WO2002007675A2 - Omega-conopeptides - Google Patents

Omega-conopeptides Download PDF

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Publication number
WO2002007675A2
WO2002007675A2 PCT/US2001/023041 US0123041W WO0207675A2 WO 2002007675 A2 WO2002007675 A2 WO 2002007675A2 US 0123041 W US0123041 W US 0123041W WO 0207675 A2 WO0207675 A2 WO 0207675A2
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WIPO (PCT)
Prior art keywords
cys
ser
thr
gly
arg
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PCT/US2001/023041
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French (fr)
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WO2002007675A3 (en
Inventor
Baldomero M. Olivera
J. Michael Mcintosh
Maren Watkins
James E. Garrett
Ki-Joon Shon
Richard B. Jacobsen
Robert M. Jones
G. Edward Cartier
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University Of Utah Research Foundation
Cognetix, Inc.
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Application filed by University Of Utah Research Foundation, Cognetix, Inc. filed Critical University Of Utah Research Foundation
Priority to JP2002513413A priority Critical patent/JP2004512025A/en
Priority to CA002416287A priority patent/CA2416287A1/en
Priority to EP01957214A priority patent/EP1311283A4/en
Priority to AU2001278982A priority patent/AU2001278982A1/en
Publication of WO2002007675A2 publication Critical patent/WO2002007675A2/en
Publication of WO2002007675A3 publication Critical patent/WO2002007675A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/43504Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/06Antimigraine agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Definitions

  • the invention relates to ⁇ -conopeptides, derivatives or pharmaceutically acceptable salts thereof, and uses thereof, including the treatment of neurologic and psychiatric disorders, such as anticonvulsant agents, as neuroprotective agents, as cardiovascular agents or for the management of pain.
  • the invention further relates 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 and their venom For general information on Conus and their venom see the website address http://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 paralyse it's prey.
  • the active components of the venom are small peptides toxins, typically 12-30 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
  • 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 (NMD A) channel.
  • NMD A ligand-gated glutamate
  • 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.
  • 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 Mclntosh et al., 1998).
  • ⁇ -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 O-linked glycopeptide whose C-tenninus resembles neurotensin. It is an agonist of neurotensin receptors, but appears significantly more potent than neurotensin in inhibiting pain in in vivo assays.
  • Ischemic damage to the central nervous system may result form either global or focal ischemic conditions.
  • Global ischemia occurs under conditions in which blood flow to the entire brain ceases for a period of time, such as may result from cardiac arrest.
  • Focal ischemia occurs under conditions in which a portion of the brain is deprived of its normal blood supply, such as may result from thromboembolytic occlusion of a cerebral vessel, traumatic head or spinal cord injury, edema or brain or spinal cord tumors.
  • Both global and focal ischemic conditions have the potential for widespread neuronal damage, even if the global ischemic condition is transient or the focal condition affects a very limited area.
  • Epilepsy is a recurrent paroxysmal disorder of cerebral function characterized by sudden brief attacks of altered consciousness, motor activity, sensory phenomena or inappropriate behavior caused by abnormal excessive discharge of cerebral neurons. Convulsive seizures, the most common form of attacks, begin with loss of consciousness and motor control, and tonic or clonic jerking of all extremities but any recurrent seizure pattern may be termed epilepsy.
  • the term primary or idiopathic epilepsy denotes those cases where no cause for the seizures can be identified.
  • Secondary or symptomatic epilepsy designates the disorder when it is associated with such factors as trauma, neoplasm, infection, developmental abnormalities, cerebrovascular disease, or various metabolic conditions.
  • Epileptic seizures are classified as partial seizures (focal, local seizures) or generalized seizures (convulsive or nonconvulsive). Classes of partial seizures include simple partial seizures, complex partial seizures and partial seizures secondarily generalized. Classes of generalized seizures include absence seizures, atypical absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures (grand mat) and atonic seizures. Therapeutics having anticonvulsant properties are used in the treatment of seizures. Most therapeutics used to abolish or attenuate seizures act at least through effects that reduce the spread of excitation from seizure foci and prevent detonation and disruption of function of normal aggregates of neurons.
  • the present invention is directed to ⁇ -conopeptides, derivatives or pharmaceutically acceptable salts thereof, and uses thereof, including the treatment of neurologic and psychiatric disorders, such as anticonvulsant agents, as neuroprotective agents, as cardiovascular agents or for the management of pain.
  • 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 Table 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, ornithine, 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
  • 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 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 limited to, nitro- Phe, 4-substituted-Phe wherein the substituent is -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-l-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4- piperinyl)-Ala, 2-[3-(2S)pyrrolininyl)-Gly and 2-[3-(2S)pyrrolininyI)-Ala.
  • 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 oligosacchari.de 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. Serial No. 09/420,797 filed 19 October 1999 and in PCT Application No. PCT/US99/24380 filed 19 October 1999 (PCT Published Application No. WO 00/23092), each incorporated herein by reference.
  • a preferred glycan is Gal( ⁇ l-»3)GalNAc( ⁇ 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) or Cys/Ala combinations.
  • isoteric lactam or ester-thioether replacements such as Ser/ Glu or Asp), Lys/(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 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, including the treatment of neurologic disorders, such as anticonvulsant agents, as neuroprotective agents, such as for treating stroke, as cardiovascular agents or for the management of pain.
  • neurologic disorders such as anticonvulsant agents
  • neuroprotective agents such as for treating stroke, as cardiovascular agents or for the management of pain.
  • 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
  • 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 neurologic disorders, such as anticonvulsant agents, as neuroprotective agents, such as for treating stroke, as cardiovascular agents or for the management of pain, e.g. as analgesic agents.
  • 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.
  • Voltage-gated calcium channels are present in neurons, and in cardiac, smooth, and skeletal muscle and other excitable cells, and are known to play a variety of roles in membrane excitability, muscle contraction, and cellular secretion, such as in synaptic transmission (McCleskey).
  • voltage-gated calcium channels In neuronal cells, voltage-gated calcium channels have been classified by their electrophysiological as well as by their biochemical (binding) properties.
  • Six classes of physiologically distinct calcium channels have been identified to date, namely the T, L, N, P, Q, and R-type channels.
  • Compounds blocking the so called L-type calcium channels in the CNS are useful for the treatment of the above disorders by directly blocking the calcium uptake in the CNS. Further, it is well known that the so called N- and P-types of calcium channels, as well as possibly other types of calcium channels, are involved in the regulation of neurofransmitter release. Compounds blocking the N- and/or P-types of calcium channels indirectly and very powerfully prevent calcium overload in the CNS after the hyperactivity periods of the brain as described above by inhibiting the enhanced neurofransmitter release seen after such hyperactivity periods of the CNS, and especially the neurotoxic, enhanced glutamate release after such hyperactivity periods of the CNS.
  • blockers of the N- and/or P-types of calcium channels inhibit the release of various other neurotransmitters such as aspartate, GABA, glycine, dopamine, serotonin and noradrenaline.
  • the pharmaceutical compositions of the present invention are useful as neuroprotectants, cardiovascular agents, anticonvulsants, analgesics 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 the treatment and alleviation of epilepsy and as a general anticonvulsant agent.
  • the present invention is also 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. Other uses of these compounds are described in U.S. Patent No. 5,859,186, incorporated herein by reference.
  • a “neuroprotectant” is a compound capable of preventing the neuronal death associated with a neurological disorder or disease.
  • An “anticonvulsant” is a compound capable of reducing convulsions produced by conditions such as simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery.
  • 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.
  • a “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 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 ⁇ -conopeptides described herein are sufficiently small to be chemically synthesized. General chemical syntheses for preparing the foregoing ⁇ -conotoxin peptides are described hereinafter.
  • ⁇ -conopeptides can also be obtained by isolation and purification from specific Conus species using the technique described in U.S. Patent Nos. 4,447,356 (Olivera et al., 1984); 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 synthesis of peptides containing ⁇ - carboxyglutamic acid residues is exemplified by Rivier et al. (1987), Nishiuchi et al. (1993) and Zhou et al. (1996).
  • 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 benzhydrylamme (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, CA) 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.
  • use of a BHA or MBHA resin is preferred, because cleavage directly gives the amide.
  • N-methyl 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. Patent No. 4,569,967 (Kornheim 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.
  • the ⁇ -amino protecting group is removed, as by using trifluoroacetic acid (TFA) in methylene chloride or TFA alone.
  • TFA trifluoroacetic acid
  • cleaving reagents such as HC1 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 Ho At).
  • 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 C1 2 (1:1) or in DMF or CH 2 C1 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)
  • 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.
  • 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 benzhydrylamme (BHA) resin or a methylbenzhydrylamine (MBHA) can take place at 0°C with hydrofluoric acid (HF) or TFA, followed by oxidation as described above.
  • 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-diisopropylcarb ⁇ dimide in N-methylpyrrolidinone (NMP) or by 2-(lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU) and diethylisopro- pylethylamine (DIEA).
  • NMP N-methylpyrrolidinone
  • HBTU 2-(lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate
  • DIEA diethylisopro- pylethylamine
  • 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.
  • 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. Patent 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.
  • phannaceutically 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.
  • 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). 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.
  • 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. Patent Nos. 4,352,883; 4,353,888; and 5,084,350
  • continuous release polymer implants see, e.g., U.S. Patent No. 4,883,666
  • 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. Patent No. 5,550,050 and published PCT Application Nos. WO 92/19195, WO 94/25503, WO 95/01203, WO 95/05452, WO 96/02286,
  • Suitable DNA sequences can be prepared synthetically for each active agent on the basis of the developed sequences and the known genetic code.
  • 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 phannaceutically 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.
  • amino acid sequence of the purified peptides were determined by standard methods.
  • the purified peptides were reduced and alkylated prior to sequencing by automated
  • 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 Ml 3 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 invnetion is set forth in Table 2.
  • HCCGFCDTANNRCL SEQ ID NO:26
  • AAAAA SEQ ID NO:174
  • Xaa5 Tyr, 125 I-Tyr, mono-iodo-Tyr or di-iodo-Tyr or O-sulpho-Tyr or O-Phospho-Tyr
  • Ay6.2 (A654) C EAGSYCG-STTR- - ICC-GFCAYFGKKCIDYPSN ⁇ (324 )
  • a Ayy66..33 (JJ441199)) CKAKGKPCSRIAYN CCTGSCRS--GKC# (325)
  • J414 CAGPGTIC- -PNRV- - -CC-GYCSKRTHLCHS RT# (361)
  • JG7 CMSPGGICGDFG-D CCE-ICNV-YGICVSDLPGI ⁇ (373)
  • Ra ⁇ .4 (AA688; ACTPEGGACSSGR-H CC-GFCDNVSHTCYGETPSLH ⁇ (394)

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Abstract

The invention relates to φ-conopeptides, derivatives or pharmaceutically acceptable salts thereof, and uses thereof, including the treatment of neurologic and psychiatric disorders, such as anticonvulsant agents, as neuroprotective agents, as cardiovascular agents or for the management of pain. The invention further relates to nucleic acid sequences encoding the conopeptides and encoding propeptides, as well as the propeptides.

Description

TITLE OF THE INVENTION OMEGA-CONOPEPTIDES
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims benefit under 35 USC §119(e) to U.S. provisional patent applications Serial No. 60/219,616 filed on 21 July 2000 and Serial No. 60/265,888 filed on 5 February 2001. Each of these applications are incorporated herein by reference.
[0002] 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, Maryland. The United States Government has certain rights in the invention.
BACKGROUND OF THE INVENTION
[0003] The invention relates to ω-conopeptides, derivatives or pharmaceutically acceptable salts thereof, and uses thereof, including the treatment of neurologic and psychiatric disorders, such as anticonvulsant agents, as neuroprotective agents, as cardiovascular agents or for the management of pain. The invention further relates to nucleic acid sequences encoding the conopeptides and encoding propeptides, as well as the propeptides.
[0004] 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.
[0005] 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 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 website address http://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 paralyse it's prey. The active components of the venom are small peptides toxins, typically 12-30 amino acid residues in length and are typically highly constrained peptides due to their high density of disulphide bonds.
[0006] 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- & φ-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 (NMD A) channel.
[0007] 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. [0008] 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 Mclntosh et al., 1998).
[0009] 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.
[0010] 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 MVLTA (ziconotide), an N-type calcium channel blocker (see Heading, C, 1999; U.S. Patent No. 5,859,186). ω-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. 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 O-linked glycopeptide whose C-tenninus resembles neurotensin. It is an agonist of neurotensin receptors, but appears significantly more potent than neurotensin in inhibiting pain in in vivo assays.
[0011] Ischemic damage to the central nervous system (CNS) may result form either global or focal ischemic conditions. Global ischemia occurs under conditions in which blood flow to the entire brain ceases for a period of time, such as may result from cardiac arrest. Focal ischemia occurs under conditions in which a portion of the brain is deprived of its normal blood supply, such as may result from thromboembolytic occlusion of a cerebral vessel, traumatic head or spinal cord injury, edema or brain or spinal cord tumors. Both global and focal ischemic conditions have the potential for widespread neuronal damage, even if the global ischemic condition is transient or the focal condition affects a very limited area. [0012] Epilepsy is a recurrent paroxysmal disorder of cerebral function characterized by sudden brief attacks of altered consciousness, motor activity, sensory phenomena or inappropriate behavior caused by abnormal excessive discharge of cerebral neurons. Convulsive seizures, the most common form of attacks, begin with loss of consciousness and motor control, and tonic or clonic jerking of all extremities but any recurrent seizure pattern may be termed epilepsy. The term primary or idiopathic epilepsy denotes those cases where no cause for the seizures can be identified. Secondary or symptomatic epilepsy designates the disorder when it is associated with such factors as trauma, neoplasm, infection, developmental abnormalities, cerebrovascular disease, or various metabolic conditions. Epileptic seizures are classified as partial seizures (focal, local seizures) or generalized seizures (convulsive or nonconvulsive). Classes of partial seizures include simple partial seizures, complex partial seizures and partial seizures secondarily generalized. Classes of generalized seizures include absence seizures, atypical absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures (grand mat) and atonic seizures. Therapeutics having anticonvulsant properties are used in the treatment of seizures. Most therapeutics used to abolish or attenuate seizures act at least through effects that reduce the spread of excitation from seizure foci and prevent detonation and disruption of function of normal aggregates of neurons. Traditional anticonvulsants that have been utilized include phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, clonazepam and valproate. Several novel and chemically diverse anticonvulsant medications recently have been approved for marketing, including lamotrigine, ferlbamate, gabapentin and topiramate. For further details of seizures and their therapy, see Rail & Schleifer (1985) and Hie Merck Manual (1992). [0013] 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.
SUMMARY OF THE INVENTION
[0014] The present invention is directed to ω-conopeptides, derivatives or pharmaceutically acceptable salts thereof, and uses thereof, including the treatment of neurologic and psychiatric disorders, such as anticonvulsant agents, as neuroprotective agents, as cardiovascular agents or for the management of pain. The invention is further directed to nucleic acid sequences encoding the ω-conopeptides and encoding propeptides, as well as the propeptides.
[0015] More specifically, the present invention is directed to ω-conopeptides, having the amino acid sequences set forth in Table 2 below.
[0016] The present invention is also directed to derivatives or pharmaceutically acceptable salts of the ω-conopeptides or the derivatives. Examples of derivatives include peptides in which the Arg residues may be substituted by Lys, ornithine, 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 CnH2n+2 up to and including n=8. The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L).
[0017] Examples of synthetic aromatic amino acid include, but are not limited to, nitro- Phe, 4-substituted-Phe wherein the substituent is -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-l-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4- piperinyl)-Ala, 2-[3-(2S)pyrrolininyl)-Gly and 2-[3-(2S)pyrrolininyI)-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 http://www.amino-acids.com), incorporated herein by reference, by and available from RSP Amino Acid Analogues, Inc., Worcester, MA. 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. Patent No. 5,331,001, each incorporated herein by reference.
[0018] Optionally, in the ω-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 oligosacchari.de 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-.
[0019] 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. Serial No. 09/420,797 filed 19 October 1999 and in PCT Application No. PCT/US99/24380 filed 19 October 1999 (PCT Published Application No. WO 00/23092), each incorporated herein by reference. A preferred glycan is Gal(βl-»3)GalNAc(αl— »).
[0020] Optionally, in the ω-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) 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. [0021] 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 ω-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 ω-conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
[0022] More specifically, the present invention is further directed to uses of these peptides or nucleic acids as described herein, including the treatment of neurologic disorders, such as anticonvulsant agents, as neuroprotective agents, such as for treating stroke, as cardiovascular agents or for the management of pain.
[0023] More specifically, 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.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0024] The present invention is to ω-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 neurologic disorders, such as anticonvulsant agents, as neuroprotective agents, such as for treating stroke, as cardiovascular agents or for the management of pain, e.g. as analgesic agents. The invention is further directed to nucleic acid sequences encoding the ω-conopeptides and encoding propeptides, as well as the propeptides.
[0025] The present invention, in another aspect, relates to a pharmaceutical composition comprising an effective amount of an ω-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.
[0026] Voltage-gated calcium channels are present in neurons, and in cardiac, smooth, and skeletal muscle and other excitable cells, and are known to play a variety of roles in membrane excitability, muscle contraction, and cellular secretion, such as in synaptic transmission (McCleskey). In neuronal cells, voltage-gated calcium channels have been classified by their electrophysiological as well as by their biochemical (binding) properties. Six classes of physiologically distinct calcium channels have been identified to date, namely the T, L, N, P, Q, and R-type channels. [0027] It is well known that an accumulation of calcium (calcium overload) in the brain is seen after anoxia, ischemia, migraine and other hyperactivity periods of the brain, such as after epileptic convulsions. An uncontrolled high concentration of calcium in the cells of the central nervous system (CNS) is known to cause most of the degenerative changes connected with the above diseases. Compounds which can block the calcium channels of brain cells are therefore useful in the treatment of stroke, anoxia, ischemia, migraine, psychosis, or epilepsy, any other convulsive disorder and in the prevention of the degenerative changes connected with the same.
[0028] Compounds blocking the so called L-type calcium channels in the CNS are useful for the treatment of the above disorders by directly blocking the calcium uptake in the CNS. Further, it is well known that the so called N- and P-types of calcium channels, as well as possibly other types of calcium channels, are involved in the regulation of neurofransmitter release. Compounds blocking the N- and/or P-types of calcium channels indirectly and very powerfully prevent calcium overload in the CNS after the hyperactivity periods of the brain as described above by inhibiting the enhanced neurofransmitter release seen after such hyperactivity periods of the CNS, and especially the neurotoxic, enhanced glutamate release after such hyperactivity periods of the CNS. Furthermore, blockers of the N- and/or P-types of calcium channels, as dependent upon the selectivity of the compound in question, inhibit the release of various other neurotransmitters such as aspartate, GABA, glycine, dopamine, serotonin and noradrenaline.
[0029] Thus, the pharmaceutical compositions of the present invention are useful as neuroprotectants, cardiovascular agents, anticonvulsants, analgesics 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. [0030] More specifically, the present invention is directed to the use of these compounds for the treatment and alleviation of epilepsy and as a general anticonvulsant agent. The present invention is also 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. Other uses of these compounds are described in U.S. Patent No. 5,859,186, incorporated herein by reference.
[0031] A "neuroprotectant" is a compound capable of preventing the neuronal death associated with a neurological disorder or disease. An "anticonvulsant" is a compound capable of reducing convulsions produced by conditions such as simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery. 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. A "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.
[0032] 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.
[0033] 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 ω-conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof. The pain may be acute, persistent, inflammatory or neuropathic pain.
[0034] In a second 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 ω-conopeptide described herein or a pharmaceutically acceptable salt or solvate thereof. [0035] The ω-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 ω-conopeptides can also be obtained by isolation and purification from specific Conus species using the technique described in U.S. Patent Nos. 4,447,356 (Olivera et al., 1984); 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.
[0036] Although the ω-conopeptides of the present invention can be obtained by purification from cone snails, because the amounts of ω-conopeptides obtainable from individual snails are very small, the desired substantially pure ω-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 ω- 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 ω-conopeptides peptides depends of course upon correct determination of the amino acid sequence.
[0037] The ω-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 ω-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.
[0038] One method of forming disulfide bonds in the ω-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.
[0039] 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.
[0040] 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. Patent 4,105,603 (Vale et al., 1978). The fragment condensation method of synthesis is exemplified in U.S. Patent 3,972,859 (1976). Other available syntheses are exemplified by U.S.
Patents No. 3,842,067 (1974) and 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).
[0041] 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.
[0042] 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.
[0043] 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 benzhydrylamme (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, CA) 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-CH2-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. Patent 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).
[0044] 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 HC1 in dioxane, and conditions for removal of specific α- amino protecting groups may be used as described in Schroder & Lubke (1965). [0045] 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 Ho At).
[0046] 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). [0047] 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):CH2C12 (1:1) or in DMF or CH2C12 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). [0048] 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. [0049] 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 benzhydrylamme (BHA) resin or a methylbenzhydrylamine (MBHA), can take place at 0°C with hydrofluoric acid (HF) or TFA, followed by oxidation as described above.
[0050] 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-diisopropylcarbόdimide in N-methylpyrrolidinone (NMP) or by 2-(lH- benzotriazole-l-yl)-l,l,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.
[0051] 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. Patent Nos. 5,545,723 (see particularly col. 2, line 50~col. 3, line 8); 5,534,615 (see particularly col. 19, line 45— col. 22, line 33); and 5,364,769 (see particularly col. 4, line 55~col. 7, line 26), each herein incorporated by reference.
[0052] The ω-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 ω-conopeptide to effectively minimize the CNS damage which the patient will experience.
[0053] The ω-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 ω-conopeptide is administered in a therapeutically effective amount to overcome or to ease the pain.
[0054] 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, 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. Patent No. 5,844,077, incorporated herein by reference.
[0055] "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.
[0056] 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.
[0057] Examples of such phannaceutically 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.
[0058] 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.
[0059] 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.
[0060] 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.
[0061] 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.
[0062] 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. [0063] For example, administration of the active agent according to this invention may be achieved using any suitable delivery means, including:
(a) pump (see, e.g., Luer & Hatton (1993), Zimm et al. (1984) and Ettinger et al. (1978));
(b), microencapsulation (see, e.g., U.S. Patent Nos. 4,352,883; 4,353,888; and 5,084,350); (c) continuous release polymer implants (see, e.g., U.S. Patent No. 4,883,666);
(d) macroencapsulation (see, e.g., U.S. Patent Nos. 5,284,761, 5,158,881, 4,976,859 and 4,968,733 and published PCT patent applications WO92/19195, WO 95/05452);
(e) naked or unencapsulated cell grafts to the CNS (see, e.g., U.S. Patent Nos. 5,082,670 and 5,618,531); (f) injection, either subcutaneously, intravenously, intra-arterially, intramuscularly, or to other suitable site; or
(g) oral administration, in capsule, liquid, tablet, pill, or prolonged release formulation. [0064] 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.
[0065] 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.
[0066] 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. Patent 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.
[0067] 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 Remington 's Parmaceutical Sciences.
[0068] 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.
[0069] 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.
[0070] 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.
[0071] 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.
[0072] 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 phannaceutically 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.
[0073] 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; 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-TV (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 [0074] 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.
EXAMPLE 1 Isolation of ω -Conotoxins
[0075] 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 C18 semi-preparative column (10 x 250 mm). Further purification of bioactive peaks was done on a Vydac C18 analytical column (4.6 x 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).
[0076] 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 477 A Protein Sequencer with a 120 A Analyzer (DNA/Peptide Facility, University of Utah) (Martinez et al., 1995; Shon et al., 1994). [0077] In accordance with this method, the ω-conopeptides described as "isolated" in Table 1 were obtained. These ω-conopeptides, as well as the other ω-conopeptides and the ω- conopeptide precursors set forth in Table 1 are synthesized as described in U.S. Patent No. 5,591,821.
EXAMPLE 2 Isolation of DNA Encoding ω -Conopeptides [0078] DNA coding for ω-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 Ml 3 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 ω-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 ω-conopeptides of the present invnetion is set forth in Table 2.
