5 10 15 Pro Gln Arg Cys Cys Ala 20 498 23 PRT Conus lynceus 498 Gly Arg Asp Cys Cys Thr Pro Pro Arg Lys Cys Arg Asp Arg Ala Cys 1 5 10 15 Lys Pro Gln Arg Cys Cys Gly 20 499 22 PRT Conus lynceus 499 Glx Arg Leu Cys Cys Gly Phe Pro Lys Ser Cys Arg Ser Arg Gln Cys 1 5 10 15 Lys Pro His Arg Cys Cys 20 500 22 PRT Conus laterculatus 500 Arg Asp Cys Cys Thr Pro Pro Lys Lys Cys Arg Asp Arg Gln Cys Lys 1 5 10 15 Pro Ala Arg Cys Cys Gly 20 501 22 PRT Conus laterculatus 501 Arg Pro Pro Cys Cys Thr Tyr Asp Gly Ser Cys Leu Lys Glu Ser Cys 1 5 10 15 Met Arg Lys Ala Cys Cys 20 502 22 PRT Conus laterculatus 502 Arg Pro Pro Cys Cys Thr Tyr Asp Gly Ser Cys Leu Lys Glu Ser Cys 1 5 10 15 Lys Arg Lys Ala Cys Cys 20 503 22 PRT Conus geographus PEPTIDE (1)..(22) Xaa is Hyp 503 Arg Asp Cys Cys Thr Xaa Xaa Lys Lys Cys Lys Asp Arg Gln Cys Lys 1 5 10 15 Xaa Gln Arg Cys Cys Ala 20 504 22 PRT Conus geographus PEPTIDE (1)..(22) Xaa is Hyp 504 Arg Asp Cys Cys Thr Xaa Xaa Arg Lys Cys Lys Asp Arg Arg Cys Lys 1 5 10 15 Xaa Met Lys Cys Cys Ala 20 505 22 PRT Conus geographus PEPTIDE (1)..(22) Xaa is Hyp 505 Arg Asp Cys Cys Thr Xaa Xaa Lys Lys Cys Lys Asp Arg Arg Cys Lys 1 5 10 15 Xaa Leu Lys Cys Cys Ala 20 506 22 PRT Conus purpurascens PEPTIDE (1)..(22) Xaa is Hyp 506 Glx Arg Leu Cys Cys Gly Phe Xaa Lys Ser Cys Arg Ser Arg Gln Cys 1 5 10 15 Lys Xaa His Arg Cys Cys 20 507 22 PRT Conus magus 507 Arg Asp Cys Cys Thr Pro Pro Lys Lys Cys Lys Asp Arg Gln Cys Lys 1 5 10 15 Pro Gln Arg Cys Cys Ala 20 508 24 PRT Conus marmoreus 508 Arg Gly Gly Cys Cys Thr Pro Pro Arg Lys Cys Lys Asp Arg Ala Cys 1 5 10 15 Lys Pro Ala Arg Cys Cys Gly Pro 20 509 23 PRT Conus nobilis 509 Glx Lys Cys Cys Thr Gly Lys Lys Gly Ser Cys Ser Gly Lys Ala Cys 1 5 10 15 Lys Asn Leu Lys Cys Cys Ser 20 510 24 PRT Conus parius 510 Arg Gly Gly Cys Cys Thr Pro Pro Lys Lys Cys Lys Asp Arg Ala Cys 1 5 10 15 Lys Pro Ala Arg Cys Cys Gly Pro 20 511 23 PRT Conus parius 511 Arg Gly Cys Cys Thr Pro Pro Arg Lys Cys Lys Asp Arg Ala Cys Lys 1 5 10 15 Pro Ala Arg Cys Cys Gly Pro 20 512 24 PRT Conus radiatus PEPTIDE (1)..(24) Xaa is Hyp 512 Leu Xaa Ser Cys Cys Ser Leu Asn Leu Arg Leu Cys Xaa Val Xaa Ala 1 5 10 15 Cys Lys Arg Asn Xaa Cys Cys Thr 20 513 24 PRT Conus radiatus PEPTIDE (1)..(24) Xaa is Hyp 513 Glx Gln Arg Cys Cys Thr Val Lys Arg Ile Cys Xaa Val Xaa Ala Cys 1 5 10 15 Arg Ser Lys Xaa Cys Cys Lys Ser 20 514 24 PRT Conus radiatus 514 Arg Gly Gly Cys Cys Thr Pro Pro Arg Lys Cys Lys Asp Arg Ala Cys 1 5 10 15 Lys Pro Ala Arg Cys Cys Gly Pro 20 515 23 PRT Conus stercusmuscarum 515 Glx Lys Cys Cys Thr Gly Lys Lys Gly Ser Cys Ser Gly Lys Ala Cys 1 5 10 15 Lys Asn Leu Lys Cys Cys Ser 20 516 21 PRT Conus tulipa PEPTIDE (1)..(21) Xaa is Hyp 516 His Gly Cys Cys Lys Gly Xaa Glu Gly Cys Ser Ser Arg Glu Cys Arg 1 5 10 15 Xaa Gln His Cys Cys 20 517 21 PRT Conus tulipa 517 His Gly Cys Cys Glu Gly Pro Lys Gly Cys Ser Ser Arg Glu Cys Arg 1 5 10 15 Pro Gln His Cys Cys 20 518 23 PRT Conus wittigi 518 Leu Pro Ser Cys Cys Asp Phe Glu Arg Leu Cys Val Val Pro Ala Cys 1 5 10 15 Ile Arg His Gln Cys Cys Thr 20 519 17 PRT Conus omaria 519 Cys Cys Lys Tyr Gly Trp Thr Cys Leu Leu Gly Cys Thr Pro Cys Asp 1 5 10 15 Cys 520 17 PRT Conus omaria 520 Cys Cys Arg Tyr Gly Trp Thr Cys Trp Leu Gly Cys Thr Pro Cys Gly 1 5 10 15 Cys

Claims (42)

What is claimed is:
1. An isolated peptide selected from the group consisting of:
(a) a peptide set forth in Table 1 or Table 2 and (b) a derivative of the peptide in (a).
2. The isolated peptide of claim 1, wherein Xaal is Glu, Xaa2 is pyro-Glu, Xaa4 is Trp and Xaa5 is Tyr.
3. The derivative of the peptide of claim 1, in which the Arg residues may be substituted by Lys, omithine, homoargine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any synthetic basic amino acid; the Lys residues may be substituted by Arg, omithine, homoargine, nor-Lys, or any synthetic basic amino acid; the Tyr residues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic hydroxy containing amino acid; the Ser residues may be substituted with Thr or any synthetic hydroxylated amino acid; the Thr residues may be substituted with Ser or any synthetic hydroxylated amino acid; the Phe residues may be substituted with any synthetic aromatic amino acid; the Trp residues may be substituted with Trp (D), neo-Trp, halo-Trp (D or L) or any aromatic synthetic amino acid; the Asn, Ser, Thr or Hyp residues may be glycosylated;. the Tyr residues may also be substituted with the 3-hydroxyl or 2-hydroxyl isomers (meta-Tyr or ortho-Tyr, respectively) and corresponding O-sulpho- and -phospho-derivatives; the acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g., tetrazolyl derivatives of Gly and Ala; the aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains CnH2n+2 up to and including n=8; the Met residues may be subsituted by Nle; the Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L); pairs of Cys residues may be replaced pairwise with isoteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/Glu (or Asp) or Cys/Ala combinations; and the peptide may be radioiodinated or radiotriated.
4. A substantially pure μ-conotoxin peptide derivative comprising a permutant of the peptide of claim 1.
5. A substantially pure μ-conotoxin peptide derivative comprising the peptide or peptide derivative of claim 1 modified to contain an O-glycan, an S-glycan or an N-glycan.
6. A substantially pure μ-conotoxin peptide derivative comprising the peptide derivative of claim 4 modified to contain an O-glycan, an S-glycan or an N-glycan.
7. An isolated nucleic acid encoding a μ-conopeptide propeptide having an amino acid sequence set forth in Table 1.
8. The isolated nucleic acid of claim 7, wherein the nucleic acid comprises a nucleotide sequence set forth in Table 1.
9. An isolated μ-conopeptide propeptide having an amino acid sequence set forth in Table 1.
10. A method for treating or preventing disorders associated with voltage gated neuronal sodium channel disorders in which comprises administering to a patient in need thereof a therapeutically effective amount of a peptide of claim 1 or a pharmaceutically acceptable salt thereof.
11. The method of claim 10, wherein said disorder is a neurologic disorder.
12. The method of claim 11, wherein said neurologic disorder is Amytrophic Lateral Sclerosis.
13. The method of claim 11, wherein said neurologic disorder is head trauma.
14. The method of claim 11, wherein said neurologic disorder is epilepsy.
15. The method of claim 11, wherein said neurologic disorder is a neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia.
16. The method of claim 15, wherein said neurotoxic injury is associated with stroke, cerebrovascular accident, brain or spinal cord trauma, myocardial infarct, physical trauma, drownings, suffocation, perinatal asphyxia, or hypoglycemic events.