TABLE 1
DNA and Amino Acid Sequences of ω -Conopeptides and Precursors
Name: J410
Species: Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGCATGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGT CAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCATGCCCTGAGGTC GACCACCAATTTCTCCACGTTGACTCGTCGCTGCCTTTCTCCCGGATCACGATGTCA TAAGACAATGCGTAACTGCTGCACTTCATGCTCTTCATACAAAGGGAAATGTCGGCC TCGAAAATGAACCACTCATCACCTACTCCTCTGGAGGCCTCAGAGGAATTACATTGA AATAAAAGCCGCATTACAAAAAAAAAAAAAAAAA (SEQ ID NO:l)
Translation: MKLTCMNINAVLLLTACQLITADDSRGTQKHHALRSTTNFSTLTRRCLSPGSRCHKTMR NCCTSCSSYKGKCRPRK (SEQ TD NO:2) Toxin Sequence:
Cys-Leu-Ser-Xaa3-Gly-Ser-Arg-Cys-His-Lys-Thr-Met-Arg-Asn-Cys-Cys-Thr-Ser-Cys-Ser-Ser- Xaa5-Lys-Gly-Lys-Cys-Arg-Xaa3-Arg-Lys-A (SEQ TD NO:3)
Name: J411
Species: Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGCGTGGTGATCGTCGCCGTGCTGCTCCTGACGGTCTGT CAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCATGCCCTGAGGTC GACCACCAATTTCTCCACGTCGACTCGTCGCTGCAAACCTCCCGGAAGAAAATGTCT GAATAGAAAGAATGAATGCTGCAGCAAGTTTTGCAATGAACACCTACATATGTGTG GATAAATGGCTAAAAACTGAATAAAAGCCGCATTGCAAAAAAAAAAAAAAAAAAA AA (SEQ ID NO:4)
Translation:
MKLTCNNINANLLLTNCQLITADDSRGTQKHHALRSTTNFSTSTRRCKPPGRKCLNRKN ECCSKFCNEHLHMCG (SEQ TD NO:5)
Toxin Sequence:
Cy s-Ly s-Xaa3 -Xaa3 -Gly- Arg-Ly s-Cy s-Leu- Asn- Arg-Ly s- Asn-Xaal -Cys-Cy s-S er-Ly s-Phe- Cys-Asn-Xaal-His-Leu-His-Met-Cys-# (SEQ TD NO:6)
Name: J413
Species: Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGCGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGT
CAACTCGTCACAGCTGATGGCTCCAGAGGTATGCAGAAGCATTATGCCCTGAGGTC
GACCACCAATCTCTCCATATCGTCTCGCTGCAAACCTCCCAGAAGAAAATGTCTGAA GATTAAGGATAAATGCTGCAACTTTTGCAATACACACCTAAATATGTGTGGATAAAT
GGCTAAAAACTGAATAAAAGCCGCATTGCAAAAAAAAAAAAAAAAAAA (SEQ TD NO:7)
Translation: MKLTCNNINAVLLLTACQLNTAX GSRGMQKHYALRSTTNLSISSRCKRPPJ KCLKIKDK
CCNFCNTHLNMCG (SEQ ID NO:8)
Toxin Sequence:
Cys-Lys-Xaa3-Xaa3-Arg-Arg-Lys-Cys-Leu-Lys-Ile-Lys-Asp-Lys-Cys-Cys-Asn-Phe-Cys-Asn- Thr-His-Leu-Asn-Met-Cys-# (SEQ TD NO:9) Name: J414
Species: Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGATGGCCTGT CAACTCGTCACAGCTGATGGCTCCAGAGGTATGCACAAGCATTATGCCCTGAGGTC GACCACCAAACTCTCCATGTCGACTCGCTGCGCAGGTCCAGGAACAATTTGTCCTAA TAGGGTATGCTGCGGTTATTGCAGTAAAAGAACACATCTATGTCATTCGCGAACTGG CTGATCTTCCCCCTTCTGCGCTCCATCCTTTTCTGCCTGAGTCCTCCATACCTGAGAA TGGTCATGAACCACTCAACACCTACTCCTCTGGAGGGCCTCAGAAGAGCTACATTG AAATAAAAGCCGCATTACAAAAAAAAAAAAAAAAAA (SEQ ID NO: 10)
Translation: MKLTCVNINANLLLMACQLNTADGSRGMHKHYALRSTTKLSMSTRCAGPGTICPNRNC CGYCSKRTHLCHSRTG (SEQ ID ΝO: 11)
Toxin Sequence:
Cys-Ala-Gly-Xaa3-Gly-Thr-Ile-Cys-Xaa3-Asn-Arg-Nal-Cys-Cys-Gly-Xaa5-Cys-Ser-Lys-Arg- Thr-His-Leu-Cys-His-Ser-Arg-Thr-# (SEQ ID ΝO: 12)
Name: Arό.10
Species: arenatus Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGCATGGTGATCATCGCCGTGCTGTTCCTGACGGCCTGT CAACTCATTACAGGTGAGCAGAAGGACCATGCTCTGAGGTCAACTGACAAAAACTC CAAGTTGACTAGGCAGTGCTCGGCTAACGGTGGATCTTGTACTCGTCATTTTCACTG
CTGCAGCCTCTATTGCAATAAAGATTCCAGTGTATGTGTGGCAACCTCATACCCGTG AGTGGCCATGAACCCCTCAATACCCTCTCCTCTGGAGGCTTCAGAGGAACTGCATTG AAATAAAACCGCATTGCAATAAAAAAAAAAAAAAAAAAA (SEQ TD NO: 13)
Translation:
MKLTCMNIIANLFLTACQLITGEQKDHALRSTDKNSKLTRQCSANGGSCTRHFHCCSLY CNKDSSVCVATSYP (SEQ ID NO: 14)
Toxin Sequence: Xaa2-Cys-Ser-Ala-Asn-Gly-Gly-Ser-Cys-Thr-Arg-His-Phe-His-Cys-Cys-Ser-Leu-Xaa5-Cys- Asn-Lys-Asp-Ser-Ser-Nal-Cys-Val-Ala-Thr-Ser-Xaa5-Xaa3-A (SEQ TD ΝO:15)
Name: Ar6.2 Species: arenatus Cloned: Yes DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGCGTGTTGATTATCGCCGTGCTGTTC CTGACGGCCTGTCAACTCATTACAGCTGAGACTTACTCCAGAGGTGAGCAGAAGCA CCATGCTCTGAGGTCAACTGACAGAAACTCCAAGTTGACCAGGACATGCAACACTC CCACTGAATATTGTACTTTGCATCGACACTGCTGCAGCGGCTACTGCCATAAAACAA TCCAGGCATGTTCATAATACCGGTGAGTGGTCATGAACCACTCAATACCCTCTCCTC TGGAGGCTTCAGAGGAACTGCATTGAAATAAAAGCCGCATTGC (SEQ ID NO: 16)
Translation: MKLTCNLπANLFLTACQLITAETYSRGEQKHHALRSTDRNSKLTRTCNTPTEYCTLHRH CCSGYCHKTIQACS (SEQ TD NO: 17)
Toxin Sequence:
Thr-Cys-Asn-Thr-Xaa3-Thr-Xaal-Xaa5-Cys-Thr-Leu-His-Arg-His-Cys-Cys-Ser-Gly-Xaa5- Cys-His-Lys-Thr-Ile-Gln-Ala-Cys-Ser-Λ (SEQ ID NO: 18)
Name: Ar6.3
Species: arenatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGCGTGTTGATCATCGCCGTGCTGTTC CTGACGGCCTGTCAACTCATTACAGCTGAGACTTACTCCAGAGGTGAGCAGATGCA CCGTGCTCTGAGGTCAACTGACAAAAACTCCAAGTTGACTAGGCAGTGCACGCCTA
ACGGTGGATCTTGTTCTCGTCATTTTCACTGCTGCAGCCTCTATTGCAATAAAAGTA CTGGCGTATGTATTGCAACCTCATACCCGTGAGTGGTCATGAACCACTCAATACCCT CTCCTCTGGAGGCTTCAGAGGAACTGCATTGAAATAAAAGCCGCATTGC (SEQ TD NO: 19)
Translation:
MKLTCNLIIANLFLTACQLITAETYSRGEQMHRALRSTDKNSKLTRQCTPNGGSCSRHF HCCSLYCNKSTGNCIATSYP (SEQ TD ΝO:20)
Toxin Sequence:
Xaa2-Cys-Thr-Xaa3-Asn-Gly-Gly-Ser-Cys-Ser-Arg-His-Phe-His-Cys-Cys-Ser-Leu-Xaa5-Cys- Asn-Lys-Ser-Thr-Gly-Val-Cys-Ile-Ala-Thr-Ser-Xaa5-Xaa3-A (SEQ TD ΝO:21)
Name: Ar6.4
Species: arenatus Cloned: Yes
DNA Sequence: GGATCCATGAAACTGACGTGCATGGTGATTATCGCCGTGCTGTTCCTGACGGCCTGT CAACTCATTACAGCTGAGACTTACTCCAGAGGTGAGCAGAAGCACCATGCTCTGAG GTCAACTGACAAAAACTCCAAGTTGACCAGGACATGCAACACTCCCACCGAATATT GTACTTTGCATCAACACTGCTGCAGCGGCTACTGCCATAAAACAATCCAGGCATGTT CATAATACCGGTGAGTGGTCATGAACCACTCAATACCCTCTCCTCTGGAGGCTTCAG AGGAACTGCATTGAAATAAAACCGCATTACAAAAAAAAAAAAAAAAAAA (SEQ TD NO:22)
Translation:
MKLTCMVIIANLFLTACQLITAETYSRGEQKHHALRSTDKNSKLTRTCNTPTEYCTLHQ HCCSGYCHKTIQACS (SEQ ID NO:23)
Toxin Sequence:
Thr-Cys-Asn-Thr-Xaa3-Thr-Xaal-Xaa5-Cys-Thr-Leu-His-Gln-His-Cys-Cys-Ser-Gly-Xaa5- Cys-His-Lys-Thr-Ile-Gln-Ala-Cys-Ser-Λ (SEQ TD NO:24)
Name: Ar6.6
Species: arenatus Cloned: Yes
DNA Sequence: GGATCCATGAAACTGACGTGTATGGTGATCATCGCCGTACTGTTCCTGACGGCCTGT CAACTCATTACAGCTGAGACTTACTCCAGAGGTAAGCAGATGCACCGCGCTCTGAG GTCAACTGACAAAAACTCCCAGTTGACCAGGGAATGCACACCTCCCGGTGGAGCTT GTGGTTTACCTACACACTGCTGCGGGTTTTGCGATACTGCAAACAACAGATGTCTGT AAAGCTGGTCTGGCGTCTGATATTCCCCTTCTGTGCTCTATCCTCTTTGGCCTGAGTC ATCCGTACCTGTGAGTGGTCATGAACTACTCAATACCCTCTCCTCTGGAGGCTTCAG
AGGAACTACAATGAAATAAAACCCGCATTGCAGAGAAAAAAAAAAAAAAAAAA (SEQ ID NO:25)
Translation: MKLTCMNIIANLFLTACQLITAETYSRGKQMHRALRSTDKNSQLTRECTPPGGACGLPT
HCCGFCDTANNRCL (SEQ ID NO:26)
Toxin Sequence:
Xaal-Cys-Thr-Xaa3-Xaa3-Gly-Gly-Ala-Cys-Gly-Leu-Xaa3-Thr-His-Cys-Cys-Gly-Phe-Cys- Asp-Thr-Ala-Asn-Asn-Arg-Cys-Leu-A (SEQ TD NO:27)
Name: Ar6.7
Species: arenatus Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGCGTGGTGATTATCGCCGTGCTGTTCCTGACGGCCTGT CAACTCATTACAGCTGAGACTTACTCCAGAGGTGAGCAGAATCACCATGTTCTGAG GTCAACTGACAAAAACTCCAAGTTGACCAGGACATGCAACACTCCCACTGAATATT GTACTTTGCATCAACACTGCTGCAGCGGCCACTGCCATAAAACAATCCAGGCATGT GCATAATACCGGTGGGTGGTCATGAACCACTCAATACCCTCTCCTCTGGAGGCTTCA GAGGAACTGCATTGAAATAAAACCGCATTGCAATGAANAAAAAAAAAAAAAAAAA AAAAAAAA (SEQ TD NO:28)
Translation: MKLTCVNIIANLFLTACQLITAETYSRGEQNHHNLRSTDKNSKLTRTCNTPTEYCTLHQ HCCSGHCHKTIQACA (SEQ ID NO:29)
Toxin Sequence:
Thr-Cys-Asn-Thr-Xaa3-Thr-Xaal-Xaa5-Cys-Thr-Leu-His-Gln-His-Cys-Cys-Ser-Gly-His-Cys- His-Lys-Thr-Ile-Gln-Ala-Cys-Ala-Λ (SEQ TD NO:30)
Name: Ar6.8
Species: arenatus Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGTGTGGTGATCATCGCCGTGCTGTTCCTGACGGCCTGT CAACTCACTACAGGTGAGCAGAAGGACCATGCTCTGAGGTCAACTGACAAAAACTC CAAGTTGACTAGGCAGTGCTCGCCTATCGGTGGATATTGTACTCTTCATATTCACTG CTGCAGCAACCATTGCATTAAACCTATCGGCCGATGTGTGGCAACCTGATACCCGTG CGTGGTCATGAACCCCTCAATACCCTCTCCTCTGGAGGCTTCAGAGGAACTGCATTG AAATAAAACCGCATTGCAATAAAAAAAAAAAAAAAAAA (SEQ ID NO:31)
Translation:
MKLTCWIIAVLFLTACQLTTGEQKDHALRSTDKNSKLTRQCSPIGGYCTLHTHCCSNHC IKPIGRCVAT (SEQ TD NO:32)
Toxin Sequence:
Xaa2-Cys-Ser-Xaa3-Ile-Gly-Gly-Xaa5-Cys-Thr-Leu-His-Ile-His-Cys-Cys-Ser-Asn-His-Cys-Ile- Lys-Xaa3-Ile-Gly-Arg-Cys-Val-Ala-Tlιr-Λ (SEQ ID NO:33)
Name: Ar6.9
Species: arenatus Cloned: Yes
DNA Sequence: GGATCCATGAAACTGACGTGCGTGGTGATCATCGCCGTGCTGTTCCTGACGGCCTGT
CAACTCACTACAGGTGAGCAGAAGGACCATGCTCTGAGGTCAACTGACAAAAACTC CAAGTTGACTAGGCAGTGCTTGCCTAACGGTGGATATTGTACTCTTCATATTCACTG CTGCAGCGACCATTGCATTAAACCTATCGACCGATGTGTGGCAACCTGATACCCGG GCGTGGTCATGAACCCCTCAATACCCTCTCCTCTGGAGGCTTCAGAGGAACTGCATT GAAATAAAACCGCATTACAAAAAAAAAAAAAAAAA (SEQ TD NO:34)
Translation: MKLTCNNIIANLFLTACQLTTGEQKDHALRSTDKNSKLTRQCLPNGGYCTLHIHCCSDH CIKPIDRCVAT (SEQ TD NO:35)
Toxin Sequence:
Xaa2-Cys-Leu-Xaa3-Asn-Gly-Gly-Xaa5-Cys-Thr-Leu-His-Ile-His-Cys-Cys-Ser-Asp-His-Cys- Ile-Lys-Xaa3-Ile-Asp-Arg-Cys-Nal-Ala-Tlιr-Λ (SEQ ID NO:36)
Name: Ay6.1
Species: aurisiacus Cloned: Yes
DNA Sequence: ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGTCAACTC ATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTTCCCTGAGCTCGGCCAC CAAACTCTCCATGTCGACTCGCTGCAAGGGTAAAGGAAAACCATGCAGTAGGATTT CGTATAACTGCTGCACCGGTTCTTGCAGATCAGGTAAATGTGGCTGATCCAGCGCCT GATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCTTACCTGAGAGTG GTCATGAACCACTCATCACCTGCTCCTCTGGAGGCCCCAGAGGAGCTACATTGAAAT AAAAGTCGCATTGCAAAAAAAAAAAAAAAAAAA (SEQ ID NO:37)
Translation:
MKLTCNNINANLLLTACQLITADDSRGTQKHRSLSSATKLSMSTRCKGKGKPCSRISYN CCTGSCRSGKCG (SEQ TD NO:38)
Toxin Sequence:
Cys-Lys-Gly-Lys-Gly-Lys-Xaa3-Cys-Ser-Arg-Ile-Ser-Xaa5-Asn-Cys-Cys-Thr-Gly-Ser-Cys- Arg-Ser-Gly-Lys-Cys-# (SEQ ID NO:39)
Name: Ay6.2
Species: aurisiacus Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGTCAACTC ATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTTCCCTGAGGTCGAAGAC CAAACTCTCCATGTCGACTGGCTGCATGGAAGCCGGATCTTATTGCGGCTCTACTAC GAGAATCTGCTGCGGTTTTTGCGCTTATTTCGGCAAAAAATGTATTGACTATCCCAG CAACTGATCTTCCCCCTACTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCTTACCTGA GAGTGGTCATGAACCACTCATCACCTGCTCCTCTGGAGGCCCCAGAGGAGCTACATT GAAATAAAATCGCATTGCTAAAAAAAAAAAAAAAAAAA (SEQ ID NO:40)
Translation:
MKLTCVNINANLLLTACQLITADDSRGTQKHRSLRSKTKLSMSTGCMEAGSYCGSTTRI CCGFCAYFGKKCTDYPSΝ (SEQ TD ΝO:41) Toxin Sequence:
Cys-Met-Xaal-Ala-Gly-Ser-Xaa5-Cys-Gly-Ser-Thr-Thr-Arg-Ile-Cys-Cys-Gly-Phe-Cys-Ala- Xaa5-Phe-Gly-Lys-Lys-Cys-Ile-Asp-Xaa5-Xaa3-Ser-Asn-A (SEQ TD NO:42)
Name: Ay6.3
Species: aurisiacus
Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTTCCCTGAGCTCGGCCACCAAACTCTCCATGTCGACTCGCTGCAAGGCTAAAGGA AAACCATGCAGTAGGATTGCGTATAACTGCTGCACCGGTTCTTGCAGATCAGGTAA ATGTGGCTGATCCAGTGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGA GTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTGCTCCTCTGGAGGCCC CAGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ ID NO:43)
Translation:
MKLTCVVIVAVLLLTACQLITADDSRGTQKHRSLSSATKLSMSTRCKAKGKPCSRTAYN CCTGSCRSGKCG (SEQ ID NO:44)
Toxin Sequence: Cys-Lys-Ala-Lys-Gly-Lys-Xaa3-Cys-Ser-Arg-Ile-Ala-Xaa5-Asn-Cys-Cys-Thr-Gly-Ser-Cys- Arg-Ser-Gly-Lys-Cys-# (SEQ TD NO:45)
Name: Ay 6.4 Species: aurisiacus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGACCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGGAGCATC
GTGCCCTGAGGTCGAAGACAAAACTCTCCATGTTAACTTTGCGCTGCGCATCTTACG GAAAACCTTGTGGTATTGACAACGACTGCTGCAATGCATGCGATCCAGGAAGAAAT ATATGTACGTAGCTGATCCAGCGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCT GCCCGAGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTGCTCCCTGGA GGCCTCAGAGGAGCTACAATGAAATAAAAGCCGCATTGC (SEQ ID NO:46)
Translation:
MKLTCWΓVAVLLLTTCQLITADDSRGTQEHRALRSKTKLSMLTLRCASYGKPCGIDND CCNACDPGRNICT (SEQ TD NO:47)
Toxin Sequence:
Cys-Ala-Ser-Xaa5-Gly-Lys-Xaa3-Cys-Gly-Ile-Asp-Asn-Asp-Cys-Cys-Asn-Ala-Cys-Asp-Xaa3- Gly-Arg-Asn-Ile-Cys-ThX (SEQ TD NO:48)
Name: Bu6.1 Species: bullarus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGCGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAGCTCATTACAGCTGAAGACTCCAGAGGTACGCATGAGCATC TTGCCCTGAAGTCGACCTCCAAAGTCTCCAAGTCGACTAGCTGCATGGAAGCCGGA TCTTATTGCGGACCTGCTACTACGAAAATCTGCTGCGATTTTTGCAGTCCATTCAGC GATAGATGTATGAACAATCCCAACAATTGATCTTCCCCCTTGTGTGCTCCATCCTTTT CTGCCTGAGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCT GGAGGCTTCAGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ ID NO:49)
Translation:
MKLTCVAIVAVLLLTACQLITAEDSRGTHEHLALKSTSKVSKSTSCMEAGSYCGPATTK ICCDFCSPFSDRCMΝΝPΝΝ (SEQ TD ΝO:50)
Toxin Sequence:
Ser-Thr-Ser-Cys-Met-Xaal-Ala-Gly-Ser-Xaa5-Cys-Gly-Xaa3-Ala-Thr-Tlιr-Lys-Ile-Cys-Cys- Asp-Phe-Cys-Ser-Xaa3-Phe-Ser-Asp-Arg-Cys-Met-Asn-Asn-Xaa3-Asn-Asn-A (SEQ ID NO:51)
Name: Bu6.2
Species: bullatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAGCTCATTACAGCTGAAGACTCCAGAGGTACGCAGTTGCATC GTGCCCTGAGGAAGGCCACCAAACACCCTGTGTCGACTCGCTGCATTACTCCAGGA ACACGATGTAAGGTTCCGAGCCAATGCTGCAGAGGTCCTTGCAAGAACGGTCGTTG TACTCCATCCCCTTCTGAATGGTAAATGTGGTTGATCCAGCGCCTGATCTTCCCCCTT
CGTCGTGCTCCATCCTTTTCTGCCTGAGTCCTCCTTACCTGAGAGTGGTCATGAACC ACTCATCACCTACTCCCCTGGAGGCTTCAGAGGAGCTACATTGAAATAAAAGCCGC ATTGC (SEQ ID NO:52)
Translation:
MKLTCNVTVAVLLLTACQLITAEDSRGTQLHRALRKATKHPVSTRCITPGTRCKVPSQC CRGPCKΝGRCTPSPSEW (SEQ TD ΝO:53)
Toxin Sequence: Cys-Ile-Thr-Xaa3-Gly-Thr-Arg-Cys-Lys-Val-Xaa3-Ser-Gln-Cys-Cys-Arg-Gly-Xaa3-Cys-Lys- Asn-Gly-Arg-Cys-Thr-Xaa3-Ser-Xaa3-Ser-Xaal-Xaa4-A (SEQ TD NO:54) Name: Bu6.3
Species: bullatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGCGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAGCTCATTACAGCTGAGGACTCCAGAGATACGCAGAAGCATC GTGCCCTGAGGTCGGACACCAAACTCTCCATGTTGACTTTGCGCTGCGCAACTTACG GAAAACCTTGTGGTATTCAAAACGACTGCTGCAATACATGCGATCCAGCCAGAAGG ACATGTACGTAGCTGATCCGGCGTCTTGATCCTCCGCTTCTGTGCTCCATCTTTTCTG CCTGAGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTGGA GGCTTTAGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ ID NO:55)
Translation:
MKLTCVAINANLLLTACQLITAEDSRDTQKHRALRSDTKLSMLTLRCATYGKPCGIQND CCNTCDPARRTCT (SEQ TD NO:56)
Toxin Sequence:
Cys-Ala-Thr-Xaa5-Gly-Lys-Xaa3-Cys-Gly-Ile-Gln-Asn-Asρ-Cys-Cys-Asn-Thr-Cys-Asρ-Xaa3- Ala-Arg-Arg-Thr-Cys-Thr-A (SEQ ID NO:57)
Name: Bu6.4
Species: bullatus Cloned: Yes
DNA Sequence: ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGCGATCGTCGCCGTGCTGCT
CCTGACGGCCTGTCAGCTCATTACAGCTGAAGACTCCAGAGGTACGCAGTTGCATC GTGCCCTGAGGAAGACCACCAAACTCTCCTTGTCGACTCGCTGCAAGGGTCCAGGA GCATCATGTATAAGGATTGCGTATAACTGCTGCAAGTATTCTTGCAGAAATGGTAAA TGTGGCTGATCCAGCGCCTGATCTTCCCCCTTGTGTGCTCCATCCTTTTCTGCCTGAG TCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTGGAGGCTTC
AGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ ID NO:58)
Translation:
MKLTCNAIVANLLLTACQLITAEDSRGTQLHRALRKTTKLSLSTRCKGPGASCIRIAYNC CKYSCRNGKCG (SEQ ID NO:59)
Toxin Sequence:
Cys-Lys-Gly-Xaa3-Gly-Ala-Ser-Cys-Ile-Arg-Ile-Ala-Xaa5-Asn-Cys-Cys-Lys-Xaa5-Ser-Cys- Arg-Asn-Gly-Lys-Cys-# (SEQ TD NO:60) Name: Bu6.5
Species: bullatus Cloned: Yes
DNA Sequence:
ATCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTC CTGACGGCCTGTCAGCTCATTACAGCTGAAGACTCCAGAGGTACGCATGAGCATCTT GCCCTGAAGTCGACCTCCAAAGTCTCCAAGTCGACTAGCTGCATGGCAGCCGGATC TTATTGCGGACCTGCTACTACGAATATCTGCTGCGATTTTTGCAGTCCATTCAGCGA TAGATGTATGAAAAAGCCCAACAATTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCT GCCTGAGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTGG AGGCTTCAGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ TD NO:61)
Translation: MKLTCNVIVANLLLTACQLITAEDSRGTHEHLALKSTSKNSKSTSCMAAGSYCGPATTN ICCDFCSPFSDRCMKKPNN (SEQ ID NO:62)
Toxin Sequence:
Ser-Thr-Ser-Cys-Met-Ala-Ala-Gly-Ser-Xaa5-Cys-Gly-Xaa3-Ala-Thr-Thr-Asn-Ile-Cys-Cys- Asρ-Phe-Cys-Ser-Xaa3-Phe-Ser-Asp-Arg-Cys-Met-Lys-Lys-Xaa3-Asn-Asn-A (SEQ TD NO:63)
Name: Bu6.6
Species: bullatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAGCTCATTATAGCTGAGGACTCCAGAGGTACGCAGTTGCATCG TGCCCTGAGGAAGGCCACCAAACTCTCCGTGTCGACTCGCTGCAAGAGTAAAGGAT
CATCATGTCATAGGACTTCGTATGACTGCTGCACGGGTTCTTGCAGAAATGGTAGAT GTGGCTGATCCAGCGCCTGATCTTCCCCCTTCTGTGCTCCATCCTTTTCTGCCTGAGT CCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTGGAGGCTTCA GAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ TD NO:64)
Translation:
MKLTCNNINANLLLTACQLIIAEDSRGTQLHRALRKATKLSNSTRCKSKGSSCHRTSYD CCTGSCRΝGRCG (SEQ TD ΝO:65)
Toxin Sequence:
Cys-Lys-Ser-Lys-Gly-Ser-Ser-Cys-His-Arg-Thr-Ser-Xaa5-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg- Asn-Gly-Arg-Cys-# (SEQ TD NO:66)
Name: Ca6.4
Species: caracteristicus Cloned: Yes DNA Sequence:
GGATCCATGAAACTGACGTGCGTGGTGATCATCGCCGTGCTGTTCCTGACGGCCTGT CAACTCATTACAGGTGAGCAGAAGGACCATGCTCTGAGGTCAACTGACAAAAACTC CAAGTTGACTAGGCAGTGCTCGGCTAACGGTGGATCTTGTACTCGTCATTTTCACTG CTGCAGCCTCTATTGCAATAAAGATTCCAGTGTATGTGTGGCAACCTCATACCCGTG AGTGGCCATGAACCCCTCAATACCCTCTCCTCTGGAGGCTTCAGAGGAACTGCATTG AAATAAAACCGCATTACAAAAAAAAAAAAAAAAAAAA (SEQ ID NO:67)
Translation:
MKLTCNNIIANLFLTACQLITGEQKDHALRSTDKNSKLTRQCSANGGSCTRHFHCCSLY CNKDSSVCVATSYP (SEQ ID NO:68)
Toxin Sequence: Xaa2-Cys-Ser-Ala-Asn-Gly-Gly-Ser-Cys-Thr-Arg-His-Phe-His-Cys-Cys-Ser-Leu-Xaa5-Cys- Asn-Lys-Asp-Ser-Ser-Val-Cys-Val-Ala-Thr-Ser-Xaa5-Xaa3-A (SEQ ID NO:69)
Name: C6.1 Species: catus Cloned: Yes
DNA Sequence:
Translation:
CKSTGASCRRTSYDCCTGSCRSGRCG (SEQ ID NO:70)
Toxin Sequence:
Cys-Lys-Ser-Thr-Gly-Ala-Ser-Cys-Arg-Arg-Thr-Ser-Xaa5-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg- Ser-Gly-Arg-Cys-# (SEQ ID NO:71)
Name: C6.4
Species: catus Cloned: Yes
DNA Sequence:
TCGACTCGCTGCCAGGGTAGAGGAGCATCATGTCGTAAGACTATGTATAACTGCTG CAGCGGTTCTTGCAACAGAGGTAGTTGTGGCTGATCCGGCGCCTGATCTTCCCCCTT CCGTGCTCTATCCTTTTCTGCCTGATTCCTCCTTACCTGAGAGCGGTCATGAACCACT
CATCACCTGCTCCTCTGGAGGCCTCAGAGGAGCTACATTGAAATAAAAGCCGCATT GC (SEQ TD NO:72)
Translation: STRCQGRGASCRKTMYNCCSGSCNRGSCG (SEQ TD NO:73)
Toxin Sequence: Cys-Gln-Gly-Arg-Gly-Ala-Ser-Cys-Arg-Lys-Tlιr-Met-Xaa5-Asn-Cys-Cys-Ser-Gly-Ser-Cys- Asn-Arg-Gly-Ser-Cys-# (SEQ TD NO:74)
Name: C6.5
Species: catus Cloned: Yes
DNA Sequence: TCGACACGCTGCTTGCCTGCCGGAGAGTCTTGCCTTTTTAGTAGGATTAGATGCTGC GGTACTTGCAGTTCAGTCTTAAAGTCATGTGTGAGCTGATCCAGCTGCTGATCTTCC TCCTCCTGTGCTCCATCCTTTTCTGCCTGAGTCCTCCTTATCTGAGAGTGGTCATGAA CCACTCACCACCTACTCTTCTGGAGGCTTCAGAGGAGCTACAGTGAAATAAAAGCC GCATTGC (SEQ ID NO:75)
Translation:
STRCLPAGESCLFSRTRCCGTCSSNLKSCVS (SEQ ID ΝO:76)
Toxin Sequence: Cys-Leu-Xaa3-Ala-Gly-Xaal-Ser-Cys-Leu-Phe-Ser-Arg-Ile-Arg-Cys-Cys-Gly-Thr-Cys-Ser- Ser-Val-Leu-Lys-Ser-Cys-Nal-Ser-A (SEQ TD ΝO:77)
Name: C6.6 Species: catus Cloned: Yes
DNA Sequence: TCGACACGCTGCCAGGGTAGAGGAGGACCATGTACTAAGGCTGTGTTTAACTGCTG CAGCGGTTCTTGCAACAGAGGTAGATGTGGCTGATCCAGCGCCTGATCTTCCCCCTT
CTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCTTACTGAGAGTAGTCATGAACCACTC ATCACCTACTCCTCTGGAGGCCTCAGAGAGCTACATTGAAATAAAAGCCGCATTGC (SEQIDNO:78) Translation:
STRCQGRGGPCTKAVFNCCSGSCNRGRCG (SEQ ID NO:79)
Toxin Sequence:
Cys-Gln-Gly-Arg-Gly-Gly-Xaa3-Cys-Thr-Lys-Ala-Val-Phe-Asn-Cys-Cys-Ser-Gly-Ser-Cys- Asn-Arg-Gly-Arg-Cys-# (SEQ ID NO:80)
Name: C6.7
Species: catus Cloned: Yes
DNA Sequence: TTAACTTTGCGCTGCGCAACTTACGGAAAACCTTGTGGTATTCAAAACGACTGCTGC AATACATGCGATCCAGCCAGAAAGACATGTACGTAGCTGATCCGGCGTCTGATCTC CCCCCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCTTACCTGAGAGTGGTCATG AACCACTCATCACCTGCTCCTCTGGAGGCCTCGGGGGAGCTACATTGAAATAAAAG CCGCATTGC (SEQ TD NO:81)
Translation:
LTLRCATYGKPCGIQNDCCNTCDPARKTCT (SEQ ID NO:82)
Toxin Sequence:
Cys-Ala-Thr-Xaa5-Gly-Lys-Xaa3-Cys-Gly-Ile-Gln-Asn-Asp-Cys-Cys-Asn-Thr-Cys-Asp-Xaa3- Ala-Arg-Lys-Thr-Cys-Thr-A (SEQ TD NO:83)
Name: C6.8
Species: catus Cloned: Yes
DNA Sequence: TCGACTCGCTGCCGGGGTAGAGGAGGACCATGTACTAAGGCTATGTTTAACTGCTG
CAGCGGTTCTTGCAACAGAGGTAGATGTGGCTGATCCAGCGCCTGATCTTCCCCCTT CTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCTTAACTGAGAGTAGTCATGAACCACT CATCACCTACTCCTCTGGAGGCCTCAGAGAAGCATCATTGAAATAAAAGCCGCATT GC (SEQ TD NO: 84)
Translation:
STRCRGRGGPCTKAMFNCCSGSCNRGRCG (SEQ TD NO:85)
Toxin Sequence: Cys-Arg-Gly-Arg-Gly-Gly-Xaa3-Cys-Thr-Lys-Ala-Met-Phe-Asn-Cys-Cys-Ser-Gly-Ser-Cys-
Asn-Arg-Gly-Arg-Cys-# (SEQ ID NO:86)
Name: Crβ.l
Species: circumcisus
Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGACCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGGAGCATC GTGCCCTGAGGTCGGACACCAAACTCCCCATGTCGACTCGCTGCAAGGGTAAAGGA GCATCATGTCGTAAGACTATGTATAACTGCTGCAGCGGTTCTTGCAGCAACGGTAGA TGTGGCTGATCCAGCGCCTGATCTTCCCCCTTCTGCTGCTCTATCCTTTTCTGCCTGA GTCCTCCTTACCTGAGAGCTGGTCATGAACCACTCATCACCTGCTCCTCTGGAGGCC CAGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ ID NO:87)
Translation: MKLTCVVIVAVLLLTTCQLITADDSRGTQEHRALRSDTKLPMSTRCKGKGASCRKTMY NCCSGSCSNGRCG (SEQ TD NO:88)
Toxin Sequence:
Cys-Lys-Gly-Lys-Gly-Ala-Ser-Cys-Arg-Lys-Thr-Met-Xaa5-Asn-Cys-Cys-Ser-Gly-Ser-Cys-Ser- Asn-Gly-Arg-Cys-# (SEQ TD NO: 89)
Name: Cr6.2
Species: circumcisus
Cloned: Yes
DNA Sequence: ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGACCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGGCCACCAAAGTCTCCAAGTCGACTAGCTGCATGGAAGCCGGA TCTTATTGCCGCTCTACTACGAGAACCTGCTGCGGTTATTGCTCTTATTTCAGCAAAA AATGTATTGACTTTCCCAGCAACTGATCTTCCCCCTACTGTGCTCTATCCTTTTCTGC CTGAGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCCTACTCCTCTGGA GGCCCAGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ TD NO:90)
Translation:
MKLTCVVIVAVLLLTTCQLITADDSRGTQKHRALRSATKVSKSTSCMEAGSYCRSTTRT CCGYCSYFSKKCIDFPSN (SEQ ID NO:91)
Toxin Sequence:
Ser-Thr-Ser-Cys-Met-Xaal-Ala-Gly-Ser-Xaa5-Cys-Arg-Ser-Thr-Thr-Arg-Thr-Cys-Cys-Gly- Xaa5-Cys-Ser-Xaa5-Phe-Ser-Lys-Lys-Cys-Ile-Asρ-Phe-Xaa3-Ser-Asn-A (SEQ TD NO:92)
Name: Cr6.3
Species: circumcisus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGACCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGGAGCATC GTGCCCTGAGGTCGGACACCAAACTCCCCATGTCGACTCGCTGCAAGAGTAAAGGA GCAAAATGTTCAAGGCTTATGTATGACTGCTGCAGCGGTTCTTGCAGCAGGTACTCA GGTAGATGTGGCTGATCCAGCGCCTGATCTTCCCCCTTCTGCTGCTCTATCCTTTTCT
GCCTGAGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTGG AGGCCCAGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ ED NO:93)
Translation: MKLTCVVIVAVLLLTTCQLITADDSRGTQEHRALRSDTKLPMSTRCKSKGAKCSRLMY DCCSGSCSRYSGRCG (SEQ TD NO:94) Toxin Sequence:
Cys-Lys-Ser-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-Xaa5-Asp-Cys-Cys-Ser-Gly-Ser-Cys-Ser- Arg-Xaa5-Ser-Gly-Arg-Cys-# (SEQ ID NO:95)
Name: Cr6.4
Species: circumcisus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGACCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTTCCCTGACGTCGGCCACCAAAGTCTCCAAGTCGACTGGCTGCATGAAAGCCGGA TCTTATTGCCGCTCTACTACGAGAACTTGCTGCGGTTATTGCGCTTATTTCGGCAAA AAATGTATTGACTATCCCAGCAACTGATCTTCCCCCTACTGTGCTCTATCCTTTTCTG CCTAAGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCCTACTCCTCTGG AGGCCCAGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ ID NO:96)
Translation: MKLTCWINANLLLTTCQLITADDSRGTQKHRSLTSATKNSKSTGCMKAGSYCRSTTRT CCGYCAYFGKKCTDYPSΝ (SEQ ID ΝO:97)
Toxin Sequence:
Ser-Trιr-Gly-Cys-Met-Lys-Ala-Gly-Ser-Xaa5-Cys-Arg-Ser-Thr-Thr-Arg-Thr-Cys-Cys-Gly- Xaa5-Cys-Ala-Xaa5-Phe-Gly-Lys-Lys-Cys-Ile-Asp-Xaa5-Xaa3-Ser-Asn-A (SEQ ID NO:98)
Name: Cn6.1
Species: consors Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGTCAACTC
CTCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGAAGTCTTACAC CAAACTCTCCATGTTAACTTTGCGCTGCGCATCTTACGGAAAACCTTGTGGTATTGA
CAACGACTGCTGCAATACATGCGATCCAGCCAGAAAGACATGTACGTAGCTGATCC GGCGTCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCTTACCT GAGAGTGGTCATGAACCACTCATCACCTAGCTCCTCTGGAGGCTTCAGAGGAGCTA CAATGAAATAAAAGCGCATTGC (SEQ TD NO:99)
Translation:
MKLTCNNTVAVLLLTACQLLTADDSRGTQKHRALKSYTKLSMLTLRCASYGKPCGTDN DCCNTCDPARKTCT (SEQ TD NO:100)
Toxin Sequence:
Cys-Ala-Ser-Xaa5-Gly-Lys-Xaa3-Cys-Gly-Ile-Asp-Asn-Asp-Cys-Cys-Asn-Thr-Cys-Asp-Xaa3- Ala-Arg-Lys-Thr-Cys-Thr-A (SEQ ID NO: 101) Name: Cn6.2
Species: consors Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGTCAACTC CTCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGAGGTCGGACAC CAAACTCTCCATGTCGACT'CGCTGCAAGGGTACAGGAAAACCATGCAGTAGGATTG CGTATAACTGCTGCACCGGTTCTTGCAGATCAGGTAAATGTGGCTGATCCAGCGCCT GATCTCCCCCC (SEQ ID NO: 102)
Translation: MKLTCNVTVAVLLLTACQLLTADDSRGTQKHRALRSDTKLSMSTRCKGTGKPCSRIAY ΝCCTGSCRSGKCG (SEQ TD ΝO:103)
Toxin Sequence:
Cys-Lys-Gly-Thr-Gly-Lys-Xaa3-Cys-Ser-Arg-Ile-Ala-Xaa5-Asn-Cys-Cys-Thr-Gly-Ser-Cys- Arg-Ser-Gly-Lys-Cys-# (SEQ ID NO:104)
Name: Cn6.3
Species: consors Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGTCAACTC
ATCACAGCTGATGACTCCAAAGGTACGCAGAAGCATCGTTCCCTGAGGTCGACCAC CAAAGTCTCCAAGGCGACTGACTGCATTGAAGCCGGAAATTATTGCGGACCTACTG
TTATGAAAATCTGCTGCGGCTTTTGCAGTCCATACAGCAAAATATGTATGAACTATC CCCAAAATTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCTTAC CTGAGAGTGGTCATGAACCACTCATCACCTCGTCCC (SEQ TD NO: 105)
Translation:
MKLTCVVTVAVLLLTACQLITADDSKGTQKHRSLRSTTKVSKATDCIEAGNYCGPTVM KICCGFCSPYSKICMNYPQN (SEQ TD NO: 106)
Toxin Sequence: Ala-Thr-Asρ-Cys-Ile-Xaal-Ala-Gly-Asn-Xaa5-Cys-Gly-Xaa3-Thr-Nal-Met-Lys-Ile-Cys-Cys-
Gly-Phe-Cys-Ser-Xaa3-Xaa5-Ser-Lys-Ile-Cys-Met-Asn-Xaa5-Xaa3-Gln-Asn-A (SEQ TD ΝO:107)
Name: Cn6.4
Species: consors Cloned: Yes DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGTCAACTC CTCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGAGGTCGGACAC CAAACTCTCCATGTCGACTCGCTGCAAAGGTAAAGGAGCATCATGTACAAGGCTTA TGTATGACTGCTGCCACGGTTCTTGCAGCAGCAGCAAGGGTAGATGTGGCTGATCC GGCGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCTTACCT GAGAGGTGGTCATGAACCACTCATCACCTGCTCCCCTG (SEQ TD NO: 108)
Translation:
MKLTCNNINAVLLLTACQLLTADDSRGTQKHRALRSDTKLSMSTRCKGKGASCTRLM YDCCHGSCSSSKGRCG (SEQ ID ΝO:19)
Toxin Sequence: Cys-Lys-Gly-Lys-Gly-Ala-Ser-Cys-Thr-Arg-Leu-Met-Xaa5-Asp-Cys-Cys-His-Gly-Ser-Cys- Ser-Ser-Ser-Lys-Gly-Arg-Cys-# (SEQ ID NO: 110)
Name: Cn6.5 Species: consors Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGCATGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGT CAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGAGGTC
GGACACCAAACTCTCCATGTCAACTCGCTGCAAGGGTAAAGGAGCATCATGTCATA GGACTTCGTATGACTGCTGCACCGGTTCTTGCAACAGAGGTAAATGTGGCTGATCCG GCGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCATCCATACCTG TGCTCGAG (SEQ TD NO: 111)
Translation:
MKLTCMNIVANLLLTACQLITADDSRGTQKHRALRSDTKLSMSTRCKGKGASCHRTSY DCCTGSCΝRGKCG (SEQ ID ΝO: 112)
Toxin Sequence:
Cys-Lys-Gly-Lys-Gly-Ala-Ser-Cys-His-Arg-Thr-Ser-Xaa5-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Asn- Arg-Gly-Lys-Cys-# (SEQ ID ΝO:l 13)
Name: Cn6.6
Species: consors Cloned: Yes
DNA Sequence: GGATCCATGAAACTGACGTGCGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGT CAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGAAGTC GGACACCAAACTCTCCATGTTAACTTTGCGCTGCGCATCTTACGGAAAACCTTGTGG TATTTACAACGACTGCTGCAATACATGCGATCCAGCCAGAAAGACATGTACGTAGC TGATCCGGCGTCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCATCC ATACCTGTGCTCGAG (SEQ TD NO:l 14)
Translation:
MK TCNNIVANLLLTACQLITADDSRGTQKHRALKSDTKLSMLTLRCASYGKPCGIYN DCCNTCDPARKTCT (SEQ TD NO: 115)
Toxin Sequence: Cys-Ala-Ser-Xaa5-Gly-Lys-Xaa3-Cys-Gly-Ile-Xaa5-Asn-Asp-Cys-Cys-Asn-Thr-Cys-Asp- Xaa3-Ala-Arg-Lys-Thr-Cys-Thr-A (SEQ ID NO:l 16)
Name: Cn6.7 Species: consors Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGT CAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGAGGTC
GGACACCAAACTCTCCATGTCGACTCGCTGCAAGGGTACAGGAAAACCATGCAGTA GGGTTGCGTATAACTGCTGCACCGGTTCTTGCAGATCAGGTAAATGTGGCTGATCCA GTGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCTTACCTG AGAGTGGTCATGAACCACTCATCACCTGCTCCTCTGGAGGCTTCAGAGGAGCTACAT TGAAATAAAAGCCGCATTGCANTGNANAAAANNNNNNNNNNNNNNNNNNNNNfNN NNN^WNNNNNNNNNNNNGGAAAAAAAAAAAAAAAAAAAA (SEQ TD NO: 117)
Translation:
MKLTCNNINANLLLTACQLITADDSRGTQKHRALRSDTKLSMSTRCKGTGKPCSRNAY ΝCCTGSCRSGKCG (SEQ ID ΝO: 118)
Toxin Sequence:
Cys-Lys-Gly-Thr-Gly-Lys-Xaa3-Cys-Ser-Arg-Nal-Ala-Xaa5-Asn-Cys-Cys-Thr-Gly-Ser-Cys- Arg-Ser-Gly-Lys-Cys-# (SEQ TD ΝO:119)
Name: Cn6.8
Species: consors
Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGCATGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGT CAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTTCCCTGAGGTC GACCACCAAAGTCTCCAAGTCGACTAGCTGCATGAAAGCCGGGTCTTATTGCCGCTC TACTACGAGAACCTGCTGCGGTTATTGCGCTTATTTCGGCAAATTTTGTATTGACTTT CCCAGCAACTGATCTTCCCCCTACTGTGCTCTATCCTTTTCTGCCTCTGCCTGAGTCC TCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTGCTCCCCTGGAGGCCTCAGA GGAGCTACAATGAAATAAAAGCCGCATTGCAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 120)
Translation: MKLTCMVINANLLLTACQLITADDSRGTQKHRSLRSTTKNSKSTSCMKAGSYCRSTTRT CCGYCAYFGKFCTDFPSΝ (SEQ TD ΝO:121)
Toxin Sequence:
Ser-Thr-Ser-Cys-Met-Lys-Ala-Gly-Ser-Xaa5-Cys-Arg-Ser-Thr-Thr-Arg-Thr-Cys-Cys-Gly- Xaa5-Cys-Ala-Xaa5-Phe-Gly-Lys-Phe-Cys-Ile-Asp-Phe-Xaa3-Ser-Asn-A (SEQ TD NO: 122)
Name: Da6.8
Species: dalli Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGTTC CTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAAGTACGCAGAAGCATCG TGCTCTGAGGTCGACCATCAAACACTCCATGTTGACTAGGAGCTGCACGCCTCCCGG
AGGACCTTGTGGTTATTATAATGACTGCTGCAGTCATCAATGCAATATAAGCAGAA ATAAATGCGAGTAGCTGATCCGGCATCTGATCTTCCCCTTCTGTGCTCGTCCTAACC TGAGAGTGGTCATGAACCATCATCACCTACTCCTCTGGAGGCTTCAGAGGAGCTAC ATGGAAATAAAAGCCGCATTGC (SEQ ID NO: 123)
Translation:
MKLTCNNTVANLFLTACQLITADDSRSTQKHRALRSTIKHSMLTRSCTPPGGPCGYYND CCSHQCNISRNKCE (SEQ ID NO: 124)
Toxin Sequence:
Ser-Cys-Tlιr-Xaa3-Xaa3-Gly-Gly-Xaa3-Cys-Gly-Xaa5-Xaa5-Asn-Asp-Cys-Cys-Ser-His-Gln- Cys-Asn-Ile-Ser-Arg-Asn-Lys-Cys-Xaal-A (SEQ ID NO: 125)
Name: Di6.1
Species: distans Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGCGTGTTGATCATCGCCGTGCTGTTC
CTGACGGCCTGTCAACTCACTAGAGGAAAGCTGGAGCGTCCTGTTCTGAGGTCGAG
CGACCAAACCTCCGGGTCAACGAAGAGATGCGAAGATCCTGGTGAACCTTGCGGAA
GTGATCATTCCTGCTGCGGCGGTAGTTGCAACCACAACGTCTGCGCCTGAAGCTGGT
CTGGCATCTGACCATTCCCCTTCTGTACTCTATCTCTATTGCCTGAGTCATCTTTACC
TGTGAGTGGTCATGAATCTCTCAATACCTTCTCCCCTGGAGGCTTCAGAAGAACTAG
ATTGAAATA (SEQ TD NO: 126) Translation:
MKLTCNLIIANLFLTACQLTRGKLERPNLRSSDQTSGSTKRCEDPGEPCGSDHSCCGGSC ΝHΝNCA (SEQ TD ΝO:127)
Toxin Sequence:
Cys-Xaal-Asp-Xaa3-Gly-Xaal-Xaa3-Cys-Gly-Ser-Asp-His-Ser-Cys-Cys-Gly-Gly-Ser-Cys- Asn-His-Asn-Val-Cys-Ala-Λ (SEQ TD NO: 128)
Name: E6.2
Species: ermineus Cloned: Yes
DNA Sequence: ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGTCAACTC ATCACAGCTGACGACTCCAGACGTACGCAGAAGCATCGTGCCCTGAGGTCGACCAC CAAACGCGCCACGTCGAATCGCCCCTGCAAGCCGAAAGGACGAAAATGTTTTCCGC ATCAGAAGGACTGCTGCAATAAAACGTGCACCAGATCAAAATGTCCCTGATCTTCC CCCTTCTGTGCTGTATCCTTTTCTGCCTGAGTCCTCCTTACCTGAGAGTGGTCAGTAA CCACTCATCACCATCTCCTCTGGAGG (SEQ ID NO: 129)
Translation:
MKLTCNNINANLLLTACQLITADDSRRTQKHRALRSTTKRATSNRPCKPKGRKCFPHQK DCCNKTCTRSKCP (SEQ ID NO: 130)
Toxin Sequence:
Xaa3 -Cy s-Lys-Xaa3 -Ly s-Gly- Arg-Lys-Cys-Phe-Xaa3 -His-Gln-Lys- Asp-Cys-Cys- Asn-Ly s-Thr- Cys-Thr-Arg-Ser-Lys-Cys-Xaa3-A (SEQ TD NO:131)
Name: E6.3
Species: ermineus Cloned: Yes
DNA Sequence:
AACTCATCACAGCTGATGACTCCAGAGGTACGCAGAACGATCGTGCCCTGAGGTCG ACCACCAAACTCTCCATGCTGACTCGGGCCTGCTGGTCTTCCGGAACACCTTGTGGT ACTGATAGTTTATGCTGCGGTGGATGCAATGTATCCAAAAGTAAATGTAACTAGCTG ATTCGGCGTCTGAACTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCCGAGTCCTCCAT ACCTGAGAATGGTCATGAACCACTCATCACCTACTCCTCTGGAGACCTCAGAAGAG
CTACACTGAAATAAAAGCGCTTGC (SEQ ID NO:132)
Translation:
LITADDSRGTQNDRALRSTTKLSMLTRACWSSGTPCGTDSLCCGGCNVSKSKCN (SEQ TD NO:133)
Toxin Sequence: Ala-Cys-Xaa4-Ser-Ser-Gly-Thr-Xaa3-Cys-Gly-Thr-Asp-Ser-Leu-Cys-Cys-Gly-Gly-Cys-Asn- Nal-Ser-Lys-Ser-Lys-Cys-Asn-A (SEQ ID ΝO:134)
Name: G6.1
Species: geographus
Cloned: Yes
DNA Sequence: GGATCCATGAAACTGACGTGCGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGT CAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGGGGTC GACCACCGAACTCTCCTTGTCGACTCGCTGCAAGTCACCCGGATCTTCATGTTCACC GACTAGTTATAATTGCTGCAGGTCTTGCAATCCATACGCCAAAAGATGTTACGGCTA ATCCAGCGCCTGATCTTCCCCCTTCTGTGCTCTATCCCTTCCTGTCTGAGTCCTCCTT ACCTGAGAGTGGTCATGAACCACTCCTCACCTACTTCTCTGGAGGCTTCGGAGGAGC TACATTGAAATAAAAGCCGCATTGTAAAAAAAAAAAAAAAAAA (SEQ ID NO: 135)
Translation:
MKLTCVNINANLLLTACQLITADDSRGTQKHRALGSTTELSLSTRCKSPGSSCSPTSYNC CRSCNPYAKRCYG (SEQ ID NO: 136)
Toxin Sequence:
Cys-Lys-Ser-Xaa3-Gly-Ser-Ser-Cys-Ser-Xaa3-Thr-Ser-Xaa5-Asn-Cys-Cys-Arg-Ser-Cys-Asn- Xaa3-Xaa5-Ala-Lys-Arg-Cys-Xaa5-# (SEQ TD NO: 137)
Name: G6.2
Species: geographus
Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGT
CAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGAGGTC
GTCCACCAAACTCACCTTGTCGACTCGCTGCAAATCACCCGGAACTCCATGTTCAAG GGGTATGCGTGATTGCTGCACGCCTTGCTTGTTATACAGCAACAAATGTAGGCGCTA
CTAACCCAGCGCCTGATCTTCCCCCTTCTGTGCTCTATTCCTTTCTGCCTGAGTCCTC CTTACCTGAAAGTGGTCATGAACCACTCATCACCTACTTCTCTGGAGGCTTCAGAAG AGCTACATTGAAATAAAAGCCGCATTGCAATGACAAAAAAAAAAAAAAAAAAAA (SEQ TD NO: 138)
Translation:
MKLTCNVINANLLLTACQLITADDSRGTQKHRALRSSTKLTLSTRCKSPGTPCSRGMRD CCTPCLLYSΝKCRRY (SEQ ID ΝO:139)
Toxin Sequence:
Cys-Lys-Ser-Xaa3-Gly-Thr-Xaa3-Cys-Ser-Arg-Gly-Met-Arg-Asp-Cys-Cys-Thr-Xaa3-Cys-Leu- Leu-Xaa5-Ser-Asn-Lys-Cys-Arg-Arg-Xaa5-A (SEQ TD NO: 140) Name: w-GVIA
Species: geographus Cloned: Yes
DNA Sequence:
GGAATTCCGTTTCTGCGCTGCTTCCTTTGGCATCACCAAAACCATCATCAAAATGAA ACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGTCAACTCATCAC AGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGGGGTCGACCACCGAAC TCTCCTTGTCGACTCGCTGCAAGTCACCCGGATCTTCATGTTCACCGACTAGTTATA ATTGCTGCAGGTCTTGCAATCCATACACCAAAAGATGTTACGGCTAATCCAGCGCCT GATCTTCCCTGCTCTGAGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACC TACTTCTCTAGGCGGTTCGGAGGAGCTACATTGAAATAAAAGCCGCATTGCAAAAA AAAAAAAAAA (SEQ ID NO:141)
Translation:
MKLTCWIVAVLLLTACQLITADDSRGTQKHRALGSTTELSLSTRCKSPGSSCSPTSYNC CRSCNPYTKRCYG (SEQ ID NO: 142)
Toxin Sequence:
Cys-Lys-Ser-Xaa3-Gly-Ser-Ser-Cys-Ser-Xaa3-Thr-Ser-Xaa5-Asn-Cys-Cys-Arg-Ser-Cys-Asn- Xaa3-Xaa5-Thr-Lys-Arg-Cys-Xaa5-# (SEQ ID NO: 143)
Name: w-GVTB
Species: geographus Isolated: Yes
Toxin Sequence:
Cys-Lys-Ser-Xaa3-Gly-Ser-Ser-Cys-Ser-Xaa3-Thr-Ser-Xaa5-Asn-Cys-Cys-Arg-Ser-Cys-Asn- Xaa3-Xaa5-Thr-Lys-Arg-Cys-Xaa5-GTy-# (SEQ ID NO: 144)
Name: w-GVIC
Species: geographus Isolated: Yes
Toxin Sequence: Cys-Lys-Ser-Xaa3-Gly-Ser-Ser-Cys-Ser-Xaa3-Thr-Ser-Xaa5-Asn-Cys-Cys-Arg-Ser-Cys-Asn- Xaa3-Xaa5-Thr-Lys-Arg-Cys-# (SEQ ID NO: 145)
Name: w-GVIIA
Species: geographus Isolated: Yes
Cloned: Yes DNA Sequence:
CATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGAGGTCGTCCA CCAAACTCACCTTGTCGACTCGCTGCAAATCACCCGGAACTCCATGTTCAAGGGGTA TGCGTGATTGCTGCACGTCTTGCTTGTTATACAGCAACAAATGTAGGCGCTACTAAC CCAGCGCCTGATCTTCCCCCTTCTGTGCTCTATTCCTTTCTGCCTGAGTCCTCCTTAC CTGAAAGTGGTCATGAACCACTCATCACCTACTTCTCTGGAGGCTTCAGAAGAGCTA CATTGAAATAAAAGCCGCATTGCAATGAC (SEQ TD NO: 146)
Translation:
ITADDSRGTQKHRALRSSTKLTLSTRCKSPGTPCSRGMRDCCTSCLLYSNKCRRY (SEQ ID NO: 147)
Toxin Sequence: Cys-Lys-Ser-Xaa3-Gly-Thr-Xaa3-Cys-Ser-Arg-Gly-Met-Arg-Asp-Cys-Cys-Thr-Ser-Cys-Leu- Leu-Xaa5-Ser-Asn-Lys-Cys-Arg-Arg-Xaa5-# (SEQ ID NO: 148)
Name: w-GVIIB Species: geographus Isolated: Yes
Toxin Sequence:
Cys-Lys-Ser-Xaa3-Gly-Tlιr-Xaa3-Cys-Ser-Arg-Gly-Met-Arg-Asp-Cys-Cys-Thr-Ser-Cys-Leu- Ser-Xaa5-Ser-Asn-Lys-Cys-Arg-Arg-Xaa5-# (SEQ ID NO: 149)
Name: La6.1
Species: laterculatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT
CCTGACGGCCTGTCAACTCATCACCGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGACCACCAATCTCTCCATGCTGACTCGGAAGTGCTGGCCTTCCG GAAGCTATTGTCGTGCGAATAGTAAATGCTGCAGTGGATGCGATCGGAACAGAAAT AAATGTTACTAGCTGATTCGGCGTCTGAACTTCCTCCTTCTGTGCTCTATCCTTTTCT GCCCGAGTCCTCCATACCTGAGAGTGGTCATGAACCACTCAACTCCTACTCCTCTGG AGGCCTCAGAAGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ TD NO: 150)
Translation:
MKLTCNNINANLLLTACQLITADDSRGTQKHRALRSTTNLSMLTRKCWPSGSYCRANS KCCSGCDRNRNKCY (SEQ TD NO: 151)
Toxin Sequence:
Lys-Cys-Xaa4-Xaa3-Ser-Gly-Ser-Xaa5-Cys-Arg-Ala-Asn-Ser-Lys-Cys-Cys-Ser-Gly-Cys-Asp- Arg-Asn-Arg-Asn-Lys-Cys-Xaa5-A (SEQ ID NO:152) Name: La6.2
Species: laterculatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGACCACCAAACTCTCCATATCGACTCGCTGCCTTCCTCCCGGAT CATATTGTAAGGCGACAACGGAAGTCTGCTGCTCTTCTTGCCTTCAATTCGCTCAGA TATGTTCGGGTTGATCTTCCCTCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCAT ACCTGAGAATGGTCATGAACCACTCAACATCTACTCCTCTGGAGGCCTCAGAAGAG CTATATTGAAATAAAAGCCGCATTGC (SEQ ID NO:153)
Translation:
MKLTCNNINANLLLTACQLITADDSRGTQKHRALRSTTKLSISTRCLPPGSYCKATTENC CSSCLQFAQICSG (SEQ TD ΝO:154)
Toxin Sequence:
Cys-Leu-Xaa3-Xaa3-Gly-Ser-Xaa5-Cys-Lys-Ala-Tlιr-Thr-Xaal-Val-Cys-Cys-Ser-Ser-Cys-Leu- Gln-Phe-Ala-Gln-Ile-Cys-Ser-# (SEQ TD NO: 155)
Name: La6.3
Species: laterculatus
Cloned: Yes
DNA Sequence: ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGACCACCAATCTCTCCATGTCGACTCGCTGCAAGTCTCCCGGAT CATCATGTAGCGTGTCTATGCGTAACTGCTGCACTTCTTGCAATTCACGCACCAAGA AATGTACGCGACGTGGCTGAACTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCCGAGT CCTCCATACCTGAGAGTGGTCATGAACCACTCAACATCTACTCCTCTGGAGGCCTCA
GAAGAGCTATATTGAAATAAAAGCCGCATTGC (SEQ TD NO: 156)
Translation:
MKLTCVVIVAVLLLTACQLITADDSRGTQKHRALRSTTNLSMSTRCKSPGSSCSVSMRN CCTSCNSRTKKCTRRG (SEQ TD NO: 157)
Toxin Sequence:
Cys-Lys-Ser-Xaa3-Gly-Ser-Ser-Cys-Ser-Val-Ser-Met-Arg-Asn-Cys-Cys-Thr-Ser-Cys-Asn-Ser- Arg-Thr-Lys-Lys-Cys-Thr-Arg-Arg-# (SEQ TD NO:158) Name: La6.4
Species: laterculatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGACAACCAAACTCTCCATGCTGACTCGGACCTGCTGGCCTTCCG GAACAGCTTGTGGTATTGATAGTAACTGCTGCAGTGGATGCAATGTATCCAGAAGT AAATGTAACTAGCTGATTCGGCGTCTAAACTTCCTCCTTCTGCCTGAGTCCTCCATA CCTGAGAGTGGTCATGAACCACATCATCACCTCATCTCTGGAGGCCTC (SEQ ID NO:159)
Translation: MKLTCNVIVAVLLLTACQLITADDSRGTQKHRALRSTTKLSMLTRTCWPSGTACGTDSN CCSGCNVSRSKCN (SEQ TD NO:160)
Toxin Sequence:
Thr-Cys-Xaa4-Xaa3-Ser-Gly-Tlιr-Ala-Cys-Gly-Ile-Asρ-Ser-Asn-Cys-Cys-Ser-Gly-Cys-Asn- Val-Ser-Arg-Ser-Lys-Cys-Asn-A (SEQ TD NO:161)
Name: La6.5
Species: laterculatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGACCACCAATCTCTCCATGCTGACTCGGAAGTGCTGGCCTTCCG
GAAGCTATTGTCGTGCGAATAGTAAATGCTGCAGTGGATGCGATCGGAACAGAAGT AAATGTAACTAGCTGATTCGGCGTCTAAACTTCCTCCTTCTGCCTGAGTCCTCCATA CCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTGGAGGCCTCAAAGGAGCT ACATTGAAATAAAAGCCGCATTGC (SEQ TD NO: 162)
Translation:
MKLTCVVIVAVLLLTACQLITADDSRGTQKHRALRSTTNLSMLTRKCWPSGSYCRANS KCCSGCDRNRSKCN (SEQ ID NO: 163)
Toxin Sequence:
Lys-Cys-Xaa4-Xaa3-Ser-Gly-Ser-Xaa5-Cys-Arg-Ala-Asn-Ser-Lys-Cys-Cys-Ser-Gly-Cys-Asp- Arg-Asn-Arg-Ser-Lys-Cys-Asn-A (SEQ TD NO:164)
Name: Lp6.1
Species: leopardus Cloned: Yes DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTAGCTGTGCTGTTCCTGACGGCCTGTCAACTC ACTACAGCTGACATCTCCAGAGGTACGCGGAAGCGTCGTGCTCTGAGGTCGACCAC CAAACTCTCCAGGTCGCTCTTTGAGTGCGCGCCTTCCGGTGGACGTTGTGGTTTTTTA AAGTCCTGCTGCGAAGGATATTGCGATGGGGAAAGCACTTCATGTGTGAGTGGCCC ATACAGCATCTGATCTTCCCGCCTTCAGTGCTCTATCCTTTTCTGCCTGAGTCCTCCA TACCTCTGAGCGGTCATGAACCACTCAACACCTACTCCTCTGGAGGCTTCAGGGAAC TATATTAAAATAAAGCCGCATTGCAACGAAANAAAAAAAAAAAAAAAAA (SEQ TD NO: 165)
Translation:
MKLTCNNINAVLFLTACQLTTADISRGTRKRRALRSTTKLSRSLFECAPSGGRCGFLKSC CEGYCDGESTSCNSGPYSI (SEQ ID ΝO:166)
Toxin Sequence:
Ser-Leu-Phe-Xaal-Cys-Ala-Xaa3-Ser-Gly-Gly-Arg-Cys-Gly-Phe-Leu-Lys-Ser-Cys-Cys-Xaal- Gly-Xaa5-Cys-Asp-Gly-Xaal-Ser-Thr-Ser-Cys-Nal-Ser-Gly-Xaa3-Xaa5-Ser-Ile-A (SEQ TD ΝO:167)
Name: Lp6.2
Species: leopardus
Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCTGTGCTGTTCCTGACGGCCTGTCAACTC ACTACAGCTGACATCTCCAGAGGTACGTGGAAGCATCGTGGTGTGGGGTCGACCAC CGGACTCTCCCCGTGGCCCTTGGACTGCACGGCTCCCAGTCAACCTTGTGGTTATTT TCCTAGGTGCTGTGGACATTGCGATGTACGCAGGGTATGTACGAGTGGCTGATCCG GCGTCTGATCTTTCCGCCTTCTGTGCTGTATCCTTTTCTGCCTGAGTCCTCCATACCC GTGAGTGGTCATGAACCACTCAACACCTACTCCTCTGGAGGCTTCAGAGGAACTAT ATTAAAATAAAGCCGCATTGCAATG (SEQ TD NO: 168)
Translation:
MKLTC IVAVLFLTACQLTTADISRGTWKmGVGSTTGLSPWPLDCTAPSQPCGYFPR CCGHCDVRRVCTSG (SEQ ID ΝO:169)
Toxin Sequence: Xaa4-Xaa3-Leu-Asp-Cys-Thr-Ala-Xaa3-Ser-Gln-Xaa3-Cys-Gly-Xaa5-Phe-Xaa3-Arg-Cys-Cys- Gly-His-Cys-Asp-Val-Arg-Arg-Val-Cys-Thr-Ser-# (SEQ ID NO: 170)
Name: Lp6.3 Species: leopardus Cloned: Yes DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCTGTGCTGTTCCTGACGGCCTGTCAACTC ACTACAGCTGACATCTCCAGAGGTACGCGGAAGCATCGTGCTCTGAGGTCGACCAC CAAACTCTCCAGGTCGCCCTCTAGGTGCATGTCTCCCGGTGGAATTTGTGGTGATTT TGGTGACTGCTGCGAAATTTGCAATGTGTACGGTATATGTGTGAGTGACTTACCCGG CATCTGATCTTTCCGCCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCCTCCATACCCCT GAGTGGTCATGGACCACTCAACACCTACTCCTCTGGAGGCTTCAGAGGAACTACATT AAAATAAAGCCGCATTGCAAAAAAAAAAAAAAAAAAAA (SEQ ID NO:171)
Translation:
MKLTCVVIVAVLFLTACQLTTADISRGTRKHRALRSTTKLSRSPSRCMSPGGICGDFGDC CEICNVYGICVSDLPGI (SEQ TD NO: 172)
Toxin Sequence: Cys-Met-Ser-Xaa3-Gly-Gly-Ile-Cys-Gly-Asρ-Phe-Gly-Asp-Cys-Cys-Xaal-Ile-Cys-Asn-Val- Xaa5-Gly-Ile-Cys-Nal-Ser-Asp-Leu-Xaa3-Gly-Ile-A (SEQ ID ΝO:173)
Name: Lp6.4 Species: leopardus Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCTGTGCTGTTCCTGACGGCCTGTCAACTC ACTACAGCTGATGATTCCAGAGGTACACGGAAGCATCGTGCTCTGAGGTCAACCAC
CAAACTCTCCAGGTGGCCCAGGTACTGCGCGCCTCCCGGTGGAGCTTGTGGGTTTTT TGATCACTGCTGCGGATATTGCGAAACGTTTTACAATACGTGTAGATGAGTTGGCTG ATCCGGCGCTTGATCTTTCCGCCTTCTGTTGCTCTATCTTTTTCTGCCTGAGTCCTCCC ATACCCCGTTGAGTGGTCCATGAACCACTCCAACACCTACTCCCTCCTTGGAAGCTT CCAAAGGAAACGACATTTAAAATAAATTCCCCATTGCAATTGGAAAAAAAAAAAAA
AAAAA (SEQ ID NO:174)
Translation:
MKLTCNNINANLFLTACQLTTADDSRGTRKHRALRSTTKLSRV PRYCAPPGGACGFFD HCCGYCETFYΝTCR (SEQ TD ΝO:175)
Toxin Sequence:
Xaa5-Cys-Ala-Xaa3-Xaa3-Gly-Gly-Ala-Cys-Gly-Phe-Phe-Asp-His-Cys-Cys-Gly-Xaa5-Cys- Xaal-Thr-Phe-Xaa5-Asn-Thr-Cys-Arg-A (SEQ TD NO: 176)
Name: L6.1
Species: lynceus Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGTCAACTC ATCACAGCTGATGACTCCAGACGTACACAGAAGCATCGTGCCCTGAGGTCGACCAC CAATCTCTCCATGTCGACTCGCTGCAAGTCTCCCGGATCACCATGTAGTGTGACATC GTATAACTGCTGCACTTTTTGCTCTTCATACACTAAGAAATGTCGGGCCTCTTTATGA ACCACTCATCACCTACTCCTCTGGAGGCCTCAGAAGAGCTACACTGAAATAAAAGC CGCATTGG (SEQ ID NO: 177)
Translation:
MKLTCNNTNANLLLTACQLITADDSRRTQKHRALRSTTNLSMSTRCKSPGSPCSNTSYN CCTFCSSYTKKCRASL (SEQ ID NO:178)
Toxin Sequence:
Cys-Lys-Ser-Xaa3-Gly-Ser-Xaa3-Cys-Ser-Val-Thr-Ser-Xaa5-Asn-Cys-Cys-Thr-Phe-Cys-Ser- Ser-Xaa5-Thr-Lys-Lys-Cys-Arg-Ala-Ser-Leu-A (SEQ ID NO: 179)
Name: L6.2
Species: lynceus Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGTCAACTC ATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGAGGTCGACCAC CAAACTATCCATGTATACTCGCTGCGCAGGTCCAGGAGCAATTTGTCCTAATAGGGT ATGCTGCGGTTATTGCAGTAAAAGAACACATCTATGTCATTCGCGAACTGGCTGATC TTCCCCCTTCTGTGCTCTATCCTTTTTCTGCCTGAGTCCTCCATACCTGAGAATGGTC
ATGAACCACTCATCACCTACTCCTCTTGGAGACCTCAGAGGAGCTACACTGAAATA AAAGCCGCATTGGC (SEQ TDNO:180)
Translation: MKLTCNNINANLLLTACQLITADDSRGTQKHRALRSTTKLSMYTRCAGPGAICPNRNCC
GYCSKRTHLCHSRTG (SEQ ID ΝO:181)
Toxin Sequence:
Cys-Ala-Gly-Xaa3-Gly-Ala-Ile-Cys-Xaa3-Asn-Arg-Val-Cys-Cys-Gly-Xaa5-Cys-Ser-Lys-Arg- Thr-His-Leu-Cys-His-Ser-Arg-Thr-# (SEQ ID NO: 182)
Name: L6.3
Species: lynceus Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCTGCTAGCGGCCTGTCAACTA CTACACGCTGATGACTCCAGAGGTACGCAGAAGACTGCTGCCCGAGGTCGACCACC AAAACTCTCCATGCTGACTCGGGCCTGCTGGTCTTCCGGAACACCTTGTGGTACTGA TAGTTTATGCTGCGGTGGATGCAATGTATCCAAAAGTAAATGTAACTAGCTGATTCG GCGTCTGAACTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCCGAGTCCTCCATACCTG AGAATGGTCATGAACCACTCATCACCTACTCCTCTGGAGACCTCAGAAGAGCTACA CTGAAATAAAAGCGCATTGC (SEQ TD NO: 183)
Translation: MKLTCNNINANLLLAACQLLHADDSRGTQKTAARGRPPKLSMLTRACWSSGTPCGTDS LCCGGCΝNSKSKCΝ (SEQ TD ΝO:184)
Toxin Sequence:
Ala-Cys-Xaa4-Ser-Ser-Gly-Thr-Xaa3-Cys-Gly-Thr-Asρ-Ser-Leu-Cys-Cys-Gly-Gly-Cys-Asn- Val-Ser-Lys-Ser-Lys-Cys-Asn-A (SEQ ID NO: 185)
Name: L6.4
Species: lynceus Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGAGCTACTCCTAACGGCCTGTCAACTC ATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCGTGCCCTGAGGTCGACCAC CAATCTCTCCATGCTGACTCGGAAGTGCTGGTCTCCCGGAACCTATTGTCGTGCGCA
TAGTAAATGCTGCCGTGGATGCGATCAGAACAGAAATAAATGTTACTAGCTGATTC GGCGTCTGAACTTCCTCCTTCTGTGCTCTATCCTTTTTCTGCCTGAGTCCTCCATACC TGAGAATGGTCATGAACCACTCATCACCTACTCCTCTGGAGGCCTCAGAGGAGCCT ACACTGAAATAAAAGCCGCATTGG (SEQ TD NO: 186)