17. The method of claim 10, wherein said disorder is pain.
18. The method of claim 17, wherein said pain is migraine, acute pain, persistent pain, chronic pain, neuropathic pain or nociceptive pain.
19. The method of claim 18, wherein the pain is phantom limb pain, neuroma pain or pain associated with trigeminal neuralgia, diabetic neuropathy or post-herpetic neuralgia.
20. The method of claim 17, wherein said pain is bum pain.
21. The method of claim 10, wherein said disorder is a neuromuscular disorder.
22. The method of claim 21, wherein said neuromuscular disorder is myofacial pain syndrome, chronic muscle spasm, dystonias or spasticity.
23. A method for providing musculoskeletal relaxation in a patient undergoing a surgical procedure requiring anesthesia which comprises administering to a patient in need thereof a therapeutically effective amount of a peptide of claim 1 or a pharmaceutically acceptable salt thereof.
24. A method of alleviating pain which comprises administering to a mammal that is either exhibiting pain or is about to be subjected to a pain-causing event a pain-alleviating amount of a peptide of claim 1 or a pharmaceutically acceptable salt thereof.
25. The method of claim 24, wherein the peptide is administered as a local anesthetic.
26. The method of claim 24, wherein the peptide is administered as an occular anesthetic.
27. A method for characterizing a pore occlusion site on a sodium channel subtype comprising determining the affinity of said site for a peptide of claim 1.
28. The method of claim 27, wherein said sodium channel subtype is a neuronal sodium channel subtype and said peptide is μ-conopeptide S3.2 comprising an amino acid sequence as set forth in SEQ ID NO:211 or SEQ ID NO:432.
29. A method for screening a small molecule library to identify a small molecule which is a selective blocking agent of a sodium channel subtype comprising (a) measuring the blocking activity of a small molecule on said sodium channel subtype, (b) measuring the blocking activity of a peptide of claim 1 on said sodium channel subtype and (c) comparing the blocking activity of said small molecule with the blocking activity of said peptide.
30. The method of claim 29, wherein said sodium channel subtype is a neuronal sodium channel subtype and said peptide is μ-conopeptide S3.2 comprising an amino acid sequence as set forth in SEQ ID NO:211 or SEQ ID NO:432.
31. A method for screening a small molecule library to identify a small molecule which is a selective blocking agent of a sodium channel subtype comprising (a) measuring the binding affinity of a small molecule on said sodium channel subtype, (b) measuring the binding affinity of a peptide of claim 1 on said sodium channel subtype and (c) comparing the binding affinity of said small molecule with the binding affinity of said peptide.
32. The method of claim 31, wherein said peptide is radiolabeled.
33. The method of claim 31, wherein said sodium channel subtype is a neuronal sodium channel subtype and said peptide is μ-conopeptide S3.2 comprising an amino acid sequence as set forth in SEQ ID NO:211 or SEQ ID NO:432.
34. The method of claim 33, wherein said peptide is radiolabeled.
35. A method for screening a small molecule library to identify a small molecule which is a selective blocking agent of a sodium channel subtype comprising (a) allowing a peptide of claim 1 to bind to a sodium channel subtype, (b) adding a small molecule and (c) measuring the amount of displacement of said peptide on said sodium channel subtype by said small molecule.
36. The method of claim 35, wherein said peptide is radiolabeled.
37. The method of claim 35, wherein said sodium channel subtype is a neuronal sodium channel subtype and said peptide is μ-conopeptide S3.2 comprising an amino acid sequence as set forth in SEQ ID NO:211 or SEQ ID NO:432.
38. The method of claim 37, wherein said peptide is radiolabeled.
39. A method for screening a small molecule library to identify a small molecule which is a selective blocking agent of a sodium channel subtype comprising (a) allowing a small molecule to bind to a sodium channel subtype, (b) adding a peptide of claim 1 and (c) measuring the amount of displacement of said small molecule on said sodium channel subtype by said small peptide.
40. The method of claim 39, wherein said sodium channel subtype is a neuronal sodium channel subtype and said peptide is μ-conopeptide S3.2 comprising an amino acid sequence as set forth in SEQ ID NO:211 or SEQ ID NO:432.
41. A method of identifying compounds that mimic the therapeutic activity of a μ-conotoxin, comprising the steps of: (a) conducting a biological assay on a test compound to determine the therapeutic activity; and (b) comparing the results obtained from the biological assay of the test compound to the results obtained from the biological assay of a μ-conotoxin, wherein said μ-conotoxin is a peptide of claim 1.
42. The method of claim 41, wherein said μ-conotoxin is S3.2 comprising an amino acid set forth in SEQ ID NO:211 or SEQ IN NO:432.
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