Translation:
MKLTCNNINAELLLTACQLITADDSRGTQKHRALRSTTNLSMLTRKCWSPGTYCRAHS KCCRGCDQNRNKCY (SEQ ID NO: 187)
Toxin Sequence:
Lys-Cys-Xaa4-Ser-Xaa3-Gly-Thr-Xaa5-Cys-Arg-Ala-His-Ser-Lys-Cys-Cys-Arg-Gly-Cys-Asp- Gln-Asn-Arg-Asn-Lys-Cys-Xaa5-A (SEQ TD NO: 188)
Name: M6.1
Species: magus Cloned: Yes
DNA Sequence: ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGGACACCAAACTCTCCATGTCGACTCGCTGCAAGGGTACAGGA AAACCATGCAGTAGGATTGCGTATAACTGCTGCACCGGTTCTTGCAGATCAGGTAA ATGTGGCTGATCCAGTGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTTCTGCCTG AGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCA (SEQ TD NO: 189)
Translation: MKLTCNNINANLLLTACQLITADDSRGTQKHRALRSDTKLSMSTRCKGTGKPCSRIAYN CCTGSCRSGKCG (SEQ TD NO: 190)
Toxin Sequence:
Cys-Lys-Gly-Thr-Gly-Lys-Xaa3-Cys-Ser-Arg-Ile-Ala-Xaa5-Asn-Cys-Cys-Thr-Gly-Ser-Cys- Arg-Ser-Gly-Lys-Cys-# (SEQ TD NO: 191)
Name: M6.2 Species: magus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAAGTCGGACACCAAACTCTCCATGTTAACTTTGCGCTGCGCATCTTACG GAAAACCTTGTGGTATTTACAACGACTGCTGCAATACATGCGATCCAGCCAGAAAG ACATGTACGTAGCTGATCCGGCGTCTGATCTTCC (SEQ ID NO:192)
Translation:
MKLTCNNINANLLLTACQLITADDSRGTQKHRALKSDTKLSMLTLRCASYGKPCGIYN DCCNTCDPARKTCT (SEQ ID NO: 193)
Toxin Sequence: Cys-Ala-Ser-Xaa5-Gly-Lys-Xaa3-Cys-Gly-Ile-Xaa5-Asn-Asp-Cys-Cys-Asn-Thr-Cys-Asp- Xaa3-Ala-Arg-Lys-Thr-Cys-Thr-A (SEQ ID NO:194)
Name: w-MVIIB Species: magus
Isolated: Yes
Cloned: Yes
DNA Sequence: GAATTTTCAGCATCACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATC GTCGCCGTGCTGCTCCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGT ACGCAGAAGCATCGTGCCCTGAGGTCGGACACCAAACTCTCCATGTCAACTCGCTG CAAGGGTAAAGGAGCATCATGTCATAGGACTTCGTATGACTGCTGCACCGGTTCTTG CAACAGAGGTAAATTTGGCTGATCCGCC (SEQ TD NO: 195)
Translation:
MKLTCVNINAVLLLTACQLITADDSRGTQKHRALRSDTKLSMSTRCKGKGASCHRTSY DCCTGSCΝRGKFG (SEQ TD ΝO:196)
Toxin Sequence:
Cys-Lys-Gly-Lys-Gly-Ala-Ser-Cys-His-Arg-Thr-Ser-Xaa5-Asρ-Cys-Cys-Thr-Gly-Ser-Cys-Asn- Arg-Gly-Lys-Cys-# (SEQ ID NO: 197) Name: Mi6.1
Species: miles Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGCGTGGTGATCATCGCCATGCTGTTCCTGACAGCCTAT CAACTCGCTACAGCTGCGAGCTACGCCAAAGGTAAACAGAAGCATCGTGCTCTGAG GCCAGCTGACAAACACCTCAGGTTGACCAAGCGTTGCAATGATCGCGGTGGAGGTT GCAGTCAACATCCTCACTGCTGCGGTGGAACTTGCAATAAGCTTATTGGCGTATGTC TGTAAAGCTGGTCTGCCGTCTGATATTCCCTTTCTGTGCTTCATCCTCTTTTGCCTGA GTCATCCATACCTGTGAATGGTTAAGAGCCACTCAATACCTATTCCTCTGGGGGCTT CAGAGGAACTACTTTAC (SEQ ID NO: 198)
Translation:
MKLTCNVπAMLFLTAYQLATAASYAKGKQKHRALRPADKHLRLTKRCNDRGGGCSQ HPHCCGGTCNKLIGVCL (SEQ TD NO:199)
Toxin Sequence:
Cys-Asn-Asp-Arg-Gly-Gly-Gly-Cys-Ser-Gln-His-Xaa3-His-Cys-Cys-Gly-Gly-Thr-Cys-Asn- Lys-Leu-Ile-Gly-Val-Cys-Leu-A (SEQ ID NO:200)
Name: Mn6.1
Species: monachus Cloned: Yes
DNA Sequence: ACCAAAACCATCATCAAAATGAAACTGACGAGTGTGGTGATCGTCGCCGTGCTGCT
CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGGACACCAAACTCTCCATATCGACTCGCTGCAAGTCTACAGGA AAATCATGCAGTAGGATTGCGTATAACTGCTGCACCGGTTCTTGCAGATCAGGTAA ATGTGGCTGATCCAGCGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGA GTCCTCCTTA (SEQ TD NO:201)
Translation:
MKLTSNNTVANLLLTACQLITADDSRGTQKHRALRSDTKLSISTRCKSTGKSCSRIAYNC CTGSCRSGKCG (SEQ TD NO:202)
Toxin Sequence:
Cys-Lys-Ser-Thr-Gly-Lys-Ser-Cys-Ser-Arg-Ile-Ala-Xaa5-Asn-Cys-Cys-Thr-Gly-Ser-Cys-Arg- Ser-Gly-Lys-Cys-# (SEQ ID NO:203)
Name: Mn6.2
Species: monachus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGAGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGGACACCAACCTCTCCATGTCGACTCGCTGCAAGGGTAAAGGA TCTTCATGTAGTAGGACCATGTATAACTGCTGCACCGGTTCTTGCAACAGAGGTAAA TGTGGCTGATCCAGCGCCTGATCTTCCCCCTTC (SEQ TD NO:204)
Translation:
MKLTSVVTVAVLLLTACQLITADDSRGTQKHRALRSDTNLSMSTRCKGKGSSCSRTMY NCCTGSCNRGKCG (SEQ TD NO:205)
Toxin Sequence: Cys-Lys-Gly-Lys-Gly-Ser-Ser-Cys-Ser-Arg-Thr-Met-Xaa5-Asn-Cys-Cys-Thr-Gly-Ser-Cys- Asn-Arg-Gly-Lys-Cys-# (SEQ ID NO:206)
Name: 06.1 Species: obscurus Cloned: Yes
DNA Sequence: ctctctctctctctgctggacAGGTCGCCTCCCTGCATGAAAGGCGGATCGTCATGCCGCGGTAC TACGGGAGTCTGTTGCGGTTTTTGCAGTGATTTCGGCTATAAATGTAGGGACTATCC
CCAAAACTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGTCCGAGTCCTCCTGACC TGAGAGTGGTCATGAACCACTCATCACCTACCCCTCTGGGGCTTCACAGGATCTACA TTGAAATAAAAGCCGCATTGC (SEQ TD NO:207)
Translation:
LLDRSPPCMKGGSSCRGTTGVCCGFCSDFGYKCRDYPQN (SEQ ID NO:208)
Toxin Sequence:
Ser-Xaa3-Xaa3-Cys-Met-Lys-Gly-Gly-Ser-Ser-Cys-Arg-Gly-Thr-Thr-Gly-Val-Cys-Cys-Gly- Phe-Cys-Ser-Asp-Phe-Gly-Xaa5-Lys-Cys-Arg-Asp-Xaa5-Xaa3-Gln-Asn-A (SEQ ID NO:209)
Name: O6.2
Species: obscurus Cloned: Yes
DNA Sequence: ctctctctctctctgctggacAGGTCGACTCGCTGCTTGCCTGACGGAACGTCTTGCCTTTTTAGT AGGATCAGATGCTGCGGTACTTGCAGTTCAATCTTAAAGTCATGTGTGAGCTGATCC AGCGGTTGATCTTCCTCCCTCTGTGCTCCATCCTTTTCTGCCTGAGTTCTCCTTACCT GAGAGTGGTCATGAACCACTCATCACCTACTCTTCTGGAGGCTTCAGAGGAGCTAC ATTGAAATAAAAGCCGCATTGC (SEQ TD NO:210) Translation:
RSTRCLPDGTSCLFSPJRCCGTCSSILKSCNS (SEQ TD ΝO:211)
Toxin Sequence:
Cys-Leu-Xaa3-Asρ-Gly-Thr-Ser-Cys-Leu-Phe-Ser-Arg-Ile-Arg-Cys-Cys-Gly-Thr-Cys-Ser-Ser- Ile-Leu-Lys-Ser-Cys-Nal-Ser-A (SEQ TD ΝO:212)
Name: Pu6.2
Species: pulicarius Cloned: Yes
DNA Sequence: ATGAAACTGACGTGTGTGGTGATCATCGCCGTGCTGTTCCTGACGGCCTGTC AACTC ATTACAGCTGAGACTTACTCCAGAGGTAAGCAGAAGCACCGTGCTTTGAGGTCAAC TGACAAAAACTCCAAGTTGACTAGGCAGTGCTCGCCTAACGGTGGATCTTGTTCTCG TCATTTTCACTGCTGCAGCCTCTATTGCAATAAAAATACTGGCGTATGTATTGCAAC CTAATACCCGTGTGTGGTCATGAACCACTCAATACCC.TCTCCTCTGGAGGCTTCAGA GGAACTGCATTGAAATAAAACTGCATTGCNTTGACCAAAAAAAAAA (SEQ ID NO:213)
Translation:
MKLTCVNIIANLFLTACQLITAETYSRGKQKHRALRSTDKNSKLTRQCSPNGGSCSRHF HCCSLYCNKNTGVCIAT (SEQ ID NO:214)
Toxin Sequence:
Xaa2-Cys-Ser-Xaa3-Asn-Gly-Gly-Ser-Cys-Ser-Arg-His-Phe-His-Cys-Cys-Ser-Leu-Xaa5-Cys- Asn-Lys-Asn-Thr-Gly-Nal-Cys-Ile-Ala-Thr-A (SEQ ID ΝO:215)
Name: P6.1
Species: purpurascens
Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGTTCCTGACGGCCTGTCAACTC ATCACAGCTGATGACTCCAGACGTACGCAGAAGCATCGTGCCCTGAGGTCGACCAC CAAAGGCGCCACGTCGAATCGCCCCTGCAAGACACCCGGACGAAAATGTTTTCCGC ATCAGAAGGACTGCTGCGGTCGAGCGTGCATCATCACAATATGTCCCTGATCTTCCC CCTTCTGTGCTGTATCCTTTTCTGCCTGAGTCTCCTTACCTGAGAGTGGTCATGAA (SEQ TD NO:216)
Translation: MKLTCNVTVANLFLTACQLITADDSRRTQKHRALRSTTKGATSNRPCKTPGRKCFPHQK DCCGRACπTICP (SEQ TD NO:217) Toxin Sequence:
Xaa3-Cys-Lys-Thr-Xaa3-Gly-Arg-Lys-Cys-Phe-Xaa3-His-Gln-Lys-Asp-Cys-Cys-Gly-Arg-Ala- Cys-Ile-Ile-Thr-Ile-Cys-Xaa3-A (SEQ TD NO:218)
Name: P6.2
Species: purpurascens
Isolated: Yes
Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGACCACCAAACTCTTCACGTCGAAAAGCTGCAAGCTTCCCGGA GC ATATTGTAATGCAGAAGATTATGACTGCTGCCTTAGATGC AAAGTTGGAGGTAC ATGTGGCTGATCCAGTGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGA GTCCTCCTTACCTAAGAGTGGTCATGAACCACTCATCACCTTCTCCTCTGGAGGCTT C (SEQ ID NO:219)
Translation:
MKLTCVNINANLLLTACQLITADDSRGTQKHRALRSTTKLFTSKSCKLPGAYCNAEDYD CCLRCKVGGTCG (SEQ ID NO:220)
Toxin Sequence: Ser-Cys-Lys-Leu-Xaa3-Gly-Ala-Xaa5-Cys-Asn-Ala-Xaal-Asp-Xaa5-Asp-Cys-Cys-Leu-Arg- Cys-Lys-Val-Gly-Gly-Thr-Cys-# (SEQ ID NO:221)
Name: P6.3 Species: purpurascens Cloned: Yes
DNA Sequence:
ATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGTTCCTGACGGCCTGTCAACTC ATCACAGCTGATGACTCCAGACGTACGCAGAAGCATCGTGCCCTGAGGTCGACCAC CAAACGCGCCACGTCGAATCGCCCCTGCAAGAAAACCGGACGAAAATGTTTTCCGC ATCAGAAGGACTGCTGCGGTCGAGCGTGCATCATCACAATATGTCCCTGATCTTCCC CCTTCTGTGCTGTATCCTTTTCTGCCTGAGTCCTCCTTACCTGAGAGTGGTCATGAAC CACTCATCACCTTCTCCTCTGGAGGCTTCAGAG (SEQ TD NO:222)
Translation:
MKXTCVV1NANLFLTACQLITADDSRRTQKHRALRSTTKRATSNRPCKKTGRKCFPHQK DCCGRACriTICP (SEQ TD NO:223)
Toxin Sequence:
Xaa3-Cys-Lys-Lys-Thr-Gly-Arg-Lys-Cys-Phe-Xaa3-His-Gln-Lys-Asp-Cys-Cys-Gly-Arg-Ala- Cys-Ile-Ile-Tlτr-Ile-Cys-Xaa3-A (SEQ TD NO:224) Name: R6.1
Species: radiatus Cloned: Yes
DNA Sequence:
GCTGATGCCTGATCTTCATCGTTCTTCCCTGTCTCCTTTGGCATCACCAAAACCATCA TCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGGTCCTGACGGCCTGTC AACTCATCACAGCTGATGACTCCAGAGGTATGCAGAAACATCATGCCCTGGGGTCG ATCAGCAGTCTCTTTAAGTCGACCCGTCATGGCTGCAAACCCCTCAAACGTCGTTGT TTCAATGATAAAGAATGCTGCAGCAAATTTTGCAATTCAGTCCGAAAGCAGTGTGG ATAAATGGCTAAAAAACTGAATAAAAGCCGCATTGCAAAAAAAA (SEQ TD NO:225)
Translation:
MKLTCVVIVAVLVLTACQLITADDSRGMQKHHALGSISSLFKSTRHGCKPLKRRCFNDK ECCSKFCNSVRKQCG (SEQ ID NO:226)
Toxin Sequence: His-Gly-Cys-Lys-Xaa3-Leu-Lys-Arg-Arg-Cys-Phe-Asn-Asp-Lys-Xaal -Cys-Cys-Ser-Lys-Phe- Cys-Asn-Ser-Val-Arg-Lys-Ghι-Cys-# (SEQ TD NO:227)
Name: R6.2 Species: radiatus Cloned: Yes
DNA Sequence:
GAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGGTCCTGACGGCCTGTCA ACTCATCACAGCTGATGACTCCAGAGGTATGCAGAAACATCATGCCCTGGGGTCGA TCAGCAGTCTCTTTAAGTCGACCCGTCGTGGCTGCAAACCCCTCAAACGTCGTTGTT TCAATGATAAAGAATGCTGCAGCAAATTTTGCAATTCAGTCCGAAACCAGTGTGGA TAAATGGCTAAAAACTGAATAAAAG (SEQ ID NO:228)
Translation:
MKLTCWΓVAVLVLTACQLITADDSRGMQKHHALGSISSLFKSTRRGCKPLKRRCFNDK ECCSKFCNSVRNQCG (SEQ TD NO:229)
Toxin Sequence: Arg-Gly-Cys-Lys-Xaa3-Leu-Lys-Arg-Arg-Cys-Phe-Asn-Asp-Lys-Xaal-Cys-Cys-Ser-Lys-Phe- Cys-Asn-Ser-Val-Arg-Asn-Gln-Cys-# (SEQ TD NO:230)
Name: w-RVIA Species: radiatus Cloned: Yes DNA Sequence:
GGAATTCCGCTTGCACGGCGAACCTGACTTCATCTTTCTTCCCTGCCTCCTTTGGCAT
CACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGG
TCCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTATGCAGAAGCAT
CATGCCCTGAGGTCGATCACCAAACTCTCCCTGTCGACTCGCTGCAAACCTCCCGGA
TCACCATGTAGAGTTTCTTCGTATAACTGCTGCTCTTCTTGCAAATCATACAACAAG
AAATGTGGCTGAACTTCCCCTTCTGTGCTCTATCCTTTTCCTGCCCGAGTCCTCCATA
CCTGAGAGTAGTCATGAACCACTGATTACCTACTCCTCTGGAGGGCCTCAGAGGAG
CTACTTTGAAATAAAAGCCCGCATTGCAAAAAAAAAA (SEQ TD NO:231)
Translation:
MKLTCNNIVANLNLTACQLITADDSRGMQKHHALRSITKLSLSTRCKPPGSPCRNSSYN CCSSCKSYNKKCG (SEQ TD NO:232)
Toxin Sequence:
Cys-Lys-Xaa3-Xaa3-Gly-Ser-Xaa3-Cys-Arg-Val-Ser-Ser-Xaa5-Asn-Cys-Cys-Ser-Ser-Cys-Lys- Ser-Xaa5-Asn-Lys-Lys-Cys-Gly-# (SEQ TD NO:233)
Name: Ra6.1
Species: rattus Cloned: Yes
DNA Sequence: GGATCCATGAAACTGACGTGCATGGTGATCATCGCCGTGCTGTTCCTGACAGCCTGT
CAATTCGATACAGCTGCGAGCTACGACAAAGGTAAGCAGAAACCTCCTACTCTGAG GCCAGCTGACAAACACATCAGGTTGACCAAGCGTTGCAATGCTCGCAATGATGGTT GCAGTCAACATTCTCAATGCTGCAGTGGATCTTGCAATAAGACTGCAGGCGTATGTC TGTAAAGCTGGTCTGCCGTCTGATATTCCCTTTCTGTGCTTTATCCTCTTTTGCCTGA GTCATCCATACCTGTGAATGGTTAAGAGCCACTCAATACCTACTCCTCTGGGGGCTT
CAGAGGAACTACATTAAATAAAGCCACATTGCAAAAAAAAAAAAAAAAAAA (SEQ TD NO:234)
Translation: MKLTCMVIIANLFLTACQFDTAASYDKGKQKPPTLRPADKHIRLTKRCNARNDGCSQH
SQCCSGSCNKTAGVCL (SEQ ID NO:235)
Toxin Sequence:
Cys-Asn-Ala-Arg-Asn-Asp-Gly-Cys-Ser-Gln-His-Ser-Gln-Cys-Cys-Ser-Gly-Ser-Cys-Asn-Lys- Thr-Ala-Gly-Val-Cys-Leu-A (SEQ TD NO:236)
Name: Ra6.2
Species: rattus Cloned: Yes
DNA Sequence: GGATCCATGAAACTGACGTGCGTGGTGATCATCGCCGTGCTGTTCCTGACAGCCTGT CAACTCGATGCAGCTGCGAGCTACGACAAAGGTAAGCAGAAACCTCCTACTCTGAG GCCAGCTGACAAACACTTCAGGTTGATCAAGCGTTGCAATGCTCGCAATAGTGGTT GCAGTCAACATCCTCAATGCTGCAGTGGATCTTGCAATAAGACTGCAGGCGTATGTC TGTAAAGCTGGTCTGCCGTCTGATATTCCCTTTCTGTGCTTTATCCTCTTTTGCCTGA GTCATCCATACCTGTGAATGGTTAAGAGCCACTCAATACCTACTCCTCTGGGGGCTT CAGAGGAACTACATTAAATAAAGCCACATTGCAACGAAAAAAAAAAAAAAAAAA (SEQ TD NO:237)
Translation:
MKLTCVNπAVLFLTACQLDAAASYDKGKQKPPTLRPADKHFRLIKRCNARNSGCSQHP QCCSGSCNKTAGVCL (SEQ TD NO:238)
Toxin Sequence: Cys-Asn-Ala-Arg-Asn-Ser-Gly-Cys-Ser-Gln-His-Xaa3-Gln-Cys-Cys-Ser-Gly-Ser-Cys-Asn- Lys-Thr-Ala-Gly-Val-Cys-Leu-A (SEQ ID NO:239)
Name: Ra6.3 Species: rattus Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGTGTGGTGATCATCGCCGTGCTGTTCCTGACAGCCTGT CAATTCGATACAGCTGCGAGCTACGACAAAGGTAAGCAGAAACCTCCTACTCTGAG
GCCAGCTGACAAACACTTCAGGTTGATCAAGCGTTGCAATGCTCGCAATAGTGGTT GCAGTCAACATCCTCAATGCTGCAGTGGATCTTGCAATAAGACTTTGGGCGTATGTC TGTAAAGCTGGTCTGCCGTCTGATATTCCCTTTCTGTGCTTTATCCTCTTTTGCCTGA GTCATCCATACCTGTGAATGGTTAAGAGCCACTCAATACCTACTCCTCTGGGGGCTT CAGAGGAACTACATTAAATAAAGCCACATTGAAAAAAAAAAAAAAAAAA (SEQ ID
NO:240)
Translation:
MKLTCVVIIAVLFLTACQFDTAASYDKGKQKPPTLRPADKHFRLIKRCNARNSGCSQHP QCCSGSCNKTLGVCL (SEQ ID NO:241)
Toxin Sequence:
Cys-Asn-Ala-Arg-Asn-Ser-Gly-Cys-Ser-Gln-His-Xaa3-Gln-Cys-Cys-Ser-Gly-Ser-Cys-Asn- Lys-Thr-Leu-Gly-Val-Cys-Leu-A (SEQ ID NO:242)
Name: Smβ.l
Species: stercusmuscarum
Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGAAGACCAAACTCTCCATGTCGACTCGCTGCAAGAGTAAAGGA GCAAAATGTTCAAGGCTTATGTATGACTGCTGCAGCGGTTCTTGCAGCGGCTACACA GGTAGATGTGGCTGATCCAGCGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTG CCTGGGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTGGA GGCCTCAGAGGAGTTACAATGAAATAAAAGCCGCATTGC (SEQ ID NO:243)
Translation:
MKLTCNNINANLLLTACQLITADDSRGTQKHRALRSKTKLSMSTRCKSKGAKCSRLMY DCCSGSCSGYTGRCG (SEQ TD ΝO:244)
Toxin Sequence:
Cys-Lys-Ser-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-Xaa5-Asp-Cys-Cys-Ser-Gly-Ser-Cys-Ser- Gly-Xaa5-Thr-Gly-Arg-Cys-# (SEQ TD NO:245)
Name: Sm6.2
Species: stercusmuscarum
Isolated: Yes
Toxin Sequence:
Thr-Thr-Ser-Cys-Met-Gln-Ala-Gly-Ser-Xaa5-Cys-Gly-Ser-Thr-Thr-Arg-Ile-Cys-Cys-Gly-Xaa5- Cys-Ala-Xaa5-Phe-Gly-Lys-Lys-Cys-Ile-Asp-Xaa5-Xaa3-Ser-Asn-A (SEQ TD NO:246)
Name: Sm6.3
Species: stercusmuscarum
Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGACCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGGAGCATC GTGCCCTGAGGTCGAAGACCAAACTCTCCATGTTAACTTTGCGCTGCGCATCTTACG GAAAACCTTGTGGTATTGACAACGACTGCTGCAATGCATGCGATCCAGCCAGAAAT ATATGTACGTAGCTGATCCGGCGTCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCT
GCCTGAGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCATCTACTCTCCTGG AGGCCTCAGAGGAGCTACAATGAAATAAAAGCCGCATTGC (SEQIDNO:247)
Translation: MKLTCNNINANLLLTTCQLITADDSRGTQEHRALRSKTKLSMLTLRCASYGKPCGTDND
CCNACDPARNICT (SEQ TD NO:248)
Toxin Sequence:
Cys-Ala-Ser-Xaa5-Gly-Lys-Xaa3-Cys-Gly-Ile-Asp-Asn-Asp-Cys-Cys-Asn-Ala-Cys-Asp-Xaa3- Ala-Arg-Asn-Ile-Cys-Thr-Λ (SEQ ID NO:249) Name: Sm6.4
Species: stercusmuscarum
Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGTGTGGTGATTGTCGCCGTGCTGCTCCTGACGGCCTGT CAACTCATCACAGCTGATGACTCCAGAGGTACGCAGGAGCATCGTGCCCTGAGGTC GAAGACCAAACTCTCCATGTTAACTTTGCGCTGCGTATCTTACGGAAAACCTTGTGG TATTGACAACGACTGCTGCAATGCATGCGATCCAGCCAGAAATATATGTACGTAGC TGATCCGGCGTCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGGGTCCTCC TTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTGGAGGCCTCAGAGGA GTTACAATGAAATAAAAGCCGCATTGCAAAAAAAAAAAAAAAAAAAA (SEQ TD NO:250)
Translation:
MKLTCNNINANLLLTACQLITADDSRGTQEHRALRSKTKLSMLTLRCNSYGKPCGIDND CCNACDPARNTCT (SEQ TD NO:251)
Toxin Sequence: Cys-Nal-Ser-Xaa5-Gly-Lys-Xaa3-Cys-Gly-Ile-Asp-Asn-Asp-Cys-Cys-Asn-Ala-Cys-Asp-Xaa3- Ala-Arg-Asn-Ile-Cys-Thr-A (SEQ ID ΝO:252)
Name: S6.1 Species: striatus
Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC
GTTCCCTGAGGTCGACCACCAAAGTCTCCAAGGCGACTGACTGCATTGAAGCCGGA AATTATTGCGGACCTACTGTTATGAAAATCTGCTGCGGCTTTTGCAGTCCATACAGC AAAATATGTATGAACTATCCCAAAAATTGATCTTCCCCC (SEQ TD NO:253)
Translation:
MKLTCNNTVANLLLTACQLITADDSRGTQKHRSLRSTTKNSKATDCIEAGNYCGPTNM KICCGFCSPYSKICMΝYPKΝ (SEQ TD ΝO:254)
Toxin Sequence: Ala-Thr-Asp-Cys-Ile-Xaal-Ala-Gly-Asn-Xaa5-Cys-Gly-Xaa3-Thr-Nal-Met-Lys-Ile-Cys-Cys- Gly-Phe-Cys-Ser-Xaa3-Xaa5-Ser-Lys-Ile-Cys-Met-Asn-Xaa5-Xaa3-Lys-Asn-A (SEQ TD ΝO:255)
Name: S6.2
Species: striatus Cloned: Yes DNA Sequence:
GTCGACTCGCTGCAAGCTTAAAGGACAATCATGTCGTAGGACTATGTATGACTGCTG CAGCGGTTCTTGCGGCAGGAGAGGTAAATGTGGCTGATCCAGCGCCTGATCTCCCC CCTTCTGTGCTCTATCCTTTTCTGCCTGGGTCCTCCTTACCTGAGAGTGGTCATGAAC CACTCATCACCTACTCCTCTGGAGGCCTCAGAGGAGCTACAATGAAATAAAAGCCG CATTGC (SEQ TD NO:256)
Translation: STRCKLKGQSCRRTMYDCCSGSCGRRGKCG (SEQ ID NO:257)
Toxin Sequence:
Cys-Lys-Leu-Lys-Gly-Gln-Ser-Cys-Arg-Arg-Thr-Met-Xaa5-Asp-Cys-Cys-Ser-Gly-Ser-Cys- Gly-Arg-Arg-Gly-Lys-Cys-# (SEQ TD NO:258)
Name: S6.3
Species: striatus
Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATC GTGCCCTGAGGTCGGACACCAAACTCTCCATGTCGACTCGCTGCAAGGCTGCAGGA AAATCATGCAGTAGGATTGCGTATAACTGCTGCACCGGTTCTTGCAGATCAGGTAA
ATGCGGCTGATCCAGCGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTCTGCCTGAG TCCTCTTACCTGAGAGTGGTCATGAACC (SEQ ID NO:259)
Translation: MKLTCNNTVANLLLTACQLITADDSRGTQKHRALRSDTKLSMSTRCKAAGKSCSRIAYN
CCTGSCRSGKCG (SEQ ID NO:260)
Toxin Sequence:
Cys-Lys-Ala-Ala-Gly-Lys-Ser-Cys-Ser-Arg-Ile-Ala-Xaa5-Asn-Cys-Cys-Thr-Gly-Ser-Cys-Arg- Ser-Gly-Lys-Cys-# (SEQ ID NO:261)
Name: S6.6
Species: striatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAACTCATCACAGCTGATGACTCCAGAGGTACGCAGGAGCATC GTGCCCTGAGGTCGGACACCAAACTCTCCATGTTAACTTTGCGCTGCGAATCTTACG GAAAACCTTGTGGTATTTACAACGACTGCTGCAATGCATGCGATCCAGCCAAAAAG ACATGTACGTAGCTGATCCGGCGTCTGATCT (SEQ ID NO:262) Translation:
MK TCNNTVANLLLTACQLITADDSRGTQEHRALRSDTKLSMLTLRCESYGKPCGTYND CCNACDPAKKTCT (SEQ TD NO:263)
Toxin Sequence:
Cys-Xaal-Ser-Xaa5-Gly-Lys-Xaa3-Cys-Gly-Ile-Xaa5-Asn-Asp-Cys-Cys-Asn-Ala-Cys-Asp- Xaa3-Ala-Lys-Lys-Thr-Cys-Thr-A (SEQ ID NO:264)
Name: w-SVIA
Species: striatus Cloned: Yes
DNA Sequence:
ACTAGGTCCTCCGGCAGCCCCTGTGGTGTTACTAGTATATGCTGTGGTAGATGCTAT AGGGGTAAATGTACGTAGCTCATCGGGCGTCTGATCTTCCCCCTTCTGTGCTCCATC CTTTTCTGCCTGAGTCCTCCTTACCTGAGAGTGGTCGTGAACCACTCATCGCCTACTC CTCTGGAGGCTTCAGAGGGGCTACACTAAAATAAAAGCTATATTGCAATGAAAAAA A (SEQ ID NO:265)
Translation:
CRSSGSPCGVTSICCGRCYRGKCT (SEQ TD NO:266)
Toxin Sequence:
Cys-Arg-Ser-Ser-Gly-Ser-Xaa3-Cys-Gly-Val-Thr-Ser-Ile-Cys-Cys-Gly-Arg-Cys-Xaa5-Arg- Gly-Lys-Cys-Thr-# (SEQ TD NO:267)
Name: w-SVTB
Species: striatus Isolated: Yes
Toxin Sequence: Cys-Lys-Leu-Lys-Gly-Gln-Ser-Cys-Arg-Lys-Thr-Ser-Xaa5-Asp-Cys-Cys-Ser-Gly-Ser-Cys-Gly- Arg-Ser-Gly-Lys-Cys-# (SEQ TD NO:268)
Name: Sx6.1 Species: striolatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGTCTTGCTGCTC CTGACGACCTGTCGTCTCATCACAGCTGATGACTCCAGAGGTACGCAGAAGCATCG TTCCCTGAGGTCGACTACTAAAGTCTCCATGTCGACTCGCTGCAAGGGTAAAGGAG CATCATGTCTTAGGACTGCGTATGACTGCTGCACCGGTTCTTGCAACAGAGGTAGAT GTGGCTGATCCAGCGTCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCTTGAGT CCTCCTTA (SEQ TD NO:269)
Translation: MKXTCVVIVVLLLLTTCRLITADDSRGTQKHRSLRSTTKVSMSTRCKGKGASCLRTAYD CCTGSCNRGRCG (SEQ TD NO:270)
Toxin Sequence:
Cys-Lys-Gly-Lys-Gly-Ala-Ser-Cys-Leu-Arg-Thr-Ala-Xaa5-Asp-Cys-Cys-Thr-Gly-Ser-Cys- Asn-Arg-Gly-Arg-Cys-# (SEQ ID NO:271)
Name: Sx6.2
Species: striolatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTTCTGCTG ACGGCGTGTCAACTCATCACAGCTGAGGACTCCAGAGGTACACAGAAGCATCGTAC CCTGAGGTCGACCGTCAGACGCTCCAAGTCCGAGTTGACTACGAGATGCAGGCCTT CAGGATCCAACTGTGGTAATATTAGTATCTGCTGTGGTAGATGCGTTAACAGAAGAT GTACGTAGCTCATCGGGCGTCTGATCTTTCCCC (SEQ TD NO:272)
Translation: MKLTCVVIVAVLLTACQLITAEDSRGTQKHRTLRSTVRRSKSELTTRCRPSGSNCGNTSI
CCGRCVNRRCT (SEQ TD NO:273)
Toxin Sequence:
Cys-Arg-Xaa3-Ser-Gly-Ser-Asn-Cys-Gly-Asn-Ile-Ser-Ile-Cys-Cys-Gly-Arg-Cys-Nal-Asn-Arg- Arg-Cys-Thr-A (SEQ TD ΝO:274)
Name: Sx6.3
Species: striolatus Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTTCTGTTC CTGACGGCGTGTCAACTCATCACAGCTGAGGACTCCAGAGGTACACAGAAGCATCG TTCCCTGAGGTCGACTACCAAAGTCTCCAAGTCGACTAGCTGCATGAAAGCCGGGT CTTATTGCGTCGCTACTACGAGAATCTGCTGCGGTTATTGCGCTTATTTCGGCAAAA TATGTATTGACTATCCCAAAAACTGATCTTCCCCCTACTGTGCTCTATCCTTTT (SEQ TD NO:275)
Translation:
MK TCVNINANLFLTACQLITAEDSRGTQKHRSLRSTTKNSKSTSCMKAGSYCNATTRI CCGYCAYFGKICIDYPKΝ (SEQ TD ΝO:276) Toxin Sequence:
Ser-Thr-Ser-Cys-Met-Lys-Ala-Gly-Ser-Xaa5-Cys-Nal-Ala-Thr-Thr-Arg-Ile-Cys-Cys-Gly-Xaa5- Cys-Ala-Xaa5-Phe-Gly-Lys-Ile-Cys-Ile-Asp-Xaa5-Xaa3-Lys-Asn-A (SEQ TD ΝO:277)
Name: Tx6.15
Species: textile Cloned: Yes
DNA Sequence:
GTTGACTCGGTACTGCACGCCTCATGGAGGACATTGTGGTTATCATAATGACTGCTG CAGTCATCAATGCAATATAAACAGAAATAAATGTGAGTAGCTGATCTGGCATCTGA TCTGTGCTCGTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTGG AGGC (SEQ ID NO:278)
Translation:
LTRYCTPHGGHCGYHNDCCSHQCNTNRNKCE (SEQ TD NO:279)
Toxin Sequence:
Xaa5-Cys-Thr-Xaa3-His-Gly-Gly-His-Cys-Gly-Xaa5-His-Asn-Asp-Cys-Cys-Ser-His-Gln-Cys- Asn-Ile-Asn-Arg-Asn-Lys-Cys-Xaal-A (SEQ ID NO:280)
Name: w-Tx
Species: textile Isolated: Yes
Toxin Sequence: Xaa5-Cys-Thr-Xaa3-Xaa5-Gly-Gly-His-Cys-Gly-Xaa5-His-Asn-Asρ-Cys-Cys-Ser-His-Gln- Cys-Asn-Ile-Asn-Arg-Asn-Lys-Cys-Xaal-A (SEQ ID NO:281)
Name: C. tulipa w2
Species: tulipa
Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAGCTCATCACAGCTCTGCACTCCAGAGGTACGCAGAAGCATC GTGCCCTGGGGCGGACCACCAAACTCACCTTGTCGACTCGCTGCAAATCACCCGGA TCTCCATGTTCACCGACTAGTTATAATTGCTGCTGGTCTTGCAGTCCATACAGAAAA AAATGTAGGGGCTAATCCAGCGCCTGATTTTCCCCCTTCTGTGCTCTATTCCTTTCTG CCTGAGTCCTCCTTACCTGAAAGTGGTCATGAACCACTCATCACCTACTTCTCTGGA GGCTTCGGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ TD NO:282)
Translation: MKLTCNNINANLLLTACQLITALHSRGTQKHRALGRTTKLTLSTRCKSPGSPCSPTSYNC CWSCSPYRKKCRG (SEQ TD NO:283)
Toxin Sequence:
Cys-Lys-Ser-Xaa3-Gly-Ser-Xaa3-Cys-Ser-Xaa3-Thr-Ser-Xaa5-Asn-Cys-Cys-Xaa4-Ser-Cys- Ser-Xaa3-Xaa5-Arg-Lys-Lys-Cys-Arg-# (SEQ TD NO:284)
Name: w-TVIA Species: tulipa Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAGCTCATCACAGCTCTGCACTCCAGAGGTACGCAGAAGCATC GTGCCCTGGGGTCGACCACCAAACTCACCTTGTCGACTCGCTGCTTGTCACCCGGAT CTTCATGTTCACCGACTAGTTATAATTGCTGCAGGTCTTGCAATCCATACAGCAGAA AATGTAGGGGCTAATCCAGCGCCTGATCTTCCCCCTTCTGTGCTCTATTCCTTTCTGC CTGAGTCCTCCTTACCTGAAAGTGGTCATGAACCACTCATCACCTACTTCTCTGGAG GCTTCGGAGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ TD NO:285)
Translation:
MKLTCNNTVAVLLLTACQLITALHSRGTQKHRALGSTTKLTLSTRCLSPGSSCSPTSYNC CRSCNPYSRKCRG (SEQ TD NO:286)
Toxin Sequence:
Cys-Leu-Ser-Xaa3-Gly-Ser-Ser-Cys-Ser-Xaa3-Thr-Ser-Xaa5-Asn-Cys-Cys-Arg-Ser-Cys-Asn- Xaa3-Xaa5-Ser-Arg-Lys-Cys-Arg-# (SEQ TD NO:287)
Name: Ni6.1
Species: viola Cloned: Yes
DΝA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAGCTCATTACAGCTGATGACTCCAGAGGTACGCAGTTGCATCG TGCCCTGAGGAAGGCCACCAAACTCCCCGTGTCGACTCGCTGCATTACTTTAGGAAC ACGATGTAAGGTTCCGAGTCAATGCTGCAGATCTTCTTGCAAGAACGGTCGTTGTGC TCCATCCCCTGAAGAATGGTAAATGTGGCTGATCCAGCGCCTGATCTTCCCCCTTCT
GACTGTCTCCGACCTTTTCTGCCTGAGTCCTCCTTACCTGAGAGGTGTCATGAACCA CTCATCACCTACTCCCCTGGAAGCTTCAGAGGAGCTACATTGAAATAAAAGCCGCA TTGC (SEQ TD ΝO:288)
Translation:
MKLTCNVINANLLLTACQLITADDSRGTQLHRALRKATKLPNSTRCITLGTRCKNPSQC CRSSCKΝGRCAPSPEEW (SEQ ID ΝO:289) Toxin Sequence:
Cys-Ile-Thr-Leu-Gly-Thr-Arg-Cys-Lys-Nal-Xaa3-Ser-Gln-Cys-Cys-Arg-Ser-Ser-Cys-Lys-Asn- Gly-Arg-Cys-Ala-Xaa3-Ser-Xaa3-Xaal-Xaal-Xaa4-A (SEQ TD ΝO:290)
Name: Ni6.2
Species: viola
Cloned: Yes
DΝA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAGCTCATTATAGCTGGGGACTCCAGAGGTACGCAGTTGCATCG TGCCCTGAGGAAGGCCACCAAACTCTCCGTGTCGACTCGCTGCAAGAGTAGAGGAT CATCATGTCGTAGGACTTCGTATGACTGCTGCACGGGTTCTTGCAGAAATGGTAAAT GTGGCTGATCCAGCGCCTGATCTTCCCCCTTCTGTGCTCCATCCTTTTCTGCCTGAGT CCTCCTTACCTGAGAGTGGGCATGAACCACTCATCACCTACTCCCTGGAAGCTTCAG AGGAGCTACATTGAAATAAAAGCCGCATTGC (SEQ ID ΝO:291)
Translation:
MKLTCNVINANLLLTACQLIIAGDSRGTQLHRALRKATKLSNSTRCKSRGSSCRRTSYD CCTGSCRΝGKCG (SEQ TD ΝO:292)
Toxin Sequence: Cys-Lys-Ser-Arg-Gly-Ser-Ser-Cys-Arg-Arg-Thr-Ser-Xaa5-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg- Asn-Gly-Lys-Cys-# (SEQ ID NO:293)
Name: VΪ6.3 Species: viola Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGCGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAGCTCATTACAGCTGAAGACTCCAGAGGTACGCATGAGCATC
TTGCCCTGAAGTCGACCTCCAAAGTCTCCAAGTCGACTAGCTGCATGGAAGCCAGA TCTTATTGCGGACCTGCTACTACGAAAATCTGCTGCGATTTTTGCAGTCCATTCAGC GATAGATGTATGAACAATCCCAACAATTGATCTTCCCCCTTGTGTGCTCCATCTTTTC TGCCTGAGTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTG GAGGCTTCAGAGGAGTTACATTGAAATAAAAGCCGCATGC (SEQ ID NO:294)
Translation:
MKLTCVATVAVLLLTACQLITAEDSRGTHEHLALKSTSKVSKSTSCMEARSYCGPATTKI CCDFCSPFSDRCMNNPNN (SEQ TD NO:295)
Toxin Sequence:
Ser-Thr-Ser-Cys-Met-Xaal-Ala-Arg-Ser-Xaa5-Cys-Gly-Xaa3-Ala-Thr-Thr-Lys-Ile-Cys-Cys- Asp-Phe-Cys-Ser-Xaa3-Phe-Ser-Asp-Arg-Cys-Met-Asn-Asn-Xaa3-Asn-Asn-A (SEQ TD NO:296)
Name: Ni6.4
Species: viola Cloned: Yes
DΝA Sequence: ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGCT CCTGACGGCCTGTCAGCTCATTACAGCTGAGGACTCCAGAGGTACGCAGTTGCATC GTGCCCTGAGGAAGACCACCAAACTCTCCTTGTCGACTCGCTGCAAGGGTCCAGGA GCCATATGTATAAGGATTGCGTATAACTGCTGCAAGTATTCTTGCGGAAATGGTAAA TGTGGCTGATCCAGCGCCTGATCTTCCCCCTTGTGTGCTCCATCCTTTTTCTGCCTGA GTCCTCCTTACCTGAGAGTGGTCATGAACCACTCATCACCTACTCCTCTGGAGGCTT CAGAGGAGCTACATTGAAATAAAAGCCGCATGC (SEQ ID ΝO:297)
Translation:
MKLTCNVTNANLLLTACQLITAEDSRGTQLHRALRKTTKLSLSTRCKGPGAICIRIAYNC CKYSCGNGKCG (SEQ ID NO:298)
Toxin Sequence:
Cys-Lys-Gly-Xaa3-Gly-Ala-Ile-Cys-Ile-Arg-Ile-Ala-Xaa5-Asn-Cys-Cys-Lys-Xaa5-Ser-Cys- Gly-Asn-Gly-Lys-Cys-# (SEQ TD NO:299)
Name: Vi6.5
Species: viola
Cloned: Yes
DNA Sequence:
ACCAAAACCATCATCAAAATGAAACTGACGTGTGTGGTGATCGTCGCCGTGCTGTTC
CTGACGGCCTGTCAATTCATCACAGCTGATGACTCCAGAAGTACGCAGAAGCATCG
TGCCCTGAGGTCGACCACCAAACACTTTATGTTGACTTGGTACTGCACGCCTTATGG AGGACATTGTGGTTATTATAATGACTGCTGCAGTCATCAATGCAATATAAACAGAA
ATAAATGTGAGTAGCTGATCCGGCATCTGATCTGTGCTCGCCCTAACCTGAGAGTGG TCATGAACCACTCATCATCTACTCCTCTGGAGGCTTCAGAGGAGCTACATGGAAATA AAAGCCGCATTGC (SEQ ID NO: 300)
Translation:
MKLTCVNTVANLFLTACQFITADDSRSTQKHRALRSTTKHFMLTWYCTPYGGHCGYYN DCCSHQCNINRNKCE (SEQ TD NO:301)
Toxin Sequence: Xaa5-Cys-Thr-Xaa3-Xaa5-Gly-Gly-His-Cys-Gly-Xaa5-Xaa5-Asn-Asp-Cys-Cys-Ser-His-Gln- Cys-Asn-Ile-Asn-Arg-Asn-Lys-Cys-Xaal-A (SEQ TD NO:302) Name: Pu6.4
Species: pulicarius Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGCGTGGTGATTATCGCCGTGCTGTTCCTGACGGCCTGT CAACTCATTACAGCTGAGACTTACTCCAGAGGTAAGCAGATGCACCGTGCTCTGAG GTCAACTGACAAAAACTCCAAGTTGACCAGGGAATGCACACCTCCAGATGGAGCTT GTGGTTTACCTACACACTGCTGCGGGTTTTGCGATATGGCAAACAACAGATGTCTGT AAAGCGTCTGATATTCCCCTTCTGTGCTCTATCCTCTTTGGCCTGAGTCATCCATACC TGTGCTCGAG (SEQ TD NO:303)
Translation:
MKLTCNNIIANLFLTACQLITAETYSRGKQMHRALRSTDKNSKLTRECTPPDGACGLPT HCCGFCDMANNRCL (SEQ ID NO:304)
Toxin Sequence: Xaal -Cys-Thr-Xaa3-Xaa3-Asρ-Gly-Ala-Cys-Gly-Leu-Xaa3-Thr-His-Cys-Cys-Gly-Phe-Cys- Asp-Met-Ala-Asn-Asn-Arg-Cys-Leu-A (SEQ TD NO:305)
Name: Pu6.6
Species: pulicarius
Cloned: Yes
DNA Sequence:
GGATCCATGAAACTGACGTGCGTGGTGATTATCGCCGTGCTGTTCCTGACGGCCTGT CAACTCATTACAGCTGAGACTTACTCCAGAGGTAAGCAGATGCACCGTGCTCTGAG
GTCAACTGACAAAAACTCCCAGTTGACCAGGGAATGCACACCTCCAGGTGGAGCTT GTGGTTTACCTACACACTGCTGCGGGTTTTGCGATATGGCAAACAACAGATGTCTGT AAAGCGTCTGATATTCCCCTTCTGTGCTCTATCCTCTTTGGCCTGAGTCATCCATACC TGTGCTCGAG (SEQ ID NO:306)
Translation:
MKLTCNNIIANLFLTACQLITAETYSRGKQMHRALRSTDKNSQLTRECTPPGGACGLPT HCCGFCDMANNRCL (SEQ ID NO:307)
Toxin Sequence:
Xaal-Cys-Thr-Xaa3-Xaa3-Gly-Gly-Ala-Cys-Gly-Leu-Xaa3-Thr-His-Cys-Cys-Gly-Phe-Cys- Asp-Met-Ala-Asn-Asn-Arg-Cys-Leu-A (SEQ TD NO:308)
Name: Ra6.4
Species: rattus
Cloned: Yes DNA Sequence:
GGATCCATGAAACTGACGTGTGTGGTGATCATCGCCGTGCTGTTCCTGGCAGCCTGT CAACCTGTTACAACTGAGACTTTCTCCAGAGGTAAGGAGAAGCGTCGTGCTCTGAG GTCAACTGACGGCAACTCCCGGTTGACCAGGGCATGCACGCCTGAAGGTGGAGCCT GTAGTAGTGGGCGTCACTGCTGCGGCTTTTGCGATAACGTGTCCCACACGTGCTATG GTGAAACACCATCTCTCCACTGATGTTTCCCCTTCTGTGCTCTATCTTCTTTTGCCTG AGTCATCCATACCTGTGCTCGAG (SEQ TD NO:309)
Translation:
MKLTCWIIAVLFLAACQPVTTETFSRGKEKRRALRSTDGNSRLTRACTPEGGACSSGR HCCGFCDNVSHTCYGETPSLH (SEQ ID NO:310)
Toxin Sequence: Ala-Cys-Thr-Xaa3-Xaal-Gly-Gly-Ala-Cys-Ser-Ser-Gly-Arg-His-Cys-Cys-Gly-Phe-Cys-Asp- Asn-Val-Ser-His-Thr-Cys-Xaa5-Gly-Xaal-Thr-Xaa3-Ser-Leu-His-A (SEQ TD NO:311)
Name: Sm6.7 Species: stercusmuscarum
Cloned: Yes
DNA Sequence:
AGATCCATGAAACTGACGTGCGTGGTGATCGTCGCCGTGCTGCTCCTGACGGCCTGT CAACTCATCACAGCTGATGACTCCAGAGGTACGCAGGAGCATCGTGCCCTGAGGTC
GGACACCAAACTCCCCATATCGACTCGCTGCAAGGGTAAAGGAGCATCATGTCATA AGACTATGTATGACTGCTGCAGCGGTTCCTGCACCAGAGGTAGATGTGGCTGATCC AGCGCCTGATCTTCCCCCTTCTGTGCTCTATCCTTTTCTGCCTGAGTCATCATACCTG TGCTCGAGCGTTACTAGTGGATCCGAGCTCGGTACCAAGCTTGGCGTAATCATAAA ANC (SEQ ID NO:312)
Translation:
MKLTCVVIVAVLLLTACQLITADDSRGTQEHRALRSDTKLPISTRCKGKGASCHKTMYD CCSGSCTRGRCG (SEQ ID NO:313)
Toxin Sequence:
Cys-Lys-Gly-Lys-Gly-Ala-Ser-Cys-His-Lys-Thr-Met-Xaa5-Asρ-Cys-Cys-Ser-Gly-Ser-Cys-Thr- Arg-Gly-Arg-Cys-# (SEQ ID NO:314)
Xaal = Glu or γ-Carboxy Glu Xaa2 = Gin or pyroGlu Xaa3 = Pro or Hydroxy Pro Xaa4 = Trp or Bromo Trp
Xaa5 = Tyr, 125I-Tyr, mono-iodo-Tyr or di-iodo-Tyr or O-sulpho-Tyr or O-Phospho-Tyr A = Free-carboxyl C-term or Amidated C-term, preferably Free-carboxyl # = Free-carboxyl C-term or Amidated C-term, preferably Amidated
TABLE2 Alignment of ω -Conopeptides (SEQ TD NO:)
Arδ.lC 1 (F170) QCSANGGSC-TRHFH CCSLYCNKDSSVCVATSYP^ (315)
Ar6.2 (F074) TCNTPTEYC-TLHRH CCSGYCHKTIQACS^ (316)
Ar6.3 ---QCTPNGGSC-SRHFH---CCSLYCNKSTGVCIATSYPλ (317)
Ar6.4 (F009) TCNTPTEYC-TLHQH CCSGYCHKTIQACS^ (318)
Ar6.6 (F069) ECTPPGGACGLPT-H CC-GFCDTANNRCX (319) A Arr66..77 ( (FF007733)) TCNTPTEYC-TLHQH CCSGHCHKTIQACA^ (320)
Ar6.8 (F169) ---QCSPIGGYC-TLHIH CCSNHCIKPIGRCVAX (321)
Ar6.9 (F171) QCLPNGGYC-TLHIH CCSDHCIKPIDRCVAX (322 )
Ay6.1 (A653) CKGKGKPCSRISYN CCTGSCRS--GKC# (323)
Ay6.2 (A654) C EAGSYCG-STTR- - ICC-GFCAYFGKKCIDYPSN^ (324 ) A Ayy66..33 ( (JJ441199)) CKAKGKPCSRIAYN CCTGSCRS--GKC# (325)
Ay6.4 CASYGKPCGIDN-D CCNA-CDPGRNICT (326 )
Bu6.1 -STSCMEAGSYCGPATTK--ICC-DFCSPFSDRCMNNPNNΛ (327)
Bu6.2 CITPGTRCKVPS-Q CCRGPCKNGR- -CTPSPSEW^ (328]
Bu6.3 CATYGKPCGIQN-D CC-NTCDPARRTCX (329) B Buu66..44 CKGPGASCIRIAYN CCKYSCRN--GKC# (330)
Bu6.5 -STSCMAAGSYCGPATTN--ICC-DFCSPFSDRCMKKPNNΛ (331)
Bu6.6 CKSKGSSCHRTSYD CCTGSCRN--GRC# (332)
C6.1 CKSTGASCRRTSYD CCTGSCRS- -GRC# (333 )
C6.4 CQGRGASCRKTMYN CCSGSCN- -RGSC# (33 ) C C66..55 CLPAGESCLFSRIR CC-GTCSSVLKSCVSA (335)
C6.6 CQGRGGPCTKAVFN CCSGSCN- -RGRC# (336)
C6.7 CATYGKPCGIQN-D CC-NTCDPARKTCX (337)
C6.8 CRGRGGPCTKA FN CCSGSCN--RGRC# (338 )
Ca6.4 (F168) - - -QCSANGGSC-TRHFH CCSLYCNKDSSVCVATSYP^ (339) C Cnnββ..ll CASYGKPCGIDN-D CC-NTCDPARKTCX (340)
Cnβ.2 (1583) CKGTGKPCSRIAYN CCTGSCRS- -GKC# (341)
Cnβ.3 -ATDCIEAGNYCGPTVMK--ICC-GFCSPYSKICMNYPQNΛ (342 )
Cnβ.4 CKGKGASCTRL YD CCHGSCSSSKGRC# (343 )
Cnβ.5 (1590) CKGKGASCHRTSYD CCTGSCN- -RGKC# (344 ) C Cnn6β..6β ( (11558844)) CASYGKPCGIYN-D---CC-NTCDPARKTCX (345)
Cn6.7 (J409) CKGTGKPCSRVAYN CCTGSCRS--GKC# (346)
Cnβ.8 (J407) -STSCMKAGSYCR-STTR--TCC-GYCAYFGKFCIDFPSNΛ (347)
Crβ.l CKGKGASCRKTMYN-- -CCSGSCSN- -GRC# (348 )
Crβ.2 -STSC EAGSYCR-STTR--TCC-GYCSYFSKKCIDFPSNA (349) C Crr6β..33 CKSKGAKCSRLMYD CCSGSCSRYSGRC# (350)
Crβ.4 -STGCMKAGSYCR-STTR--TCC-GYCAYFGKKCIDYPSNΛ (351)
Daβ.8 SCTPPGGPCGYYN-D CCSHQCNISRNKCE^ (352)
Diβ.l CEDOGEOCGSDH-S CCGGSCN- -HNVCA^ (353 )
E6.2 PCKPKGRKCFPHQKD CCNKTCT--RSKCP^ (354) E E66..33 ACWSSGTPCGTDS-L CCGG-CNVSKSKCN^ (355)
G6.1 (J420) CKSPGSSCSPTSYN CCR-SCNPYAKRCY# (356)
G6.2 (J423) CKSPGTPCSRGMRD CCT-PCLLYSNKC-R- -RYΛ (357)
J410 CLSPGSRCHKTMRN CCT-SCSSYKGKCRP--RKA (358)
J411 CKPPGRKCLNRKNE CCSKFCNEHLHMC# (359) J413 CKPPRRKCLKIKDK- --CC-NFCNTHLNMC# (360)
J414 CAGPGTIC- -PNRV- - -CC-GYCSKRTHLCHS RT# (361)
Laβ.l KC PSGSYCRANS-K- --CCSG-CDRNRNKCY^ (362)
Laβ.2 CLPPGSYCK-ATTE- -VCCS-SCLQFAQIC S# (363)
L6.1 CKSPGSPCSVTSYN- --CCT-FCSSYTKKCRA--SLΛ (364)
L6.2 CAGPGAIC- -PNRV- --CC-GYCSKRTHLCHS RT# (365)
L6.3 ACWSSGTPCGTDS-L- --CCGG-CNVSKSKCN^ (366)
L6.4 KC SPGTYCRAHS-K- --CCRG-CDQNRNKCYΛ (367)
La6.3 CKSPGSSCSVSMRN- --CCT-SCNSRTKKCTR--R# (368)
La6.4 TCWPSGTACGIDS-N- --CCSG-CNVSRSKCN (369)
La6.5 KC PSGSYCRANS-K- --CCSG-CDRNRSKCN^ (370)
Lpβ.l (JG4) SLFECAPSGGRCGFLK-S- --CCEGYCDGESTSCVSGPYSI^ (371)
Lpβ.2 (JG5) PLDCTAPSQPCGYFP-R- --CCG-HCDV-RRVCTS# (372)
Lpβ.3 (JG7) CMSPGGICGDFG-D CCE-ICNV-YGICVSDLPGIΛ (373)
Lp6.4 (JG15) YCAPPGGACGFFD-H CC-GYCETFYNTC-RΛ (374) 6.1 CKGTGKPCSRIAYN- - -CCTGSCRS--GKC# (375)
M6.2 CASYGKPCGIYN-D CC-NTCDPARKTCX (376)
Mi6.1 (F157; CNDRGGGC-SQHPH CCGGTCNKLIGVCL^ (377 )
Mn6.1 CKSTGKSCSRIAYN- - -CCTGSCRS- -GKC# (378)
Mn6.2 CKGKGSSCSRTMYN CCTGSCN--RGKC# (379)
06.1 -SPPCMKGGSSCR-GTTG--VCC-GFCSDFGYKCRDYPQNΛ (380)
06.2 CLPDGTSCLFSRIR CC-GTCSSILKSCVSΛ (381)
P6.1 OCKTOGRKCFOHQKD CCGRACI--ITICP^ (382)
P6.2 SCKLOGAYCNAXDYD CCLR-CKV-GGTC# (383)
P6.3 - - -PCKKTGRKCFPHQKD CCGRACI- -ITICPΛ (384 )
Pu6.2 (JG28) ---QCSPNGGSC-SRHFH CCSLYCNKNTGVCIAX (385)
Pu6.4 (AA678) ECTPPDGACGLPT-H CC-GFCD ANNRCL^ (386)
Pu6.6 (AA681) ECTPPGGACGLPT-H CC-GFCD ANNRCLΛ (387)
R6.1 - -HGCKPLKRRCFNDKE CCSKFCNSVRKQC# (388 )
R6.2 - -RGCKPLKRRCFNDKE CCSKFCNSVRNQC# (389)
Raβ.l (F206) CNARNDGC-SQHSQ CCSGSCNKTAGVCL (390)
Ra6.2 (F205) CNARNSGC-SQHPQ CCSGSCNKTAGVCL^ (392 )
Raβ.3 (F207) CNARNSGC-SQHPQ CCSGSCNKTLGVCL^ (393)
Raβ.4 (AA688; ACTPEGGACSSGR-H CC-GFCDNVSHTCYGETPSLHΛ (394)
S6.1 -ATDCIEAGNYCGPTVMK--ICC-GFCSPYSKIC NYPKNΛ (395)
S6.2 CKLKGQSCRRTMYD CCSGSCGR-RGKC# (396)
S6.3 CKAAGKSCSRIAYN- - -CCTGSCRS- -GKC# (397)
S6.6 CESYGKPCGIYN-D CC-NACDPAKKTCX (398)
Sm6 .1 (J428) CKSKGAKCSRLMYD CCSGSCSGYTGRC# (399)
Smβ .2 -TTSC QAGSYCG-STTR--ICC-GYCAYFGKKCIDYPSNΛ (400)
Smβ .3 (J429) CASYGKPCGIDN-D- - -CC-NACDPARNICX (401)
Smβ .4 (J431) CVSYGKPCGIDN-D CC-NACDPARNICX (402 )
Smβ .7 (AA689) CKGKGASCHKT YD CCSGSCTRG- -RC# (403 )
Sx6.1 CKGKGASCLRTAYD-- -CCTGSCN- -RGRC# (40 )
Sxβ .2 CRPSGSNCGNIS-I CCGR-CVN--RRCX (405)
Sxβ .3 -STSCMKAGSYCV-ATTR--ICC-GYCAYFGKICIDYPKNΛ (406)
Txβ.15 YCTPHGGHC-GYHND-- -CCSHQCNINRNKCE^ (407)
Viβ. CITLGTRCKVPS-Q CCRSSCKN- -GRCAPSPEE ^ (408)
Viβ, CKSRGSSCRRTSYD CCTGSCRN- -GKC# (409)
Viβ, -STSCMEARSYCGPATTK--ICC-DFCSPFSDRCMNNPNNΛ (410)
Viβ CKGPGAICIRIAYN CCKYSCGN- -GKC# (411)
Viβ YCTPYGGHCGYYN-D CCSHQCNINRNKCE^ (412 ) ω-Tx CTPYGGHCGYNH-D CCSHQCNINRNKCE^ (413)
C. tulipa ω2 CKSWGSOCSOTSTN CCW-SCSPYRKKC-R# (414)
EXAMPLE 3
In vivo Activity of ω-Conopeptide Frings Audiogenic Seizure Susceptible Mice
[0079] In vivo anticonvulsant activity of ω-conopeptides is analyzed in Frings audiogenic seizure susceptible mice as described by White et al. (1992). The ω-conopeptides are found to have anticonvulsant activity in this assay.
EXAMPLE 4 In vivo Activity of ω-Conopeptides in CF No. 1 Mice [0080] In vivo anticonvulsant activity of ωconopeptides is analyzed in CF No. 1 mice as described by White et al. (1995), using the maximal electroshock, subcutaneous pentylenetefrazole (Mefrazol) seizure threshold and threshold tonic extension test, ω- Conopeptides are found to have anticonvulsant activity.
EXAMPLE 5
In Vivo Activity of ω -Conopeptides in Pentylenetetrazole-Induced Threshold Seizure Model
[0081] The in vivo activity of ω-conopeptides is analyzed using timed intravenous infusion of pentylenetetrazole (White et al., 1995). At time to peak effect, the convulsant solution (0.5% pentylenetefrazole in 0.9% saline containing 10 U.S.P. units/ml heparin sodium) is infused into the tail vein at a constant rate of 0.34 ml/min. The time in seconds from the start of the infusion to the appearance of the first twitch and the onset of clonus is recorded for each drug treated or control animal. The times to each endpoint are converted to mg/kg of pentylenetetrazole for each mouse, and mean and standard error of the mean are calculated. It is found that ω- conopeptides elevate the i.v. pentylenetetrazole seizure threshold.
EXAMPLE 6
In vivo Activity of ω-Conopeptides in Pain Models [0082] The anti-pain activity of ω-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 ω-conopeptides and ω-conopeptides derivatives have analgesic properties.
[0083] More specifically, this study evaluates the effect of infrathecal administration of ω-conopeptides in mice models of nocioceptive and neuropathic pain. For nocioceptive pain, the effect of the ω-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. An ω-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, ω-conopeptides are presumed to have greatest effect on the magnitude of pain behavior in the second phase. [0084] 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 ω-conopeptides are compared with those of rats that receive vehicle infrathecal injections.
[0085] 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 prefreatment. Clearly, the clinical need is for drugs that are effective after the pain has developed. To address this issue, animals are studied in which ω-conopeptides are administered repeatedly, after the inflammation (CFA) or nerve injury has been established. In these experiments, an ω- conopeptide is injected daily by the infrathecal (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.
EXAMPLE 7 Effect of ω -Conotoxins in a Pain Model [0086] Analgesic activity of ω -conotoxins is also tested in pain models as follows. [0087] Persistent pain (formalin test). Infrathecal (it) drug injections are performed as described by Hylden and Wilcox (1980). An ω-conopeptide or vehicle is administered in a volume of 5 1. Fifteen minutes after the i.t. injection, the right hindpaw is injected with 20 1 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. ω-Conopeptides are found to be active in this model which is predictive of efficacy for treating neuropathic pain.
[0088] Acute pain ftail-flick). An ω-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.
[0089] Neuropathic pain. The partial sciatic nerve ligation model is used to assess the efficacy of Marl 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 Vz 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 1/10 the animal' s body weight. [0090] The data obtained demonstrate that ω-conopeptides have potent analgesic properties in three commonly used models of pain: acute, persistent/inflammatory and neuropathic pain models.
EXAMPLE 8
Calcium-Channel Antagonist Activity: Inhibition of Ionic Currents [0091] Ionic currents through calcium channels are examined in cells that are voltage-clamped by a single patch-clamp electrode. These whole-cell patch-clamp studies are performed mainly on N1E115 mouse neuroblastoma cells, although a variety of cell types, including human neuroblastoma cell line IMR-32, are also examined.
[0092] Most measurements are obtained using a bath saline that allowed examination of the calcium currents in the absence of other ionic currents. These solutions contained 80 mM NMDG (as a sodium replacement), 30 mM TEAC1 (to block potassium currents), 10 mM BaCl2 (as a charge-carrier through the calcium channels), and 10 mM HEPES at pH 7.3. Some solutions also contained 2 mM quinidine (to block potassium currents) and 3 μM tetrodotoxin (to block sodium currents). Normal bath saline is (mM): 140 NaCl, 10 glucose, 3 KC1, 2 CaCl2, 1 MgCl2, 10 mM HEPES pH 7.3. Intracellular solutions contained (mM): 150 CsCl, 0.5 CaCl2, 5 EGTA, 5 MgCl2, 2 K2ATP at pH 7.3-7.4. Bath saline and all internal solutions are filtered before use. [0093] Pipets are made from Corning 7052 glass (Garner Glass Company, Claremont,
Calif. 91711), coated with Sylgard (Dow Corning, Midland, Mich. 48640) and fire-polished before use. Bubble numbers are typically 5 to 6, with pipet resistances typically 2-5 MOhms. Corning 8161, Ki ble, and other glasses are also used without noticeable effect on the calcium currents observed. [0094] Recordings are carried out at room temperature with an Axopatch 1-C amplifier
(Axon Instruments, Foster City, Calif. 94404) and analyzed with pCLAMP software (Axon Instruments). Data are filtered at 1000 Hz for a typical sampling rate of 0.1 kHz; in all cases data are filtered at a frequency at most 1/5 of the sampling rate to avoid biasing. Data are collected on-line by the software. Analysis is performed on-screen with print-out via a Hewlett-Packard LaserJet Printer (Hewlett-Packard, Palo Alto, Calif. 94306).
[0095] The typical experiment is conducted as follows: after seal formation followed by series resistance compensation and capacitative transient cancellation, a voltage clamp protocol is performed wherein the cell potential is stepped from the holding potential (typically -100 mV) to test potentials that ranged from -60 mV to +20 mV in 10 mV increments. The cell is held at the holding potential for 5 seconds between pulses. Protocols starting from other holding potentials usually covered the same range of test potentials. ω-Conopeptides are found to have calcium channel blocking activity in such cell lines.
[0096] 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.
BIBLIOGRAPHY Abiko, H. et al. (1986). Brain Res. 38:328-335. Aldrete, J.A. et al. (1979). Crit. Care Med. 7:466-470. Barnay, G. et al. (2000). J. Med. Chem. Bitan, G. et al. (1997). J. Peptide Res. 49:421-426. Bodansky et al. (1966). Chem. Ind. 38:1597-98. Cartier, G.E. et al. (1996). J. Biol. Chem. 271:7522-7528. Chandler, P. et al. (1993). J. Biol. Chem. 268:17173-17178.
Chaplan S.R (1997). J Pharmacol. Exp. Ther. 280:829-838. Clark, C. et al. (1981). Toxicon 19:691-699. Codere, T.J. (1993). Eur. J. Neurosci. 5:390-393. Cruz, L.J. at al. (1976). Verliger 18:302-308. Ettinger, L.J. et al. (1978). Cancer 41:1270-1273.
Hammerland et al. (1992). Eur. J. Pharmacol. 226:239-244. Heading, C (1999). Curr. Opin. CPNS Invest. Drugs 1:153-166 Horiki, K. et al. (1978). Chemistry Letters 165-68. Hubry, V. et al. (1994). Reactive Polymers 22:231-241. Hylden, J.L.K.and Wilcox, G. (1980). Eur. J. Pharmacol. 67:313-316.
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The Merck Manual of Diagnosis and Therapy, 16 Ed., Berkow, R. et al., eds., Merck Research Laboratories, Rahway, N.J., pp. 1436-1445 (1992).
Methoden der Organischen Chemie (Houben-Weyl): Synthese von Peptiden, E. Wunsch (Ed.), Georg Thieme Verlag, Stuttgart, Ger. (1974). Nehlig, A. et al. (1990). Effects of phenobarbital in the developing rat brain. In Neonatal Seizures, Wasterlain, CG. and Vertt, P. (eds.), Raven Press, New York, pp. 285-194.
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Claims

WHAT IS CLAIMED IS:
1. An isolated peptide selected from the group consisiting of:
(a) a peptide set forth in Table 2 (b) a derivative of the peptide in (a); and
(c) a propeptide set forth in Table 1 .
2. The isolated peptide of claim 1, wherein Xaa] is Lys, Xaz^ is Tyr, Xaa3 is Glu and Xaa5 is Trp.
3. An isolated nucleic acid encoding an ω-conopeptide propeptide having an amino acid sequence set forth in Table 1.
4. The isolated nucleic acid of claim 3, wherein the nucleic acid comprises a nucleotide sequence set forth in Table 1.
5. An isolated conopeptide propeptide having an amino acid sequence set forth in Table 1.
6. A method for treating or preventing disorders associated with voltage gated ion channel disorders in which comprises administering to a patient in need thereof a therapeutically effective amount of an active agent selected from the group consisting of peptides (a) and (b) of claim 1 or a phannaceutically acceptible salt thereof.
7. The method of claim 6, wherein said disorder is a neurologic disorder.
8. The method of claim 7, wherein said neurologic disorder is a seizure.
9. The method of claim 8, wherein said seizure is seizure is associated with epilepsy.
10. The method of claim 7, wherein said neurologic disorder is a neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia.
11. The method of claim 10, wherein said neurotoxic injury is associated with sfroke, cerebrovascular accident, brain or spinal cord trauma, myocardial infarct, physical trauma, drownings, suffocation, perinatal asphyxia, or hypoglycemic events.
12. The method of claim 6, wherein said disorder is pain.
13. The method of claim 12, wherein said pain is migraine, acute pain, persistent pain, neuropathic pain or nociceptive pain.
14. The method of claim 6, wherein said disorder is inflammation.
15. The method of claim 6, wherein said disorder is a cardiovascular disorder.
1
SEQUENCE LISTING
<110> University of Utah Research Foundation Cognetix, Inc. Olivera, Baldomero . Mclntosh, J. Michael at ins, Maren Garrett, James E. Shon, Ki-Joon Jacobsen, Richard Jones, Robert M. Cartier, G. Edward
<120> Omega-Conopeptides
<130> 2314-241
<150> US 60/219,616 <151> 2000-07-21
<150> US 60/265,888 <151> 2001-02-05
<160> 413
<170> Patentln version 3.0
<210> 1
<211> 318
<212> DNA
<213> Unknown
<220>
<223> unknown Conus species
<400> 1 ggatccatga aactgacgtg catggtgatc gtcgccgtgc tgctcctgac ggcctgtcaa 60 ctcatcacag ctgatgactc cagaggtacg cagaagcatc atgccctgag gtcgaccacc 120 aatttctcca cgttgactcg tcgctgcctt tctcccggat cacgatgtca taagacaatg 180 cgtaactgct gcacttcatg ctcttcatac aaagggaaat gtcggcctcg aaaatgaacc 240 actcatcacc tactcctctg gaggcctcag aggaattaca ttgaaataaa agccgcatta 300 caaaaaaaaa aaaaaaaa 318
<210> 2
<211> 76
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<400> 2
Met Lys Leu Thr Cys Met Val lie Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu lie Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His His 20 25 30
Ala Leu Arg Ser Thr Thr Asn Phe Ser Thr Leu Thr Arg Arg Cys Leu 35 40 45 Ser Pro Gly Ser Arg Cys His Lys Thr Met Arg Asn Cys Cys Thr Ser 50 55 60
Cys Ser Ser Tyr Lys Gly Lys Cys Arg Pro Arg Lys 65 70 75
<210> 3
<211> 30
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<220>
<221> PEPTIDE <222> (1) .. (30)
<223> Xaa at residue 4 and 28 is Pro or Hyp; Xaa at residue 22 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-T y
<400> 3
Cys Leu Ser Xaa Gly Ser Arg Cys His Lys Thr Met Arg Asn Cys Cys
1 5 10 15
Thr Ser Cys Ser Ser Xaa Lys Gly Lys Cys Arg Xaa Arg Lys 20 25 30
<210> 4
<211> 283
<212> DNA
<213> Unknown
<220>
<223> unknown Conus species
<400> 4 ggatccatga aactgacgtg cgtggtgatc gtcgccgtgc tgctcctgac ggtctgtcaa 60 ctcatcacag ctgatgactc cagaggtacg cagaagcatc atgccctgag gtcgaccacc 120 aatttctcca cgtcgactcg tcgctgcaaa cctcccggaa gaaaatgtct gaatagaaag 180 aatgaatgct gcagcaagtt ttgcaatgaa cacctacata tgtgtggata aatggctaaa 240 aactgaataa aagccgcatt gcaaaaaaaa aaaaaaaaaa aaa 283
<210> 5
<211> 74
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<400> 5
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Val
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His His 20 25 30
Ala Leu Arg Ser Thr Thr Asn Phe Ser Thr Ser Thr Arg Arg Cys Lys 35 40 45 Pro Pro Gly Arg Lys Cys Leu Asn Arg Lys Asn Glu Cys Cys Ser Lys 50 55 60
Phe Cys Asn Glu His Leu His Met Cys Gly 65 70
<210> 6
<211> 27
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<220>
<221> PEPTIDE <222> (1) .. (27)
<223> Xaa at residue 14 and 22 is Glu or gamma-carboxy Glu; Xaa at resi due 3 and 4 is Pro or Hy
<400> 6
Cys Lys Xaa Xaa Gly Arg Lys Cys Leu Asn Arg Lys Asn Xaa Cys Cys
1 5 10 15
Ser Lys Phe Cys Asn Xaa His Leu His Met Cys 20 25
<210> 7
<211> 275
<212> DNA
<213> Unknown
<220>
<223> unknown Conus species
<400> 7 ggatccatga aactgacgtg cgtggtgatc gtcgccgtgc tgctcctgac ggcctgtcaa 60 ctcgtcacag ctgatggctc cagaggtatg cagaagcatt atgccctgag gtcgaccacc 120 aatctctcca tatcgtctcg ctgcaaacct cccagaagaa aatgtctgaa gattaaggat 180 aaatgctgca acttttgcaa tacacaccta aatatgtgtg gataaatggc taaaaactga 240 ataaaagccg cattgcaaaa aaaaaaaaaa aaaaa 275
<210> 8
<211> 72
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<400> 8
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu Val Thr Ala Asp Gly Ser Arg Gly Met Gin Lys His Tyr 20 25 30
Ala Leu Arg Ser Thr Thr Asn Leu Ser He Ser Ser Arg Cys Lys Pro 35 40 45 Pro Arg Arg Lys Cys Leu Lys He Lys Asp Lys Cys Cys Asn Phe Cys 50 55 60
Asn Thr His Leu Asn Met Cys Gly 65 70
<210> 9
<211> 26
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<220>
<221> PEPTIDE
<222> (1) .. (26)
<223> Xaa at residue 3 and 4 is Pro or Hyp
<400> 9
Cys Lys Xaa Xaa Arg Arg Lys Cys Leu Lys He Lys Asp Lys Cys Cys
1 5 10 15
Asn Phe Cys Asn Thr His Leu Asn Met Cys 20 25
<210> 10
<211> 377
<212> DNA
<213> Unknown
<220>
<223> unknown Conus species
<400> 10 ggatccatga aactgacgtg tgtggtgatc gtcgccgtgc tgctcctgat ggcctgtcaa 60 ctcgtcacag ctgatggctc cagaggtatg cacaagcatt atgccctgag gtcgaccacc 120 aaactctcca tgtcgactcg ctgcgcaggt ccaggaacaa tttgtcctaa tagggtatgc 180 tgcggttatt gcagtaaaag aacacatcta tgtcattcgc gaactggctg atcttccccc 240 ttctgcgctc catccttttc tgcctgagtc ctccatacct gagaatggtc atgaaccact 300 caacacctac tcctctggag ggcctcagaa gagctacatt gaaataaaag ccgcattaca 360 aaaaaaaaaa aaaaaaa 377
<210> 11
<211> 74
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<400> 11
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Met Ala
1 5 10 15
Cys Gin Leu Val Thr Ala Asp Gly Ser Arg Gly Met His Lys His Tyr 20 25 30
Ala Leu Arg Ser Thr Thr Lys Leu Ser Met Ser Thr Arg Cys Ala Gly 35 40 45
Pro Gly Thr He Cys Pro Asn Arg Val Cys Cys Gly Tyr Cys Ser Lys 50 55 60
Arg Thr His Leu Cys His Ser Arg Thr Gly 65 70
<210> 12
<211> 28
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<220>
<221> PEPTIDE <222> (1)..(28)
<223> Xaa at residue 4 and 9 is Pro or Hyp; Xaa at residue 16 is Tyr, 1 251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 12
Cys Ala Gly Xaa Gly Thr He Cys Xaa Asn Arg Val Cys Cys Gly Xaa
1 5 10 15
Cys Ser Lys Arg Thr His Leu Cys His Ser Arg Thr 20 25
<210> 13
<211> 323
<212> DNA
<213> Conus arenatus
<400> 13 ggatccatga aactgacgtg catggtgatc atcgccgtgc tgttcctgac ggcctgtcaa 60 ctcattacag gtgagcagaa ggaccatgct ctgaggtcaa ctgacaaaaa ctccaagttg 120 actaggcagt gctcggctaa cggtggatct tgtactcgtc attttcactg ctgcagcctc 180 tattgcaata aagattccag tgtatgtgtg gcaacctcat acccgtgagt ggccatgaac 240 ccctcaatac cctctcctct ggaggcttca gaggaactgc attgaaataa aaccgcattg 300 caataaaaaa aaaaaaaaaa aaa 323
<210> 14
<211> 73
<212> PRT
<213> Conus arenatus
<400> 14
Met Lys Leu Thr Cys Met Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Gly Glu Gin Lys Asp His Ala Leu Arg Ser Thr 20 25 30
Asp Lys Asn Ser Lys Leu Thr Arg Gin Cys Ser Ala Asn Gly Gly Ser 35 40 45
Cys Thr Arg His Phe His Cys Cys Ser Leu Tyr Cys Asn Lys Asp Ser 50 55 60 Ser Val Cys Val Ala Thr Ser Tyr Pro 65 70
<210> 15
<211> 33
<212> PRT
<213> Conus arenatus
<220>
<221> PEPTIDE
<222> (1).. (33)
<223> Xaa at residue 1 is Gn or pyro-Glu; Xaa at residue 33 is Pro or H yp; Xaa at residue 19 and 32 is Tyr, 1251-Tyr, mono-iodo-Tyr, di- iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 15
Xaa Cys Ser Ala Asn Gly Gly Ser Cys Thr Arg His Phe His Cys Cys
1 5 10 15
Ser Leu Xaa Cys Asn Lys Asp Ser Ser Val Cys Val Ala Thr Ser Xaa 20 25 30
Xaa
<210> 16
<211> 326
<212> DNA
<213> Conus arenatus
<400> 16 accaaaacca tcatcaaaat gaaactgacg tgcgtgttga ttatcgccgt gctgttcctg 60 acggcctgtc aactcattac agctgagact tactccagag gtgagcagaa gcaccatgct 120 ctgaggtcaa ctgacagaaa ctccaagttg accaggacat gcaacactcc cactgaatat 180 tgtactttgc atcgacactg ctgcagcggc tactgccata aaacaatcca ggcatgttca 240 taataccggt gagtggtcat gaaccactca ataccctctc ctctggaggc ttcagaggaa 300 ctgcattgaa ataaaagccg cattgc 326
<210> 17
<211> 74
<212> PRT
<213> Conus arenatus
<400> 17
Met Lys Leu Thr Cys Val Leu He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Thr Tyr Ser Arg Gly Glu Gin Lys His 20 25 30
His Ala Leu Arg Ser Thr Asp Arg Asn Ser Lys Leu Thr Arg Thr Cys 35 40 45
Asn Thr Pro Thr Glu Tyr Cys Thr Leu His Arg His Cys Cys Ser Gly 50 55 60
Tyr Cys His Lys Thr He Gin Ala Cys Ser 65 70 <210> 18
<211> 28
<212> PRT
<213> Conus arenatus
<220>
<221> PEPTIDE <222> (1) .. (28)
<223> Xaa at residue 7 is Glu or gamma-carboxy Glu; Xaa at residue 5 is Pro or Hyp; Xaa at residue 8 and 19 is Tyr, 1251-Tyr, mono-iodo- Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 18
Thr Cys Asn Thr Xaa Thr Xaa Xaa Cys Thr Leu His Arg His Cys Cys
1 5 10 15
Ser Gly Xaa Cys His Lys Thr He Gin Ala Cys Ser 20 25
<210> 19
<211> 332
<212> DNA
<213> Conus arenatus
<400> 19 accaaaacca tcatcaaaat gaaactgacg tgcgtgttga tcatcgccgt gctgttcctg 60 acggcctgtc aactcattac agctgagact tactccagag gtgagcagat gcaccgtgct 120 ctgaggtcaa ctgacaaaaa ctccaagttg actaggcagt gcacgcctaa cggtggatct 180 tgttctcgtc attttcactg ctgcagcctc tattgcaata aaagtactgg cgtatgtatt 240 gcaacctcat acccgtgagt ggtcatgaac cactcaatac cctctcctct ggaggcttca 300 gaggaactgc attgaaataa aagccgcatt gc 332
<210> 20
<211> 79
<212> PRT
<213> Conus arenatus
<400> 20
Met Lys Leu Thr Cys Val Leu He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Thr Tyr Ser Arg Gly Glu Gin Met His 20 25 30
Arg Ala Leu Arg Ser Thr Asp Lys Asn Ser Lys Leu Thr Arg Gin Cys 35 40 45
Thr Pro Asn Gly Gly Ser Cys Ser Arg His Phe His Cys Cys Ser Leu 50 55 60
Tyr Cys Asn Lys Ser Thr Gly Val Cys He Ala Thr Ser Tyr Pro 65 70 75
<210> 21
<211> 33
<212> PRT
<213> Conus arenatus
<220>
<221> PEPTIDE 8
<222> (1) .. (33)
<223> Xaa at residue 1 is Gin or pyro-Glu; Xaa at residue 4 and 33 is P ro or Hyp; Xaa at residue 19 and 32 is Tyr, 1251-Tyr, mono-iodo-T yr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 21 ,
Xaa Cys Thr Xaa Asn Gly Gly Ser Cys Ser Arg His Phe His Cys Cys
1 5 10 15
Ser Leu Xaa Cys Asn Lys Ser Thr Gly Val Cys He Ala Thr Ser Xaa 20 25 30
Xaa
<210> 22
<211> 332
<212> DNA
<213> Conus arenatus
<400> 22 ggatccatga aactgacgtg catggtgatt atcgccgtgc tgttcctgac ggcctgtcaa 60 ctcattacag ctgagactta ctccagaggt gagcagaagc accatgctct gaggtcaact 120 gacaaaaact ccaagttgac caggacatgc aacactccca ccgaatattg tactttgcat 180 caacactgct gcagcggcta ctgccataaa acaatccagg catgttcata ataccggtga 240 gtggtcatga accactcaat accctctcct ctggaggctt cagaggaact gcattgaaat 300 aaaaccgcat tacaaaaaaa aaaaaaaaaa aa 332
<210> 23
<211> 74
<212> PRT
<213> Conus arenatus
<400> 23
Met Lys Leu Thr Cys Met Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Thr Tyr Ser Arg Gly Glu Gin Lys His 20 25 30
His Ala Leu Arg Ser Thr Asp Lys Asn Ser Lys Leu Thr Arg Thr Cys 35 40 45
Asn Thr Pro Thr Glu Tyr Cys Thr Leu His Gin His Cys Cys Ser Gly 50 55 60
Tyr Cys His Lys Thr He Gin Ala Cys Ser 65 70
<210> 24
<211> 28
<212> PRT
<213> Conus arenatus
<220>
<221> PEPTIDE <222> (1)..(28)
<223> Xaa at residue 7 is Glu or gamma-carboxy Glu; Xaa at residue 5 is Pro or Hyp; Xaa at residue 8 and 19 is Tyr, 1251-Tyr, mono-iodo- Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty <400> 24
Thr Cys Asn Thr Xaa Thr Xaa Xaa Cys Thr Leu His Gin His Cys Cys
1 5 10 15
Ser Gly Xaa Cys His Lys Thr He Gin Ala Cys Ser 20 25
<210> 25
<211> 394
<212> DNA
<213> Conus arenatus
<400> 25 ggatccatga aactgacgtg tatggtgatc atcgccgtac tgttcctgac ggcctgtcaa 60 ctcattacag ctgagactta ctccagaggt aagcagatgc accgcgctct gaggtcaact 120 gacaaaaact cccagttgac cagggaatgc acacctcccg gtggagcttg tggtttacct 180 acacactgct gcgggttttg cgatactgca aacaacagat gtctgtaaag ctggtctggc 240 gtctgatatt ccccttctgt gctctatcct ctttggcctg agtcatccgt acctgtgagt 300 ggtcatgaac tactcaatac cctctcctct ggaggcttca gaggaactac aatgaaataa 360 aacccgcatt gcagagaaaa aaaaaaaaaa aaaa 394
<210> 26
<211> 73
<212> PRT
<213> Conus arenatus
<400> 26
Met Lys Leu Thr Cys Met Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Thr Tyr Ser Arg Gly Lys Gin Met His 20 25 30
Arg Ala Leu Arg Ser Thr Asp Lys Asn Ser Gin Leu Thr Arg Glu Cys 35 40 45
Thr Pro Pro Gly Gly Ala Cys Gly Leu Pro Thr His Cys Cys Gly Phe 50 55 60
Cys Asp Thr Ala Asn Asn Arg Cys Leu 65 70
<210> 27
<211> 27
<212> PRT
<213> Conus arenatus
<220>
<221> PEPTIDE <222> (1)..(27)
<223> Xaa at residue 1 is Glu or gamma-carboxy Glu; Xaa at residue 4, 5 and 12 is Pro or Hy
<400> 27
Xaa Cys Thr Xaa Xaa Gly Gly Ala Cys Gly Leu Xaa Thr His Cys Cys
1 5 10 15
Gly Phe Cys Asp Thr Ala Asn Asn Arg Cys Leu 10
20 25
<210> 28
<211> 345
<212> DNA
<213> Conus arenatus
<220>
<221> misc_feature
<222> (1) .. (345)
<223> n may be any nucldeotide
<400> 28 ggatccatga aactgacgtg cgtggtgatt atcgccgtgc tgttcctgac ggcctgtcaa 60 ctcattacag ctgagactta ctccagaggt gagcagaatc accatgttct gaggtcaact 120 gacaaaaact ccaagttgac caggacatgc aacactccca ctgaatattg tactttgcat 180 caacactgct gcagcggcca ctgccataaa acaatccagg catgtgcata ataccggtgg 240 gtggtcatga accactcaat accctctcct ctggaggctt cagaggaact gcattgaaat 300 aaaaccgcat tgcaatgaan aaaaaaaaaa aaaaaaaaaa aaaaa 345
<210> 29
<211> 74
<212> PRT
<213> Conus arenatus
<400> 29
Met Lys Leu Thr Cys Val Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Thr Tyr Ser Arg Gly Glu Gin Asn His 20 25 30
His Val Leu Arg Ser Thr Asp Lys Asn Ser Lys Leu Thr Arg Thr Cys 35 40 45
Asn Thr Pro Thr Glu Tyr Cys Thr Leu His Gin His Cys Cys Ser Gly 50 55 60
His Cys His Lys Thr He Gin Ala Cys Ala 65 70
<210> 30
<211> 28
<212> PRT
<213> Conus arenatus
<220>
<221> PEPTIDE <222> (1)..(28)
<223> Xaa at residue 7 is Glu or gamma-carboxy Glu; Xaa at residue 5 is Pro or Hyp; Xaa at residueδ is Tyr, 1251-Tyr, mono-iodo-Tyr, di -iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 30
Thr Cys Asn Thr Xaa Thr Xaa Xaa Cys Thr Leu His Gin His Cys Cys
1 5 10 15
Ser Gly His Cys His Lys Thr He Gin Ala Cys Ala 20 25 11
<210> 31
<211> 322
<212> DNA
<213> Conus arenatus
<400> 31 ggatccatga aactgacgtg tgtggtgatc atcgccgtgc tgttcctgac ggcctgtcaa 60 ctcactacag gtgagcagaa ggaccatgct ctgaggtcaa ctgacaaaaa ctccaagttg 120 actaggcagt gctcgcctat cggtggatat tgtactcttc atattcactg ctgcagcaac 180 cattgcatta aacctatcgg ccgatgtgtg gcaacctgat acccgtgcgt ggtcatgaac 240 ccctcaatac cctctcctct ggaggcttca gaggaactgc attgaaataa aaccgcattg 300 caataaaaaa aaaaaaaaaa aa 322
<210> 32
<211> 70
<212> PRT
<213> Conus arenatus
<400> 32
Met Lys Leu Thr Cys Val Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu Thr Thr Gly Glu Gin Lys Asp His Ala Leu Arg Ser Thr 20 25 30
Asp Lys Asn Ser Lys Leu Thr Arg Gin Cys Ser Pro He Gly Gly Tyr 35 40 45
Cys Thr Leu His He His Cys Cys Ser Asn His Cys He Lys Pro He 50 55 60
Gly Arg Cys Val Ala Thr 65 70
<210> 33
<211> 30
<212> PRT
<213> Conus arenatus
<220>
<221> PEPTIDE
<222> (1)..(30)
<223> Xaa at residue 1 is Gin or pyro-Glu; Xaa at residue 4 and 23 is P ro or Hyp; Xaa at residue 8 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-i odo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 33
Xaa Cys Ser Xaa He Gly Gly Xaa Cys Thr Leu His He His Cys Cys
1 5 10 15
Ser Asn His Cys He Lys Xaa He Gly Arg Cys Val Ala Thr 20 25 30
<210> 34
<211> 318
<212> DNA
<213> Conus arenatus
<400> 34 ggatccatga aactgacgtg cgtggtgatc atcgccgtgc tgttcctgac ggcctgtcaa 60 12
ctcactacag gtgagcagaa ggaccatgct ctgaggtcaa ctgacaaaaa ctccaagttg 120 actaggcagt gcttgcctaa cggtggatat tgtactcttc atattcactg ctgcagcgac 180 cattgcatta aacctatcga ccgatgtgtg gcaacctgat acccgggcgt ggtcatgaac 240 ccctcaatac cctctcctct ggaggcttca gaggaactgc attgaaataa aaccgcatta 300 caaaaaaaaa aaaaaaaa 318
<210> 35
<211> 70
<212> PRT
<213> Conus arenatus
<400> 35
Met Lys Leu Thr Cys Val Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu Thr Thr Gly Glu Gin Lys Asp His Ala Leu Arg Ser Thr 20 25 30
Asp Lys Asn Ser Lys Leu Thr Arg Gin Cys Leu Pro Asn Gly Gly Tyr 35 40 45
Cys Thr Leu His He His Cys Cys Ser Asp His Cys He Lys Pro He 50 55 60
Asp Arg Cys Val Ala Thr 65 70
<210> 36
<211> 30
<212> PRT
<213> Conus arenatus
<220>
<221> PEPTIDE
<222> (1)..(30)
<223> Xaa at residue 1 is Gin or pyro-Glu; Xaa at residue 4 and 23 is P ro or Hyp; Xaa at residue 8 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-i odo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 36
Xaa Cys Leu Xaa Asn Gly Gly Xaa Cys Thr Leu His He His Cys Cys
1 5 10 15
Ser Asp His Cys He Lys Xaa He Asp Arg Cys Val Ala Thr 20 25 30
<210> 37
<211> 374
<212> DNA
<213> Conus aurisiacus
<400> 37 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgctcc tgacggcctg tcaactcatc 60 acagctgatg actccagagg tacgcagaag catcgttccc tgagctcggc caccaaactc 120 tccatgtcga ctcgctgcaa gggtaaagga aaaccatgca gtaggatttc gtataactgc 180 tgcaccggtt cttgcagatc aggtaaatgt ggctgatcca gcgcctgatc ttcccccttc 240 13 tgtgctctat ccttttctgc ctgagtcctc cttacctgag agtggtcatg aaccactcat 300 cacctgctcc tctggaggcc ccagaggagc tacattgaaa taaaagtcgc attgcaaaaa 360 aaaaaaaaaa aaaa 374
<210> 38
<211> 71
<212> PRT
<213> Conus aurisiacus
<400> 38
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ser Leu Ser Ser Ala Thr Lys Leu Ser Met Ser Thr Arg Cys Lys Gly 35 40 45
Lys Gly Lys Pro Cys Ser Arg He Ser Tyr Asn Cys Cys Thr Gly Ser 50 55 60
Cys Arg Ser Gly Lys Cys Gly 65 70
<210> 39
<211> 25
<212> PRT
<213> Conus aurisiacus
<220>
<221> PEPTIDE <222> (1) .. (25)
<223> Xaa at residue 7 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Ty r, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 39
Cys Lys Gly Lys Gly Lys Xaa Cys Ser Arg He Ser Xaa Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 40
<211> 380
<212> DNA
<213> Conus aurisiacus
<400> 40 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgctcc tgacggcctg tcaactcatc 60 acagctgatg actccagagg tacgcagaag catcgttccc tgaggtcgaa gaccaaactc 120 tccatgtcga ctggctgcat ggaagccgga tcttattgcg gctctactac gagaatctgc 180 tgcggttttt gcgcttattt cggcaaaaaa tgtattgact atcccagcaa ctgatcttcc 240 ccctactgtg ctctatcctt ttctgcctga gtcctcctta cctgagagtg gtcatgaacc 300 actcatcacc tgctcctctg gaggccccag aggagctaca ttgaaataaa atcgcattgc 360 taaaaaaaaa aaaaaaaaaa 380 14
<210> 41
<211> 77
<212> PRT
<213> Conus aurisiacus
<400> 41
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ser Leu Arg Ser Lys Thr Lys Leu Ser Met Ser Thr Gly Cys Met Glu 35 40 45
Ala Gly Ser Tyr Cys Gly Ser Thr Thr Arg He Cys Cys Gly Phe Cys 50 55 60
Ala Tyr Phe Gly Lys Lys Cys He Asp Tyr Pro Ser Asn 65 70 75
<210> 42
<211> 32
<212> PRT
<213> Conus aurisiacus
<220>
<221> PEPTIDE
<222> (1) .. (32)
<223> Xaa at residue 3 is Glu or gamma-carboxy Glu; Xaa at residue 30 i s Pro or Hyp; Xaa at residue 7, 21 and 29 is Tyr, 1251-Tyr, mono- iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 42
Cys Met Xaa Ala Gly Ser Xaa Cys Gly Ser Thr Thr Arg He Cys Cys
1 5 10 15
Gly Phe Cys Ala Xaa Phe Gly Lys Lys Cys He Asp Xaa Xaa Ser Asn 20 25 30
<210> 43
<211> 373
<212> DNA
<213> Conus aurisiacus
<400> 43 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgttccctg 120 agctcggcca ccaaactctc catgtcgact cgctgcaagg ctaaaggaaa accatgcagt 180 aggattgcgt ataactgctg caccggttct tgcagatcag gtaaatgtgg ctgatccagt 240 gcctgatctt cccccttctg tgctctatcc ttttctgcct gagtcctcct tacctgagag 300 tggtcatgaa ccactcatca cctgctcctc tggaggcccc agaggagcta cattgaaata 360 aaagccgcat tgc 373
<210> 44
<211> 71
<212> PRT
<213> Conus aurisiacus 15
<400> 44
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ser Leu Ser Ser Ala Thr Lys Leu Ser Met Ser Thr Arg Cys Lys Ala 35 40 45
Lys Gly Lys Pro Cys Ser Arg He Ala Tyr Asn Cys Cys Thr Gly Ser 50 55 60
Cys Arg Ser Gly Lys Cys Gly 65 70
<210> 45
<211> 25
<212> PRT
<213> Conus aurisiacus
<220>
<221> PEPTIDE <222> (1) .. (25)
<223> Xaa at residue 7 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Ty r, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 45
Cys Lys Ala Lys Gly Lys Xaa Cys Ser Arg He Ala Xaa Asn Cys Cys .
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 46
<211> 379
<212> DNA
<213> Conus aurisiacus
<400> 46 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acgacctgtc aactcatcac agctgatgac tccagaggta cgcaggagca tcgtgccctg 120 aggtcgaaga caaaactctc catgttaact ttgcgctgcg catcttacgg aaaaccttgt 180 ggtattgaca acgactgctg caatgcatgc gatccaggaa gaaatatatg tacgtagctg 240 atccagcgcc tgatcttccc ccttctgtgc tctatccttt tctgcccgag tcctccttac 300 ctgagagtgg tcatgaacca ctcatcacct gctccctgga ggcctcagag gagctacaat 360 gaaataaaag ccgcattgc 379
<210> 47
<211> 72
<212> PRT
<213> Conus aurisiacus
<400> 47
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Thr
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Glu His Arg 20 25 30 16
Ala Leu Arg Ser Lys Thr Lys Leu Ser Met Leu Thr Leu Arg Cys Ala 35 40 45
Ser Tyr Gly Lys Pro Cys Gly He Asp Asn Asp Cys Cys Asn Ala Cys 50 55 60
Asp Pro Gly Arg Asn He Cys Thr 65 70
<210> 48
<211> 26
<212> PRT
<213> Conus aurisiacus
<220>
<221> PEPTIDE <222> (1)..(26)
<223> Xaa at residue 7 and 20 is Pro or Hyp; Xaa at residue 4 is Tyr, 1 251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 48
Cys Ala Ser Xaa Gly Lys Xaa Cys Gly He Asp Asn Asp Cys Cys Asn
1 5 10 15
Ala Cys Asp Xaa Gly Arg Asn He Cys Thr 20 25
<210> 49
<211> 382
<212> DNA
<213> Conus bullatus
<400> 49 accaaaacca tcatcaaaat gaaactgacg tgtgtggcga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcattac agctgaagac tccagaggta cgcatgagca tcttgccctg 120 aagtcgacct ccaaagtctc caagtcgact agctgcatgg aagccggatc ttattgcgga 180 cctgctacta cgaaaatctg ctgcgatttt tgcagtccat tcagcgatag atgtatgaac 240 aatcccaaca attgatcttc ccccttgtgt gctccatcct tttctgcctg agtcctcctt 300 acctgagagt ggtcatgaac cactcatcac ctactcctct ggaggcttca gaggagctac 360 attgaaataa aagccgcatt gc 382
<210> 50
<211> 78
<212> PRT
<213> Conus bullatus
<400> 50
Met Lys Leu Thr Cys Val Ala He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Asp Ser Arg Gly Thr His Glu His Leu 20 25 30
Ala Leu Lys Ser Thr Ser Lys Val Ser Lys Ser Thr Ser Cys Met Glu 35 40 45
Ala Gly Ser Tyr Cys Gly Pro Ala Thr Thr Lys He Cys Cys Asp Phe 17
50 55 60
Cys Ser Pro Phe Ser Asp Arg Cys Met Asn Asn Pro Asn Asn 65 70 75
<210> 51
<211> 36
<212> PRT
<213> Conus bullatus
<220>
<221> PEPTIDE
<222> (1) .. (36)
<223> Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 13, 25 and 34 is Pro or Hyp; Xaa at residuelO is Tyr, 1251-Tyr, mono -iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 51
Ser Thr Ser Cys Met Xaa Ala Gly Ser Xaa Cys Gly Xaa Ala Thr Thr
1 5 10 15
Lys He Cys Cys Asp Phe Cys Ser Xaa Phe Ser Asp Arg Cys Met Asn 20 25 30
Asn Xaa Asn Asn 35
<210> 52
<211> 400
<212> DNA
<213> Conus bullatus
<400> 52 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcattac agctgaagac tccagaggta cgcagttgca tcgtgccctg 120 aggaaggcca ccaaacaccc tgtgtcgact cgctgcatta ctccaggaac acgatgtaag 180 gttccgagcc aatgctgcag aggtccttgc aagaacggtc gttgtactcc atccccttct 240 gaatggtaaa tgtggttgat ccagcgcctg atcttccccc ttcgtcgtgc tccatccttt 300 tctgcctgag tcctccttac ctgagagtgg tcatgaacca ctcatcacct actcccctgg 360 aggcttcaga ggagctacat tgaaataaaa gccgcattgc 400
<210> 53
<211> 76
<212> PRT
<213> Conus bullatus
<400> 53
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Asp Ser Arg Gly Thr Gin Leu His Arg 20 25 30
Ala Leu Arg Lys Ala Thr Lys His Pro Val Ser Thr Arg Cys He Thr 35 40 45
Pro Gly Thr Arg Cys Lys Val Pro Ser Gin Cys Cys Arg Gly Pro Cys 50 55 60 18
Lys Asn Gly Arg Cys Thr Pro Ser Pro Ser Glu Trp 65 70 75
<210> 54
<211> 31
<212> PRT
<213> Conus bullatus
<220>
<221> PEPTIDE <222> (1) .. (31)
<223> Xaa at residue 30 is Glu or gamma-carboxy Glu; Xaa at residue 4, 11, 18, 26 and 28 is Pro or Hyp; Xaa at residue 31is Trp or Bromo Tr
<400> 54
Cys He Thr Xaa Gly Thr Ala Cys Lys Val Xaa Ser Gin Cys Cys Arg
1 5 10 15
Gly Xaa Cys Lys Asn Gly Arg Cys Thr Xaa Ser Xaa Ser Xaa Xaa 20 25 30
<210> 55
<211> 379
<212> DNA
<213> Conus bullatus
<400> 55 accaaaacca tcatcaaaat gaaactgacg tgtgtggcga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcattac agctgaggac tccagagata cgcagaagca tcgtgccctg 120 aggtcggaca ccaaactctc, catgttgact ttgcgctgcg caacttacgg aaaaccttgt 180 ggtattcaaa acgactgctg caatacatgc gatccagcca gaaggacatg tacgtagctg 240 atccggcgtc ttgatcctcc gcttctgtgc tccatctttt ctgcctgagt cctccttacc 300 tgagagtggt catgaaccac tcatcaccta ctcctctgga ggctttagag gagctacatt 360 gaaataaaag ccgcattgc 379
<210> 56
<211> 72
<212> PRT
<213> Conus bullatus
<400> 56
Met Lys Leu Thr Cys Val Ala He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Asp Ser Arg Asp Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Ser Met Leu Thr Leu Arg Cys Ala 35 40 45
Thr Tyr Gly Lys Pro Cys Gly He Gin Asn Asp Cys Cys Asn Thr Cys 50 55 60
Asp Pro Ala Arg Arg Thr Cys Thr 65 70
<210> 57 <211> 26 19
<212> PRT
<213> Conus bullatus
<220>
<221> PEPTIDE <222> (1)..(26)
<223> Xaa at residue 7 and 20 is Pro or Hyp; Xaa at residue 4 is Tyr, 1 251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 57
Cys Ala Thr Xaa Gly Lys Xaa Cys Gly He Gin Asn Asp Cys Cys Asn
1 5 10 15
Thr Cys Asp Xaa Ala Arg Arg Thr Cys Thr 20 25
<210> 58
<211> 373
<212> DNA
<213> Conus bullatus
<400> 58 accaaaacca tcatcaaaat gaaactgacg tgtgtggcga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcattac agctgaagac tccagaggta cgcagttgca tcgtgccctg 120 aggaagacca ccaaactctc cttgtcgact cgctgcaagg gtccaggagc atcatgtata 180 aggattgcgt ataactgctg caagtattct tgcagaaatg gtaaatgtgg ctgatccagc 240 gcctgatctt cccccttgtg tgctccatcc ttttctgcct gagtcctcct tacctgagag 300 tggtcatgaa ccactcatca cctactcctc tggaggcttc agaggagcta cattgaaata 360 aaagccgcat tgc 373
<210> 59
<211> 71
<212> PRT
<213> Conus bullatus
<400> 59
Met Lys Leu Thr Cys Val Ala He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Asp Ser Arg Gly Thr Gin Leu His Arg 20 25 30
Ala Leu Arg Lys Thr Thr Lys Leu Ser Leu Ser Thr Arg Cys Lys Gly 35 40 45
Pro Gly Ala Ser Cys He Arg He Ala Tyr Asn Cys Cys Lys Tyr Ser 50 55 60
Cys Arg Asn Gly Lys Cys Gly 65 70
<210> 60
<211> 25
<212> PRT
<213> Conus bullatus
<220>
<221> PEPTIDE 20
<222> (1)..(25)
<223> Xaa at residue 4 is Pro or Hyp; Xaa at residue 13 and 18 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-T y
<400> 60
Cys Lys Gly Xaa Gly Ala Ser Cys He Arg He Ala Xaa Asn Cys Cys
1 5 10 15
Lys Xaa Ser Cys Arg Asn Gly Lys Cys 20 25
<210> 61
<211> 382
<212> DNA
<213> Conus bullatus
<400> 61 atcaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcattac agctgaagac tccagaggta cgcatgagca tcttgccctg 120 aagtcgacct ccaaagtctc caagtcgact agctgcatgg cagccggatc ttattgcgga 180 cctgctacta cgaatatctg ctgcgatttt tgcagtccat tcagcgatag atgtatgaaa 240 aagcccaaca attgatcttc ccccttctgt gctctatcct tttctgcctg agtcctcctt 300 acctgagagt ggtcatgaac cactcatcac ctactcctct ggaggcttca gaggagctac 360 attgaaataa aagccgcatt gc 382
<210> 62
<211> 78
<212> PRT
<213> Conus bullatus
<400> 62
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Asp Ser Arg Gly Thr His Glu His Leu 20 25 30
Ala Leu Lys Ser Thr Ser Lys Val Ser Lys Ser Thr Ser Cys Met Ala 35 40 45
Ala Gly Ser Tyr Cys Gly Pro Ala Thr Thr Asn He Cys Cys Asp Phe 50 55 60
Cys Ser Pro Phe Ser Asp Arg Cys Met Lys Lys Pro Asn Asn 65 70 75
<210> 63
<211> 36
<212> PRT
<213> Conus bullatus
<220>
<221> PEPTIDE
<222> (1)..(36)
<223> Xaa at residue 13, 25 and 34 is Pro or Hyp; Xaa at residue 10 is
Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phos pho-Ty 21
<400> 63
Ser Thr Ser Cys Met Ala Ala Gly Ser Xaa Cys Gly Xaa Ala Thr Thr
1 5 10 15
Asn He Cys Cys Asp Phe Cys Ser Xaa Phe Ser Asp Arg Cys Met Lys 20 25 30
Lys Xaa Asn Asn 35
<210> 64
<211> 373
<212> DNA
<213> Conus bullatus
<400> 64 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcattat agctgaggac tccagaggta cgcagttgca tcgtgccctg 120 aggaaggcca ccaaactctc cgtgtcgact cgctgcaaga gtaaaggatc atcatgtcat 180 aggacttcgt atgactgctg cacgggttct tgcagaaatg gtagatgtgg ctgatccagc 240 gcctgatctt cccccttctg tgctccatcc ttttctgcct gagtcctcct tacctgagag 300 tggtcatgaa ccactcatca cctactcctc tggaggcttc agaggagcta cattgaaata 360 aaagccgcat tgc 373
<210> 65
<211> 71
<212> PRT
<213> Conus bullatus
<400> 65
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He He Ala Glu Asp Ser Arg Gly Thr Gin Leu His Arg 20 25 30
Ala Leu Arg Lys Ala Thr Lys Leu Ser Val Ser Thr Arg Cys Lys Ser 35 40 45
Lys Gly Ser Ser Cys His Arg Thr Ser Tyr Asp Cys Cys Thr Gly Ser 50 55 60
Cys Arg Asn Gly Arg Cys Gly 65 70
<210> 66
<211> 25
<212> PRT
<213> Conus bullatus
<220>
<221> PEPTIDE <222> (1) .. (25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 66
Cys Lys Ser Lys Gly Ser Ser Cys His Arg Thr Ser Xaa Asp Cys Cys
1 5 10 15 22
Thr Gly Ser Cys Arg Asn Gly Arg Cys 20 25
<210> 67
<211> 321
<212> DNA
<213> Conus caracteristicus
<400> 67 ggatccatga aactgacgtg cgtggtgatc atcgccgtgc tgttcctgac ggcctgtcaa 60 ctcattacag gtgagcagaa ggaccatgct ctgaggtcaa ctgacaaaaa ctccaagttg 120 actaggcagt gctcggctaa cggtggatct tgtactcgtc attttcactg ctgcagcctc 180 tattgcaata aagattccag tgtatgtgtg gcaacctcat acccgtgagt ggccatgaac 240 ccctcaatac cctctcctct ggaggcttca gaggaactgc attgaaataa aaccgcatta 300 caaaaaaaaa aaaaaaaaaa a 321
<210> 68
<211> 73
<212> PRT
<213> Conus caracteristicus
<400> 68
Met Lys Leu Thr Cys Val Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Gly Glu Gin Lys Asp His Ala Leu Arg Ser Thr 20 25 30
Asp Lys Asn Ser Lys Leu Thr Arg Gin Cys Ser Ala Asn Gly Gly Ser 35 40 45
Cys Thr Arg His Phe His Cys Cys Ser Leu Tyr Cys Asn Lys Asp Ser 50 55 60
Ser Val Cys Val Ala Thr Ser Tyr Pro 65 70
<210> 69
<211> 33
<212> PRT
<213> Conus caracteristicus
<220>
<221> PEPTIDE
<222> (1)..(33)
<223> Xaa at residue 1 is Gin or pyro-Glu; Xaa at residue 33 is Pro or
Hyp; Xaa at residue 19 and 32 is Tyr, 1251-Tyr, mono-iodo-Tyr, di
-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 69
Xaa Cys Ser Ala Asn Gly Gly Ser Cys Thr Arg His Phe His Cys Cys
1 5 10 15
Ser Leu Xaa Cys Asn Lys Asp Ser Ser Val Cys Val Ala Thr Ser Xaa 20 25 30
Xaa 23
<210> 70
<211> 26
<212> PRT
<213> Conus catus
<400> 70
Cys Lys Ser Thr Gly Ala Ser Cys Arg Arg Thr Ser Tyr Asp Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Arg Cys Gly 20 25
<210> 71
<211> 25
<212> PRT
<213> Conus catus
<220>
<221> PEPTIDE <222> (1)..(25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 71
Cys Lys Ser Thr Gly Ala Ser Cys Arg Arg Thr Ser Xaa Asp Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Arg Cys 20 25
<210> 72
<211> 229
<212> DNA
<213> Conus catus
<400> 72 tcgactcgct gccagggtag aggagcatca tgtcgtaaga ctatgtataa ctgctgcagc 60 ggttcttgca acagaggtag ttgtggctga tccggcgcct gatcttcccc cttccgtgct 120 ctatcctttt ctgcctgatt cctccttacc tgagagcggt catgaaccac tcatcacctg 180 ctcctctgga ggcctcagag gagctacatt gaaataaaag ccgcattgc 229
<210> 73
<211> 29
<212> PRT
<213> Conus catus
<400> 73
Ser Thr Arg Cys Gin Gly Arg Gly Ala Ser Cys Arg Lys Thr Met Tyr
1 5 10 15
Asn Cys Cys Ser Gly Ser Cys Asn Arg Gly Ser Cys Gly 20 25
<210> 74
<211> 25
<212> PRT
<213> Conus catus
<220>
<221> PEPTIDE
<222> (1)..(25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O 24
-sulpho-Tyr or O-phospho-Ty
<400> 74
Cys Gin Gly Arg Gly Ala Ser Cys Arg Lys Thr Met Xaa Asn Cys Cys
1 5 10 15
Ser Gly Ser Cys Asn Arg Gly Ser Cys 20 25
<210> 75
<211> 235
<212> DNA
<213> Conus catus
<400> 75 tcgacacgct gcttgcctgc cggagagtct tgccttttta gtaggattag atgctgcggt 60 acttgcagtt cagtcttaaa gtcatgtgtg agctgatcca gctgctgatc ttcctcctcc 120 tgtgctccat ccttttctgc ctgagtcctc cttatctgag agtggtcatg aaccactcac 180 cacctactct tctggaggct tcagaggagc tacagtgaaa taaaagccgc attgc 235
<210> 76
<211> 31
<212> PRT
<213> Conus catus
<400> 76
Ser Thr Arg Cys Leu Pro Ala Gly Glu Ser Cys Leu Phe Ser Arg He
1 5 10 15
Arg Cys Cys Gly Thr Cys Ser Ser Val Leu Lys Ser Cys Val Ser 20 25 30
<210> 77
<211> 28
<212> PRT
<213> Conus catus
<220>
<221> PEPTIDE <222> (1) .. (28)
<223> Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 3 is Pro or Hy
<400> 77
Cys Leu Xaa Ala Gly Xaa Ser Cys Leu Phe Ser Arg He Arg Cys Cys
1 5 10 15
Gly Thr Cys Ser Ser Val Leu Lys Ser Cys Val Ser 20 25
<210> 78
<211> 227
<212> DNA
<213> Conus catus
<400> 78 tcgacacgct gccagggtag aggaggacca tgtactaagg ctgtgtttaa ctgctgcagc 60 ggttcttgca acagaggtag atgtggctga tccagcgcct gatcttcccc cttctgtgct 120 ctatcctttt ctgcctgagt cctccttact gagagtagtc atgaaccact catcacctac 180 25 tcctctggag gcctcagaga gctacattga aataaaagcc gcattgc 227
<210> 79
<211> 29
<212> PRT
<213> Conus catus
<400> 79
Ser Thr Arg Cys Gin Gly Arg Gly Gly Pro Cys Thr Lys Ala Val Phe
1 5 10 15
Asn Cys Cys Ser Gly Ser Cys Asn Arg Gly Arg Cys Gly 20 25
<210> 80
<211> 25
<212> PRT
<213> Conus catus
<220>
<221> PEPTIDE
<222> (1)..(25)
<223> Xaa at residue 7 is Pro or Hyp
<400> 80
Cys Gin Gly Arg Gly Gly Xaa Cys Thr Lys Ala Val Phe Asn Cys Cys
1 5 10 15
Ser Gly Ser Cys Asn Arg Gly Arg Cys 20 25
<210> 81
<211> 236
<212> DNA
<213> Conus catus
<400> 81 ttaactttgc gctgcgcaac ttacggaaaa ccttgtggta ttcaaaacga ctgctgcaat 60 acatgcgatc cagccagaaa gacatgtacg tagctgatcc ggcgtctgat ctcccccctt 120 ctgtgctcta tccttttctg cctgagtcct ccttacctga gagtggtcat gaaccactca 180 tcacctgctc ctctggaggc ctcgggggag ctacattgaa ataaaagccg cattgc 236
<210> 82
<211> 30
<212> PRT
<213> Conus catus
<400> 82
Leu Thr Leu Arg Cys Ala Thr Tyr Gly Lys Pro Cys Gly He Gin Asn
1 5 10 15
Asp Cys Cys Asn Thr Cys Asp Pro Ala Arg Lys Thr Cys Thr 20 25 30
<210> 83
<211> 26
<212> PRT
<213> Conus catus
<220>
<221> PEPTIDE 26
<222> (1)..(26)
<223> Xaa at residue 7 and 20 is Pro or Hyp; Xaa at residue 4 is Tyr, 1 251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 83
Cys Ala Thr Xaa Gly Lys Xaa Cys Gly He Gin Asn Asp Cys Cys Asn
1 5 10 15
Thr Cys Asp Xaa Ala Arg Lys Thr Cys Thr 20 25
<210> 84
<211> 229
<212> DNA
<213> Conus catus
<400> 84 tcgactcgct gccggggtag aggaggacca tgtactaagg ctatgtttaa ctgctgcagc 60 ggttcttgca acagaggtag atgtggctga tccagcgcct gatcttcccc cttctgtgct 120 ctatcctttt ctgcctgagt cctccttaac tgagagtagt catgaaccac tcatcaccta 180 ctcctctgga ggcctcagag aagcatcatt gaaataaaag ccgcattgc 229
<210> 85
<211> 29
<212> PRT
<213> Conus catus
<400> 85
Ser Thr Arg Cys Arg Gly Arg Gly Gly Pro Cys Thr Lys Ala Met Phe
1 5 10 15
Asn Cys Cys Ser Gly Ser Cys Asn Arg Gly Arg Cys Gly 20 25
<210> 86
<211> 25
<212> PRT
<213> Conus catus
<220>
<221> PEPTIDE
<222> (1) .. (25)
<223> Xaa at residue 7 is Pro or Hyp
<400> 86
Cys Arg Gly Arg Gly Gly Xaa Cys Thr Lys Ala Met Phe Asn Cys Cys
1 5 10 15
Ser Gly Ser Cys Asn Arg Gly Arg Cys 20 25
<210> 87
<211> 374
<212> DNA
<213> Conus circumcisus
<400> 87 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acgacctgtc aactcatcac agctgatgac tccagaggta cgcaggagca tcgtgccctg 120 27 aggtcggaca ccaaactccc catgtcgact cgctgcaagg gtaaaggagc atcatgtcgt 180 aagactatgt ataactgctg cagcggttct tgcagcaacg gtagatgtgg ctgatccagc 240 gcctgatctt cccccttctg ctgctctatc cttttctgcc tgagtcctcc ttacctgaga 300 gctggtcatg aaccactcat cacctgctcc tctggaggcc cagaggagct acattgaaat 360 aaaagccgca ttgc 374
<210> 88
<211> 71
<212> PRT
<213> Conus circumcisus
<400> 88
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Thr
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Glu His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Pro Met Ser Thr Arg Cys Lys Gly 35 40 45
Lys Gly Ala Ser Cys Arg Lys Thr Met Tyr Asn Cys Cys Ser Gly Ser 50 55 60
Cys Ser Asn Gly Arg Cys Gly 65 70
<210> 89
<211> 25
<212> PRT
<213> Conus circumcisus
<220>
<221> PEPTIDE <222> (1) .. (25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 89
Cys Lys Gly Lys Gly Ala Ser Cys Arg Lys Thr Met Xaa Asn Cys Cys
1 5 10 15
Ser Gly Ser Cys Ser Asn Gly Arg Cys 20 25
<210> 90
<211> 379
<212> DNA
<213> Conus- circumcisus
<400> 90 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acgacctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcggcca ccaaagtctc caagtcgact agctgcatgg aagccggatc ttattgccgc 180 tctactacga gaacctgctg cggttattgc tcttatttca gcaaaaaatg tattgacttt 240 cccagcaact gatcttcccc ctactgtgct ctatcctttt ctgcctgagt cctccttacc 300 28 tgagagtggt catgaaccac tcatcaccct actcctctgg aggcccagag gagctacatt 360 gaaataaaag ccgcattgc 379
<210> 91
<211> 77
<212> PRT
<213> Conus circumcisus
<400> 91
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Thr
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Ala Thr Lys Val Ser Lys Ser Thr Ser Cys Met Glu 35 40 45
Ala Gly Ser Tyr Cys Arg Ser Thr Thr Arg Thr Cys Cys Gly Tyr Cys 50 55 60
Ser Tyr Phe Ser Lys Lys Cys He Asp Phe Pro Ser Asn 65 70 75
<210> 92
<211> 35
<212> PRT
<213> Conus circumcisus
<220>
<221> PEPTIDE
<222> (1) .. (35)
<223> Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 33 i s Pro or Hyp; Xaa at residue 10, 21 and 24 is Tyr, 1251-Tyr, mono -iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 92
Ser Thr Ser Cys Met Xaa Ala Gly Ser Xaa Cys Arg Ser Thr Thr Arg
1 5 10 15
Thr Cys Cys Gly Xaa Cys Ser Xaa Phe Ser Lys Lys Cys He Asp Phe 20 25 30
Xaa Ser Asn 35
<210> 93
<211> 379
<212> DNA
<213> Conus circumcisus
<400> 93 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acgacctgtc aactcatcac agctgatgac tccagaggta cgcaggagca tcgtgccctg 120 aggtcggaca ccaaactccc catgtcgact cgctgcaaga gtaaaggagc aaaatgttca 180 aggcttatgt atgactgctg cagcggttct tgcagcaggt actcaggtag atgtggctga 240 tccagcgcct gatcttcccc cttctgctgc tctatccttt tctgcctgag tcctccttac 300 ctgagagtgg tcatgaacca ctcatcacct actcctctgg aggcccagag gagctacatt 360 29 gaaataaaag ccgcattgc 379
<210> 94
<211> 73
<212> PRT
<213> Conus circumcisus
<400> 94
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Thr
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Glu His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Pro Met Ser Thr Arg Cys Lys Ser 35 40 45
Lys Gly Ala Lys Cys Ser Arg Leu Met Tyr Asp Cys Cys Ser Gly Ser 50 55 60
Cys Ser Arg Tyr Ser Gly Arg Cys Gly 65 70
<210> 95
<211> 27
<212> PRT
<213> Conus circumcisus
<220>
<221> PEPTIDE <222> (1) .. (27)
<223> Xaa at residue 13 and 23 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo -Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 95
Cys Lys Ser Lys Gly Ala Lys Cys Ser Arg Leu Met Xaa Asp Cys Cys
1 5 10 15
Ser Gly Ser Cys Ser Arg Xaa Ser Gly Arg Cys 20 25
<210> 96
<211> 379
<212> DNA
<213> Conus circumcisus
<400> 96 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acgacctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgttccctg 120 acgtcggcca ccaaagtctc caagtcgact ggctgcatga aagccggatc ttattgccgc 180 tctactacga gaacttgctg cggttattgc gcttatttcg gcaaaaaatg tattgactat 240 cccagcaact gatcttcccc ctactgtgct ctatcctttt ctgcctaagt cctccttacc 300 tgagagtggt catgaaccac tcatcaccct actcctctgg aggcccagag gagctacatt 360 gaaataaaag ccgcattgc 379
<210> 97
<211> 77
<212> PRT
<213> Conus circumcisus 30
<400> 97
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Thr
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ser Leu Thr Ser Ala Thr Lys Val Ser Lys Ser Thr Gly Cys Met Lys 35 40 45
Ala Gly Ser Tyr Cys Arg Ser Thr Thr Arg Thr Cys Cys Gly Tyr Cys 50 55 60
Ala Tyr Phe Gly Lys Lys Cys He Asp Tyr Pro Ser Asn 65 70 75
<210> 98
<211> 35
<212> PRT
<213> Conus circumcisus
<220>
<221> PEPTIDE <222> (1) .. (35)
<223> Xaa at residue 33 is Pro or Hyp; Xaa at residue 10, 21, 24 and 32 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or 0- phospho-Ty
<400> 98
Ser Thr Gly Cys Met Lys Ala Gly Ser Xaa Cys Arg Ser Thr Thr Arg
1 5 10 15
Thr Cys Cys Gly Xaa Cys Ala Xaa Phe Gly Lys Lys Cys He Asp Xaa 20 25 30
Xaa Ser Asn 35
<210> 99
<211> 362
<212> DNA
<213> Conus consors
<400> 99 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgctcc tgacggcctg tcaactcctc 60 acagctgatg actccagagg tacgcagaag catcgtgccc tgaagtctta caccaaactc 120 tccatgttaa ctttgcgctg cgcatcttac ggaaaacctt gtggtattga caacgactgc 180 tgcaatacat gcgatccagc cagaaagaca tgtacgtagc tgatccggcg tctgatcttc 240 ccccttctgt gctctatcct tttctgcctg agtcctcctt acctgagagt ggtcatgaac 300 cactcatcac ctagctcctc tggaggcttc agaggagcta caatgaaata aaagcgcatt 360 gc 362
<210> 100
<211> 72
<212> PRT
<213> Conus consors
<400> 100 31
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala 1 5 10 15
Cys Gin Leu Leu Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Lys Ser Tyr Thr Lys Leu Ser Met Leu Thr Leu Arg Cys Ala 35 40 45
Ser Tyr Gly Lys Pro Cys Gly He Asp Asn Asp Cys Cys Asn Thr Cys 50 55 60
Asp Pro Ala Arg Lys Thr Cys Thr 65 70
<210> 101
<211> 26
<212> PRT
<213> Conus consors
<220>
<221> PEPTIDE <222> (1) .. (26)
<223> Xaa at residue 7 and 20 is Pro or Hyp; Xaa at residue 4 is Tyr, 1 251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 101
Cys Ala Ser Xaa Gly Lys Xaa Cys Gly He Asp Asn Asp Cys Cys Asn
1 5 10 15
Thr Cys Asp Xaa Ala Arg Lys Thr Cys Thr 20 25
<210> 102
<211> 237
<212> DNA
<213> Conus consors
<400> 102 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgctcc tgacggcctg tcaactcctc 60 acagctgatg actccagagg tacgcagaag catcgtgccc tgaggtcgga caccaaactc 120 tccatgtcga ctcgctgcaa gggtacagga aaaccatgca gtaggattgc gtataactgc 180 tgcaccggtt cttgcagatc aggtaaatgt ggctgatcca gcgcctgatc tcccccc 237
<210> 103
<211> 71
<212> PRT
<213> Conus consors
<400> 103
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu Leu Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Ser Met Ser Thr Arg Cys Lys Gly ' 35 40 45
Thr Gly Lys Pro Cys Ser Arg He Ala Tyr Asn Cys Cys Thr Gly Ser 50 55 60 32
Cys Arg Ser Gly Lys Cys Gly 65 70
<210> 104
<211> 25
<212> PRT
<213> Conus consors
<220>
<221> PEPTIDE <222> (1)..(25)
<223> Xaa at residue 7 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Ty r, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 104
Cys Lys Gly Arg Gly Lys Xaa Cys Ser Arg He Ala Xaa Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 105
<211> 320
<212> DNA
<213> Conus consors
<400> 105 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgctcc tgacggcctg tcaactcatc 60 acagctgatg actccaaagg tacgcagaag catcgttccc tgaggtcgac caccaaagtc 120 tccaaggcga ctgactgcat tgaagccgga aattattgcg gacctactgt tatgaaaatc 180 tgctgcggct tttgcagtcc atacagcaaa atatgtatga actatcccca aaattgatct 240 tcccccttct gtgctctatc cttttctgcc tgagtcctcc ttacctgaga gtggtcatga 300 accactcatc acctcgtccc 320
<210> 106
<211> 78
<212> PRT
<213> Conus consors
<400> 106
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Lys Gly Thr Gin Lys His Arg 20 25 30
Ser Leu Arg Ser Thr Thr Lys Val Ser Lys Ala Thr Asp Cys He Glu 35 40 45
Ala Gly Asn Tyr Cys Gly Pro Thr Val Met Lys He Cys Cys Gly Phe 50 55 60
Cys Ser Pro Tyr Ser Lys He Cys Met Asn Tyr Pro Gin Asn 65 70 ' 75
<210> 107
<211> 36
<212> PRT
<213> Conus consors 33
<220>
<221> PEPTIDE
<222> (1) .. (36)
<223> Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 13, 25 and 34 is Pro or Hyp; Xaa at residue 10, 26 and 33 is Tyr, 125 I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 107
Ala Thr Asp Cys He Xaa Ala Gly Asn Xaa Cys Gly Xaa Thr Val Met
1 5 10 15
Lys He Cys Cys Gly Phe Cys Ser Xaa Xaa Ser Lys He Cys Met Asn 20 25 30
Xaa Xaa Gin Asn 35
<210> 108
<211> 321
<212> DNA
<213> Conus consors
<400> 108 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgctcc tgacggcctg tcaactcctc 60 acagctgatg actccagagg tacgcagaag catcgtgccc tgaggtcgga caccaaactc 120 tccatgtcga ctcgctgcaa aggtaaagga gcatcatgta caaggcttat gtatgactgc 180 tgccacggtt cttgcagcag cagcaagggt agatgtggct gatccggcgc ctgatcttcc 240 cccttctgtg ctctatcctt ttctgcctga gtcctcctta cctgagaggt ggtcatgaac 300 cactcatcac ctgctcccct g 321
<210> 109
<211> 73
<212> PRT
<213> Conus consors
<400> 109
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu Leu Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Ser Met Ser Thr Arg Cys Lys Gly 35 40 45
Lys Gly Ala Ser Cys Thr Arg Leu Met Tyr Asp Cys Cys His Gly Ser 50 55 60
Cys Ser Ser Ser Lys Gly Arg Cys Gly 65 70
<210> 110
<211> 27
<212> PRT
<213> Conus consors
<220>
<221> PEPTIDE 34
<222> (1) .. (27)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, 0 -sulpho-Tyr or O-phospho-Ty
<400> 110
Cys Lys Gly Lys Gly Ala Ser Cys Thr Arg Leu Met Xaa Asp Cys Cys
1 5 10 15
His Gly Ser Cys Ser Ser Ser Lys Gly Arg Cys 20 25
<210> 111
<211> 292
<212> DNA
<213> Conus consors
<400> 111 ggatccatga aactgacgtg catggtgatc gtcgccgtgc tgctcctgac .-ggcctgtcaa 60 ctcatcacag ctgatgactc cagaggtacg cagaagcatc gtgccctgag gtcggacacc 120 aaactctcca tgtcaactcg ctgcaagggt aaaggagcat catgtcatag gacttcgtat 180 gactgctgca ccggttcttg caacagaggt aaatgtggct gatccggcgc ctgatcttcc 240 cccttctgtg ctctatcctt ttctgcctga gtcatccata cctgtgctcg ag 292
<210> 112
<211> 71
<212> PRT
<213> Conus consors
<400> 112
Met Lys Leu Thr Cys Met Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Ser Met Ser Thr Arg Cys Lys Gly 35 40 45
Lys Gly Ala Ser Cys His Arg Thr Ser Tyr Asp Cys Cys Thr Gly Ser 50 55 60
Cys Asn Arg Gly Lys Cys Gly 65 70
<210> 113
<211> 25
<212> PRT
<213> Conus consors
<220>
<221> PEPTIDE <222> (1)..(25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 113
Cys Lys Gly Lys Gly Ala Ser Cys His Arg Thr Ser Xaa Asp Cys Cys
1 5 10 15
Thr Gly Ser Cys Asn Arg Gly Lys Cys 20 25 35
<210> 114
<211> 299
<212> DNA
<213> Conus consors
<400> 114 ggatccatga aactgacgtg cgtggtgatc gtcgccgtgc tgctcctgac ggcctgtcaa 60 ctcatcacag ctgatgactc cagaggtacg cagaagcatc gtgccctgaa gtcggacacc 120 aaactctcca tgttaacttt gcgctgcgca tcttacggaa aaccttgtgg tatttacaac 180 gactgctgca atacatgcga tccagccaga aagacatgta cgtagctgat ccggcgtctg 240 atcttccccc ttctgtgctc tatccttttc tgcctgagtc atccatacct gtgctcgag 299
<210> 115
<211> 72
<212> PRT
<213> Conus consors
<400> 115
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Lys Ser Asp Thr Lys Leu Ser Met Leu Thr Leu Arg Cys Ala 35 40 45
Ser Tyr Gly Lys Pro Cys Gly He Tyr Asn Asp Cys Cys Asn Thr Cys 50 55 60
Asp Pro Ala Arg Lys Thr Cys Thr 65 70
<210> 116
<211> 26
<212> PRT
<213> Conus consors
<220>
<221> PEPTIDE <222> (1) .. (26)
<223> Xaa at residue 7 and 20 is Pro or Hyp; Xaa at residue 4 and 11 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-pho spho-Ty
<400> 116
Cys Ala Ser Xaa Gly Lys Xaa Cys Gly He Xaa Asn Asp Cys Cys Asn
1 5 10 15
Thr Cys Asp Xaa Ala Arg Lys Thr Cys Thr 20 25
<210> 117
<211> 434
<212> DNA
<213> Conus consors
<220>
<221> isc feature 36
<222> (1)..(434)
<223> n may be any nucleotide
<400> 117 ggatccatga aactgacgtg tgtggtgatc gtcgccgtgc tgctcctgac ggcctgtcaa 60 ctcatcacag ctgatgactc cagaggtacg cagaagcatc gtgccctgag gtcggacacc 120 aaactctcca tgtcgactcg ctgcaagggt acaggaaaac catgcagtag ggttgcgtat 180 aactgctgca ccggttcttg cagatcaggt aaatgtggct gatccagtgc ctgatcttcc 240 cccttctgtg ctctatcctt ttctgcctga gtcctcctta cctgagagtg gtcatgaacc 300 actcatcacc tgctcctctg gaggcttcag aggagctaca ttgaaataaa agccgcattg 360 cantgnanaa aannnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnggaaaaaa 420 aaaaaaaaaa aaaa 434
<210> 118
<211> 71
<212> PRT
<213> Conus consors
<400> 118
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Ser Met Ser Thr Arg Cys Lys Gly 35 40 45
Thr Gly Lys Pro Cys Ser Arg Val Ala Tyr Asn Cys Cys Thr Gly Ser 50 55 60
Cys Arg Ser Gly Lys Cys Gly 65 70
<210> 119
<211> 25
<212> PRT
<213> Conus consors
<220>
<221> PEPTIDE <222> (1)..(25)
<223> Xaa at residue 7 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Ty r, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 119
Cys Lys Gly Thr Gly Lys Xaa Cys Ser Arg Val Ala Xaa Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 120
<211> 393
<212> DNA
<213> Conus consors
<400> 120 37 ggatccatga aactgacgtg catggtgatc gtcgccgtgc tgctcctgac ggcctgtcaa 60 ctcatcacag ctgatgactc cagaggtacg cagaagcatc gttccctgag gtcgaccacc 120 aaagtctcca agtcgactag ctgcatgaaa gccgggtctt attgccgctc tactacgaga 180 acctgctgcg gttattgcgc ttatttcggc aaattttgta ttgactttcc cagcaactga 240 tcttccccct actgtgctct atccttttct gcctctgcct gagtcctcct tacctgagag 300 tggtcatgaa ccactcatca cctgctcccc tggaggcctc agaggagcta caatgaaata 360 aaagccgcat tgcaaaaaaa aaaaaaaaaa aaa 393
<210> 121
<211> 77
<212> PRT
<213> Conus consors
<400> 121
Met Lys Leu Thr Cys Met Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ser Leu Arg Ser Thr Thr Lys Val Ser Lys Ser Thr Ser Cys Met Lys 35 40 45
Ala Gly Ser Tyr Cys Arg Ser Thr Thr Arg Thr Cys Cys Gly Tyr Cys 50 55 60
Ala Tyr Phe Gly Lys Phe Cys He Asp Phe Pro Ser Asn 65 70 75
<210> 122
<211> 35
<212> PRT
<213> Conus consors
<220>
<221> PEPTIDE
<222> (1)..(35)
<223> Xaa at residue 33 is Pro or Hyp; Xaa at residue 10, 21 and 24 is
Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phos pho-Ty
<400> 122
Ser Thr Ser Cys Met Lys Ala Gly Ser Xaa Cys Arg Ser Thr Thr Arg
1 5 10 15
Thr Cys Cys Gly Xaa Cys Ala Xaa Phe Gly Lys Phe Cys He Asp Phe 20 25 30
Xaa Ser Asn 35
<210> 123
<211> 361
<212> DNA
<213> Conus dalli
<400> 123 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgttcctg 60 38 acggcctgtc aactcatcac agctgatgac tccagaagta cgcagaagca tcgtgctσtg 120 aggtcgacca tcaaacactc catgttgact aggagctgca cgcctcccgg aggaccttgt 180 ggttattata atgactgctg cagtcatcaa tgcaatataa gcagaaataa atgcgagtag 240 ctgatccggc atctgatctt ccccttctgt gctcgtccta acctgagagt ggtcatgaac 300 catcatcacc tactcctctg gaggcttcag aggagctaca tggaaataaa agccgcattg 360 c 361
<210> 124
<211> 73
<212> PRT
<213> Conus dalli
<400> 124
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Ser Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr He Lys His Ser Met Leu Thr Arg Ser Cys Thr 35 40 45
Pro Pro Gly Gly Pro Cys Gly Tyr Tyr Asn Asp Cys Cys Ser His Gin 50 55 60
Cys Asn He Ser Arg Asn Lys Cys Glu 65 70
<210> 125
<211> 28
<212> PRT
<213> Conus dalli
<220>
<221> PEPTIDE <222> (1)..(28)
<223> Xaa at residue 28 is Glu or gamma-carboxy Glu; Xaa at residue 4, 5 and 8 is Pro or Hyp; Xaa at residue 11 and 12 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 125
Ser Cys Thr Xaa Xaa Gly Gly Xaa Cys Gly Xaa Xaa Asn Asp Cys Cys
1 5 10 15
Ser His Gin Cys Asn He Ser Arg Asn Lys Cys Xaa 20 25
<210> 126
<211> 350
<212> DNA
<213> Conus distans
<400> 126 accaaaacca tcatcaaaat gaaactgacg tgcgtgttga tcatcgccgt gctgttcctg 60 acggcctgtc aactcactag aggaaagctg gagcgtcctg ttctgaggtc gagcgaccaa 120 acctccgggt caacgaagag atgcgaagat cctggtgaac cttgcggaag tgatcattcc 180 tgctgcggcg gtagttgcaa ccacaacgtc tgcgcctgaa gctggtctgg catctgacca 240 39
ttccccttct gtactctatc tctattgcct gagtcatctt tacctgtgag tggtcatgaa 300 tctctcaata ccttctcccc tggaggcttc agaagaacta gattgaaata 350
<210> 127
<211> 66
<212> PRT
<213> Conus distans
<400> 127
Met Lys Leu Thr Cys Val Leu He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu Thr Arg Gly Lys Leu Glu Arg Pro Val Leu Arg Ser Ser 20 25 30
Asp Gin Thr Ser Gly Ser Thr Lys Arg Cys Glu Asp Pro Gly Glu Pro 35 40 45
Cys Gly Ser Asp His Ser Cys Cys Gly Gly Ser Cys Asn His Asn Val 50 55 60
Cys Ala 65
<210> 128
<211> 25
<212> PRT
<213> Conus distans
<220>
<221> PEPTIDE <222> (1) .. (25)
<223> Xaa at residue 2 and 6 is Glu or gamma-carboxy Glu; Xaa at residu e 4 and 7 is Pro or Hy
<400> 128
Cys Xaa Asp Xaa Gly Xaa Xaa Cys Gly Ser Asp His Ser Cys Cys Gly
1 5 10 15
Gly Ser Cys Asn His Asn Val Cys Ala 20 25
<210> 129
<211> 309
<212> DNA
<213> Conus ermineus
<400> 129 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgctcc tgacggcctg tcaactcatc 60 acagctgacg actccagacg tacgcagaag catcgtgccc tgaggtcgac caccaaacgc 120 gccacgtcga atcgcccctg caagσcgaaa ggacgaaaat gttttccgca tcagaaggac 180 tgctgcaata aaacgtgcac cagatcaaaa tgtccctgat cttccccctt ctgtgctgta 240 tccttttctg cctgagtcct ccttacctga gagtggtcag taaccactca tcaccatctc 300 ctctggagg 309
<210> 130 <211> 72 <212> PRT 40
<213> Conus ermineus
<400> 130
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Arg Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys Arg Ala Thr Ser Asn Arg Pro Cys Lys 35 40 45
Pro Lys Gly Arg Lys Cys Phe Pro His Gin Lys Asp Cys Cys Asn Lys 50 55 60
Thr Cys Thr Arg Ser Lys Cys Pro 65 70
<210> 131
<211> 27
<212> PRT
<213> Conus ermineus
<220>
<221> PEPTIDE
<222> (1)..(27)
<223> Xaa at residue 1, 4, 11 and 27 is Pro or Hyp
<400> 131
Xaa Xaa Lys Xaa Lys Gly Arg Lys Cys Phe Xaa His Gin Lys Asp Cys
1 5 10 15
Cys Asn Lys Thr Cys Thr Arg Ser Lys Cys Xaa 20 25
<210> 132
<211> 308
<212> DNA
<213> Conus ermineus
<400> 132 aactcatcac agctgatgac tccagaggta cgcagaacga tcgtgccctg aggtcgacca 60 ccaaactctc catgctgact cgggcctgct ggtcttccgg aacaccttgt ggtactgata 120 gtttatgctg cggtggatgc aatgtatcca aaagtaaatg taactagctg attcggcgtc 180 tgaacttccc ccttctgtgc tctatccttt tctgcccgag tcctccatac ctgagaatgg 240 tcatgaacca ctcatcacct actcctctgg agacctcaga agagctacac tgaaataaaa 300 gcgcttgc 308
<210> 133
<211> 54
<212> PRT
<213> Conus ermineus
<400> 133
Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Asn Asp Arg Ala Leu
1 5 10 15
Arg Ser Thr Thr Lys Leu Ser Met Leu Thr Arg Ala Cys Trp Ser Ser 20 25 30 41
Gly Thr Pro Cys Gly Thr Asp Ser Leu Cys Cys Gly Gly Cys Asn Val 35 40 45
Ser Lys Ser Lys Cys Asn 50
<210> 134
<211> 27
<212> PRT
<213> Conus ermineus
<220>
<221> PEPTIDE <222> (1)..(27)
<223> Xaa at 8 residue is Pro or Hyp; Xaa at residue 3 is Trp or Bromo Tr
<400> 134
Ala Cys Xaa Ser Ser Gly Thr Xaa Cys Gly Thr Asp Ser Leu Cys Cys
1 5 10 15
Gly Gly Cys Asn Val Ser Lys Ser Lys Cys Asn 20 25
<210> 135
<211> 385
<212> DNA
<213> Conus geographus
<400> 135 ggatccatga aactgacgtg cgtggtgatc gtcgccgtgc tgctcctgac ggcctgtcaa 60 ctcatcacag ctgatgactc cagaggtacg cagaagcatc gtgccctggg gtcgaccacc 120 gaactctcct tgtcgactcg ctgcaagtca cccggatctt catgttcacc gactagttat 180 aattgctgca ggtcttgcaa tccatacgcc aaaagatgtt acggctaatc cagcgcctga 240 tcttccccct tctgtgctct atcccttcct gtctgagtcc tccttacctg agagtggtca 300 tgaaccactc ctcacctact tctctggagg cttcggagga gctacattga aataaaagcc 360 gcattgtaaa aaaaaaaaaa aaaaa 385
<210> 136
<211> 73
<212> PRT
<213> Conus geographus
<400> 136
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Gly Ser Thr Thr Glu Leu Ser Leu Ser Thr Arg Cys Lys Ser 35 40 45
Pro Gly Ser Ser Cys Ser Pro Thr Ser Tyr Asn Cys Cys Arg Ser Cys 50 55 60
Asn Pro Tyr Ala Lys Arg Cys Tyr Gly 65 70 42
<210> 137
<211> 27
<212> PRT
<213> Conus geographus
<220>
<221> PEPTIDE <222> (1)..(27)
<223> Xaa at residue 4, 10 and 21 is Pro or Hyp; Xaa at residue 13, 22 and 27 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 137
Cys Lys Ser Xaa Gly Ser Ser Cys Ser Xaa Thr Ser Xaa Asn Cys Cys
1 5 10 15
Arg Ser Cys Asn Xaa Xaa Ala Lys Arg Cys Xaa 20 25
<210> 138
<211> 396
<212> DNA
<213> Conus geographus
<400> 138 ggatccatga aactgacgtg tgtggtgatc gtcgccgtgc tgctcctgac ggcctgtcaa 60 ctcatcacag ctgatgactc cagaggtacg cagaagcatc gtgccctgag gtcgtccacc 120 aaactcacct tgtcgactcg ctgcaaatca cccggaactc catgttcaag gggtatgcgt 180 gattgctgca cgccttgctt gttatacagc aacaaatgta ggcgctacta acccagcgcc 240 tgatcttccc ccttctgtgc tctattcctt tctgcctgag tcctccttac ctgaaagtgg 300 tcatgaacca ctcatcacct acttctctgg aggcttcaga agagctacat tgaaataaaa 360 gccgcattgc aatgacaaaa aaaaaaaaaa aaaaaa 396
<210> 139
<211> 74
<212> PRT
<213> Conus geographus
<400> 139
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Ser Thr Lys Leu Thr Leu Ser Thr Arg Cys Lys Ser 35 40 45
Pro Gly Thr Pro Cys Ser Arg Gly Met Arg Asp Cys Cys Thr Pro Cys 50 55 60
Leu Leu Tyr Ser Asn Lys Cys Arg Arg Tyr 65 70
<210> 140
<211> 29
<212> PRT
<213> Conus geographus 43
<220>
<221> PEPTIDE
<222> (1) .. (29)
<223> Xaa at residue 4, 7 and 18 is Pro or Hyp; Xaa at residue 22 and 2
9 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or 0
-phospho-Ty
<400> 140
Cys Lys Ser Xaa Gly Thr Xaa Cys Ser Arg Gly Met Arg Asp Cys Cys
1 5 10 15
Thr Xaa Cys Leu Leu Xaa Ser Asn Lys Cys Arg Arg Xaa 20 25
<210> 141
<211> -407
<212> DNA
<213> Conus geographus
<400> 141 . ggaattccgt ttctgcgctg cttcctttgg catcaccaaa accatcatca aaatgaaact 60 gacgtgtgtg gtgatcgtcg ccgtgctgct cctgacggcc tgtcaactca tcacagctga 120 tgactccaga ggtacgcaga agcatcgtgc cctggggtcg accaccgaac tctccttgtc 180 gactcgctgc aagtcacccg gatcttcatg ttcaccgact agttataatt gctgcaggtc 240 ttgcaatcca tacaccaaaa gatgttacgg ctaatccagc gcctgatctt ccctgctctg 300 agtcctcctt acctgagagt ggtcatgaac cactcatcac ctaαttctct aggcggttcg 360 gaggagctac attgaaataa aagccgcatt gcaaaaaaaa aaaaaaa 407
<210> 142
<211> 73
<212> PRT
<213> Conus geographus
<400> 142
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Gly Ser Thr Thr Glu Leu Ser Leu Ser Thr Arg Cys Lys Ser 35 40 45
Pro Gly Ser Ser Cys Ser Pro Thr Ser Tyr Asn Cys Cys Arg Ser Cys 50 55 60
Asn Pro Tyr Thr Lys Arg Cys Tyr Gly 65 70
<210> 143
<211> 27
<212> PRT
<213> Conus geographus
<220>
<221> PEPTIDE <222> (1)..(27)
<223> Xaa at residue 4, 10 and 21 is Pro or Hyp; Xaa at residue 13, 22 and 27 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr 44 or O-phospho-Ty
<400> 143
Cys Lys Ser Xaa Gly Ser Ser Cys Ser Xaa Thr Ser Xaa Asn Cys Cys
1 5 10 15
Arg Ser Cys Asn Xaa Xaa Thr Lys Arg Cys Xaa 20 25
<210> 144
<211> 28
<212> PRT
<213> Conus geographus
<220>
<221> PEPTIDE <222> (1)..(28)
<223> Xaa at residue 4, 10 and 21 is Pro or Hyp; Xaa at residue 13, 22 and 27 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 144
Cys Lys Ser Xaa Gly Ser Ser Cys Ser Xaa Thr Ser Xaa Asn Cys Cys
1 5 10 15
Arg Ser Cys Asn Xaa Xaa Thr Lys Arg Cys Xaa Gly 20 25
<210> 145
<211> 26
<212> PRT
<213> Conus geographus
<220>
<221> PEPTIDE
<222> (1) .. (26)
<223> Xaa at residue 4, 10 and 21 is Pro or Hyp; Xaa at residue 13 and
22 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or
O-phospho-Ty
<400> 145
Cys Lys Ser Xaa Gly Ser Ser Cys Ser Xaa Thr Ser Xaa Asn Cys Cys
1 5 10 15
Arg Ser Cys Asn Xaa Xaa Thr Lys Arg Cys 20 25
<210> 146
<211> 314
<212> DNA
<213> Conus geographus
<400> 146 catcacagct gatgactcca gaggtacgca gaagcatcgt gccctgaggt cgtccaccaa 60 actcaccttg tcgactcgct gcaaatcacc cggaactcca tgttcaaggg gtatgcgtga 120 ttgctgcacg tcttgcttgt tatacagcaa caaatgtagg cgctactaac ccagcgcctg 180 atcttccccc ttctgtgctc tattcctttc tgcctgagtc ctccttacct gaaagtggtc 240 atgaaccact catcacctac ttctctggag gcttcagaag agctacattg aaataaaagc 300 cgcattgcaa tgac 314 45
<210> 147
<211> 55
<212> PRT
<213> Conus geographus
<400> 147
He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg Ala Leu Arg
1 5 10 15
Ser Ser Thr Lys Leu Thr Leu Ser Thr Arg Cys Lys Ser Pro Gly Thr 20 25 30
Pro Cys Ser Arg Gly Met Arg Asp Cys Cys Thr Ser Cys Leu Leu Tyr 35 40 45
Ser Asn Lys Cys Arg Arg Tyr 50 55
<210> 148
<211> 29
<212> PRT
<213> Conus geographus
<220>
<221> PEPTIDE <222> (1)..(29)
<223> Xaa at residue 4 and 7 is Pro or Hyp; Xaa at residue 22 and 29 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-pho spho-Ty
<400> 148
Cys Lys Ser Xaa Gly Thr Xaa Cys Ser Arg Gly Met Arg Asp Cys Cys
1 5 10 15
Thr Ser Cys Leu Leu Xaa Ser Asn Lys Cys Arg Arg Xaa 20 25
<210> 149
<211> 29
<212> PRT
<213> Conus geographus
<220>
<221> PEPTIDE <222> (1) .. (29)
<223> Xaa at residue 4 and 7 is Pro or Hyp; Xaa at residue 22 and 29 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-pho spho-Ty
<400> 149
Cys Lys Ser Xaa Gly Thr Xaa Cys Ser Arg Gly Met Arg Asp Cys Cys
1 5 10 15
Thr Ser Cys Leu Ser Xaa Ser Asn Lys Cys Arg Arg Xaa 20 25
<210> 150
<211> 380
<212> DNA
<213> Conus laterculatus
<400> 150 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac cgctgatgac tccagaggta cgcagaagca tcgtgccctg 120 46
aggtcgacca ccaatctctc catgctgact cggaagtgct ggccttccgg aagctattgt 180 cgtgcgaata gtaaatgctg cagtggatgc gatcggaaca gaaataaatg ttactagctg 240 attcggcgtc tgaacttcct ccttctgtgc tctatccttt tctgcccgag tcctccatac 300 ctgagagtgg tcatgaacca ctcaactcct actcctctgg aggcctcaga agagctacat 360 tgaaataaaa gccgcattgc 380
<210> 151
<211> 72
<212> PRT
<213> Conus laterculatus
<400> 151
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Asn Leu Ser Met Leu Thr Arg Lys Cys Trp 35 40 45
Pro Ser Gly Ser Tyr Cys Arg Ala Asn Ser Lys Cys Cys Ser Gly Cys 50 55 60
Asp Arg Asn Arg Asn Lys Cys Tyr 65 70
<210> 152
<211> 27
<212> PRT
<213> Conus laterculatus
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa at residue 4 is Pro or Hyp; Xaa at residue 3 is Trp or Bromo Trp; Xaa at residue 8 and 27 is Tyr, 1251-Tyr, mono-iodo-Tyr, di- iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 152
Lys Cys Xaa Xaa Ser Gly Ser Xaa Cys Arg Ala Asn Ser Lys Cys Cys
1 5 10 15
Ser Gly Cys Asp Arg Asn Arg Asn Lys Cys Xaa 20 25
<210> 153
<211> 367
<212> DNA
<213> Conus laterculatus
<400> 153 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcgacca ccaaactctc catatcgact cgctgccttc ctcccggatc atattgtaag 180 gcgacaacgg aagtctgctg ctcttcttgc cttcaattcg ctcagatatg ttcgggttga 240 47 tcttccctct tctgtgctct atccttttct gcctgagtcc tccatacctg agaatggtca 300 tgaaccactc aacatctact cctctggagg cctcagaaga gctatattga aataaaagcc 360 gcattgc 367
<210> 154
<211> 73
<212> PRT
<213> Conus laterculatus
<400> 154
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys Leu Ser He Ser Thr Arg Cys Leu Pro 35 40 45
Pro Gly Ser Tyr Cys Lys Ala Thr Thr Glu Val Cys Cys Ser Ser Cys 50 55 60
Leu Gin Phe Ala Gin He Cys Ser Gly 65 70
<210> 155
<211> 27
<212> PRT
<213> Conus laterculatus
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa at residue 13 is Glu or gamma-carboxy Glu; Xaa at residue 3 a nd 4 is Pro or Hyp; Xaa at residue 7 is Tyr, 1251-Tyr, mono-iodo- Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 155
Cys Leu Xaa Xaa Gly Ser Xaa Cys Lys Ala Thr Thr Xaa Val Cys Cys
1 5 10 15
Ser Ser Cys Leu Gin Phe Ala Gin He Cys Ser 20 25
<210> 156
<211> 373
<212> DNA
<213> Conus laterculatus
<400> 156 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcgacca ccaatctctc catgtcgact cgctgcaagt ctcccggatc atcatgtagc 180 gtgtctatgc gtaactgctg cacttcttgc aattcacgca ccaagaaatg tacgcgacgt 240 ggctgaactt cccccttctg tgctctatcc ttttctgccc gagtcctcca tacctgagag 300 tggtcatgaa ccactcaaca tctactcctc tggaggcctc agaagagcta tattgaaata 360 aaagccgcat tgc 373 48
<210> 157
<211> 75
<212> PRT
<213> 'Conus laterculatus
<400> 157
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Asn Leu Ser Met Ser Thr Arg Cys Lys Ser 35 40 45
Pro Gly Ser Ser Cys Ser Val Ser Met Arg Asn Cys Cys Thr Ser Cys 50 55 60
Asn Ser Arg Thr Lys Lys Cys Thr Arg Arg Gly 65 70 75
<210> 158
<211> 29
<212> PRT
<213> Conus laterculatus
<220>
<221> PEPTIDE
<222> (1) .. (29)
<223> Xaa at residue 3 is Pro or Hyp
<400> 158
Cys Lys Ser Xaa Gly Ser Ser Cys Ser Val Ser Met Arg Asn Cys Cys
1 5 10 15
Thr Ser Cys Asn Ser Arg Thr Lys Lys Cys Thr Arg Arg 20 25
<210> 159
<211> 330
<212> DNA
<213> Conus laterculatus
<400> 159 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcgacaa ccaaactctc catgctgact cggacctgct ggccttccgg aacagcttgt 180 ggtattgata gtaactgctg cagtggatgc aatgtatcca gaagtaaatg taactagctg 240 attcggcgtc taaacttcct ccttctgcct gagtcctcca tacctgagag tggtcatgaa 300 ccacatcatc acctcatctc tggaggcctc 330
<210> 160
<211> 72
<212> PRT
<213> Conus laterculatus
<400> 160
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15 49
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys Leu Ser Met Leu Thr Arg Thr Cys Trp 35 40 45
Pro Ser Gly Thr Ala Cys Gly He Asp Ser Asn Cys Cys Ser Gly Cys 50 55 60
Asn Val Ser Arg Ser Lys Cys Asn 65 70
<210> 161
<211> 27
<212> PRT
<213> Conus laterculatus
<220>
<221> PEPTIDE <222> (1) .. (27)
<223> Xaa at residue 4 is Pro or Hyp; Xaa at residue 3 is Trp or Bromo Tr
<400> 161
Thr Cys Xaa Xaa Ser Gly Thr Ala Cys Gly He Asp Ser Asn Cys Cys
1 5 10 15
Ser Gly Cys Asn Val Ser Arg Ser Lys Cys Asn 20 25
<210> 162
<211> 363
<212> DNA
<213> Conus laterculatus
<400> 162 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcgacca ccaatctctc catgctgact cggaagtgct ggccttccgg aagctattgt 180 cgtgcgaata gtaaatgctg cagtggatgc gatcggaaca gaagtaaatg taactagctg 240 attcggcgtc taaacttcct ccttctgcct gagtcctcca tacctgagag tggtcatgaa 300 ccactcatca cctactcctc tggaggcctc aaaggagcta cattgaaata aaagccgcat 360 tgc 363
<210> 163
<211> 72 '
<212> PRT
<213> Conus laterculatus
<400> 163
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Asn Leu Ser Met Leu Thr Arg Lys Cys Trp 35 40 45 50
Pro Ser Gly Ser Tyr Cys Arg Ala Asn Ser Lys Cys Cys Ser Gly Cys 50 55 60
Asp Arg Asn Arg Ser Lys Cys Asn 65 70
<210> 164
<211> 27
<212> PRT
<213> Conus laterculatus
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa at residue4 is Pro or Hyp; Xaa at residue 3 is Trp or Bromo
Trp; Xaa at residue 8 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Ty r, O-sulpho-Tyr or O-phospho-Ty
<400> 164
Lys Cys Xaa Xaa Ser Gly Ser Xaa Cys Arg Ala Asn Ser Lys Cys Cys
1 5 10 15
Ser Gly Cys Asp Arg Asn Arg Ser Lys Cys Asn 20 25
<210> 165
<211> 391
<212> DNA
<213> Conus leopardus
<220>
<221> misc_feature
<222> (1) .. (391)
<223> n may be any nucleotide
<400> 165 atgaaactga cgtgtgtggt gatcgtagct gtgctgttcc tgacggcctg tcaactcact 60 acagctgaca tctccagagg tacgcggaag cgtcgtgctc tgaggtcgac caccaaactc 120 tccaggtcgc tctttgagtg cgcgccttcc ggtggacgtt gtggtttttt aaagtcctgc 180 tgcgaaggat attgcgatgg ggaaagcact tcatgtgtga gtggcccata cagcatctga 240 tcttcccgcc ttcagtgctc tatccttttc tgcctgagtc ctccatacct ctgagcggtc 300 atgaaccact caacacctac tcctctggag gcttcaggga actatattaa aataaagccg 360 cattgcaacg aaanaaaaaa aaaaaaaaaa a 391
<210> 166
<211> 79
<212> PRT
<213> Conus leopardus
<400> 166
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu Thr Thr Ala Asp He Ser Arg Gly Thr Arg Lys Arg Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys Leu Ser Arg Ser Leu Phe Glu Cys Ala 35 40 45 51
Pro Ser Gly Gly Arg Cys Gly Phe Leu Lys Ser Cys Cys Glu Gly Tyr 50 55 60
Cys Asp Gly Glu Ser Thr Ser Cys Val Ser Gly Pro Tyr Ser He 65 70 75
<210> 167
<211> 37
<212> PRT
<213> Conus leopardus
<220>
<221> PEPTIDE
<222> (1) .. (37)
<223> Xaa at residue 4, 20 and 26 is Glu or gamma-carboxy Glu; Xaa at r esidue 7 and 34 is Pro or Hyp; Xaa at residue 22 and 35 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-T y
<400> 167
Ser Leu Phe Xaa Cys Ala Xaa Ser Gly Gly Arg Cys Gly Phe Leu Lys
1 5 10 15
Ser Cys Cys Xaa Gly Xaa Cys Asp Gly Xaa Ser Thr Ser Cys Val Ser 20 25 30
Gly Xaa Xaa Ser He 35
<210> 168
<211> 365
<212> DNA
<213> Conus leopardus
<400> 168 atgaaactga cgtgtgtggt gatcgtcgct gtgctgttcc tgacggcctg tcaactcact 60 acagctgaca tctccagagg tacgtggaag catcgtggtg tggggtcgac caccggactc 120 tccccgtggc ccttggactg cacggctccc agtcaacctt gtggttattt tcctaggtgc 180 tgtggacatt gcgatgtacg cagggtatgt acgagtggct gatccggcgt ctgatctttc 240 cgccttctgt gctgtatcct tttctgcctg agtcctccat acccgtgagt ggtcatgaac 300 cactcaacac ctactcctct ggaggcttca gaggaactat attaaaataa agccgcattg 360 caatg 365
<210> 169
<211> 73
<212> PRT
<213> Conus leopardus
<400> 169
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu Thr Thr Ala Asp He Ser Arg Gly Thr Trp Lys His Arg 20 25 30
Gly Val Gly Ser Thr Thr Gly Leu Ser Pro Trp Pro Leu Asp Cys Thr 35 40 45 52
Ala Pro Ser Gin Pro Cys Gly Tyr Phe Pro Arg Cys Cys Gly His Cys 50 55 60
Asp Val Arg Arg Val Cys Thr Ser Gly 65 70
<210> 170
<211> 30
<212> PRT
<213> Conus leopardus
<220>
<221> PEPTIDE <222> (1) .. (30)
<223> Xaa at residue 2, 8, 11 and 16 is Pro or Hyp; Xaa at residue 1 is Trp or Bromo Trp; Xaa at residue 14 is Tyr, 1251-Tyr, mono-iodo- Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 170
Xaa Xaa Leu Asp Cys Thr Ala Xaa Ser Gin Xaa Cys Gly Xaa Phe Xaa
1 5 10 15
Arg Cys Cys Gly His Cys Asp Val Arg Arg Val Cys Thr Ser 20 25 ' 30
<210> 171
<211> 381
<212> DNA
<213> Conus leopardus
<400> 171 atgaaactga cgtgtgtggt gatcgtcgct gtgctgttcc tgacggcctg tcaactcact 60 acagctgaca tctccagagg tacgcggaag catcgtgctc tgaggtcgac caccaaactc 120 tccaggtcgc cctctaggtg catgtctccc ggtggaattt gtggtgattt tggtgactgc 180 tgcgaaattt gcaatgtgta cggtatatgt gtgagtgact tacccggcat ctgatctttc 240 cgccttctgt gctctatcct tttctgcctg agtcctccat acccctgagt ggtcatggac 300 cactcaacac ctactcctct ggaggcttca gaggaactac attaaaataa agccgcattg 360 caaaaaaaaa aaaaaaaaaa a 381
<210> 172
<211> 77
<212> PRT
<213> Conus leopardus
<400> 172
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu Thr Thr Ala Asp He Ser Arg Gly Thr Arg Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys Leu Ser Arg Ser Pro Ser Arg Cys Met 35 40 45
Ser Pro Gly Gly He Cys Gly Asp Phe Gly Asp Cys Cys Glu He Cys 50 55 60
Asn Val Tyr Gly He Cys Val Ser Asp Leu Pro Gly He 65 70 75 53
<210> 173
<211> 31
<212> PRT
<213> Conus leopardus
<220>
<221> PEPTIDE
<222> (1)..(31)
<223> Xaa at residue 16 is Glu or gamma-carboxy Glu; Xaa at residue 4 a nd 29 is Pro or Hyp; Xaa at residue 21 is Tyr, 1251-Tyr, mono-iod o-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 173
Cys Met Ser Xaa Gly Gly He Cys Gly Asp Phe Gly Asp Cys Cys Xaa
1 5 10 15
He Cys Asn Val Xaa Gly He Cys Val Ser Asp Leu Xaa Gly He 20 25 30
<210> 174
<211> 404
<212> DNA
<213> Conus leopardus
<400> 174 atgaaactga cgtgtgtggt gatcgtcgct gtgctgttcc tgacggcctg tcaactcact 60 acagctgatg attccagagg tacacggaag catcgtgctc tgaggtcaac caccaaactc 120 tccaggtggc ccaggtactg cgcgcctccc ggtggagctt gtgggttttt tgatcactgc 180 tgcggatatt gcgaaacgtt ttacaatacg tgtagatgag ttggctgatc cggcgcttga 240 tctttccgcc ttctgttgct ctatcttttt ctgcctgagt cctcccatac cccgttgagt 300 ggtccatgaa ccactccaac acctactccc tccttggaag cttccaaagg aaacgacatt 360 taaaataaat tccccattgc aattggaaaa aaaaaaaaaa aaaa 404
<210> 175
<211> 72
<212> PRT
<213> Conus leopardus
<400> 175
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu Thr Thr Ala Asp Asp Ser Arg Gly Thr Arg Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys Leu Ser Arg Trp Pro Arg Tyr Cys Ala 35 40 45
Pro Pro Gly Gly Ala Cys Gly Phe Phe Asp His Cys Cys Gly Tyr Cys 50 55 60
Glu Thr Phe Tyr Asn Thr Cys Arg 65 70
<210> 176
<211> 27
<212> PRT
<213> Conus leopardus 54
<220>
<221> PEPTIDE <222> (1)..(27)
<223> Xaa at residue 20 is Glu or gamma-carboxy Glu; Xaa at residue 4 a nd 5 is Pro or Hyp; Xaa at residue 1, 18 and 23 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 176
Xaa Cys Ala Xaa Xaa Gly Gly Ala Cys Gly Phe Phe Asp His Cys Cys
1 5 10 15
Gly Xaa Cys Xaa Thr Phe Xaa Asn Thr Cys Arg 20 25
<210> 177
<211> 292
<212> DNA
<213> Conus lynceus
<400> 177 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgctcc tgacggcctg tcaactcatc 60 acagctgatg actccagacg tacacagaag catcgtgccc tgaggtcgac caccaatctc 120 tccatgtcga ctcgctgcaa gtctcccgga tcaccatgta gtgtgacatc gtataactgc 180 tgcacttttt gctcttcata cactaagaaa tgtcgggcct ctttatgaac cactcatcac 240 ctactcctct ggaggcctca gaagagctac actgaaataa aagccgcatt gg 292
<210> 178
<211> 75
<212> PRT
<213> Conus lynceus
<400> 178
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Arg Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Asn Leu Ser Met Ser Thr Arg Cys Lys Ser 35 40 45
Pro Gly Ser Pro Cys Ser Val Thr Ser Tyr Asn Cys Cys Thr Phe Cys 50 55 60
Ser Ser Tyr Thr Lys Lys Cys Arg Ala Ser Leu 65 70 75
<210> 179
<211> 30
<212> PRT
<213> Conus lynceus
<220>
<221> PEPTIDE <222> (1)..(30)
<223> Xaa at residue 4 and 7 is Pro or Hyp; Xaa at residue 13 and 22 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-pho spho-Ty
<400> 179
.55
Cys Lys Ser Xaa Gly Ser Xaa Cys Ser Val Thr Ser Xaa Asn Cys Cys 1 5 10 15
Thr Phe Cys Ser Ser Xaa Thr Lys Lys Cys Arg Ala Ser Leu 20 25 30
<210> 180
<211> 355
<212> DNA
<213> Conus lynceus
<400> 180 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgctcc tgacggcctg tcaactcatc 60 acagctgatg actccagagg tacgcagaag catcgtgccc tgaggtcgac caccaaacta 120 tccatgtata ctcgctgcgc aggtccagga gcaatttgtc ctaatagggt atgctgcggt 180 tattgcagta aaagaacaca tctatgtcat tcgcgaactg gctgatcttc ccccttctgt 240 gctctatcct ttttctgcct gagtcctcca tacctgagaa tggtcatgaa ccactcatca 300 cctactcctc ttggagacct cagaggagct acactgaaat aaaagccgca ttggc 355
<210> 181
<211> 74
<212> PRT
<213> Conus lynceus
<400> 181
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys Leu Ser Met Tyr Thr Arg Cys Ala Gly 35 40 45
Pro Gly Ala He Cys Pro Asn Arg Val Cys Cys Gly Tyr Cys Ser Lys 50 55 60
Arg Thr His Leu Cys His Ser Arg Thr Gly 65 70
<210> 182
<211> 28
<212> PRT
<213> Conus lynceus
<220>
<221> PEPTIDE <222> (1) .. (28)
<223> Xaa at residue 4 and 9 is Pro or Hyp; Xaa at residue 16 is Tyr, 1 251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 182
Cys Ala Gly Xaa Gly Ala He Cys Xaa Asn Arg Val Cys Cys Gly Xaa
1 5 10 15
Cys Ser Lys Arg Thr His Leu Cys His Ser Arg Thr 20 25 56
<210> 183
<211> 361
<212> DNA
<213> Conus lynceus
<400> 183 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgctgc tagcggcctg tcaactacta 60 cacgctgatg actccagagg tacgcagaag actgctgccc gaggtcgacc accaaaactc 120 tccatgctga ctcgggcctg ctggtcttcc ggaacacctt gtggtactga tagtttatgc 180 tgcggtggat gcaatgtatc caaaagtaaa tgtaactagc tgattcggcg tctgaacttc 240 ccccttctgt gctctatcct tttctgcccg agtcctccat acctgagaat ggtcatgaac 300 cactcatcac ctactcctct ggagacctca gaagagctac actgaaataa aagcgcattg 360 c 361
<210> 184
<211> 72
<212> PRT
<213> Conus lynceus
<400> 184
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Ala Ala
1 5 10 15
Cys Gin Leu Leu His Ala Asp Asp Ser Arg Gly Thr Gin Lys Thr Ala 20 25 30
Ala Arg Gly Arg Pro Pro Lys Leu Ser Met Leu Thr Arg Ala Cys Trp 35 40 45
Ser Ser Gly Thr Pro Cys Gly Thr Asp Ser Leu Cys Cys Gly Gly Cys 50 55 60
Asn Val Ser Lys Ser Lys Cys Asn 65 70
<210> 185
<211> 27
<212> PRT
<213> Conus lynceus
<220>
<221> PEPTIDE <222> (1) .. (27)
<223> Xaa at residue 8 is Pro or Hyp; Xaa at residue 3 is Trp or Bromo Tr
<400> 185
Ala Cys Xaa Ser Ser Gly Thr Xaa Cys Gly Thr Asp Ser Leu Cys Cys
1 5 10 15
Gly Gly Cys Asn Val Ser Lys Ser Lys Cys Asn 20 25
<210> 186
<211> 364
<212> DNA
<213> Conus lynceus
<400> 186 57 atgaaactga cgtgtgtggt gatcgtcgcc gagctactcc taacggcctg tcaactcatc 60 acagctgatg actccagagg tacgcagaag catcgtgccc tgaggtcgac caccaatctc 120 tccatgctga ctcggaagtg ctggtctccc ggaacctatt gtcgtgcgca tagtaaatgc 180 tgccgtggat gcgatcagaa cagaaataaa tgttactagc tgattcggcg tctgaacttc 240 ctccttctgt gctctatcct ttttctgcct gagtcctcca tacctgagaa tggtcatgaa 300 ccactcatca cctactcctc tggaggcctc agaggagcct acactgaaat aaaagccgca 360 ttgg 364
<210> 187
<211> 72
<212> PRT
<213> Conus lynceus
<400> 187
Met Lys Leu Thr Cys Val Val He Val Ala Glu Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Asn Leu Ser Met Leu Thr Arg Lys Cys Trp 35 40 45
Ser Pro Gly Thr Tyr Cys Arg Ala His Ser Lys Cys Cys Arg Gly Cys 50 55 60
Asp Gin Asn Arg Asn Lys Cys Tyr 65 70
<210> 188
<211> 27
<212> PRT
<213> Conus lynceus
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa at residue 5 is Pro or Hyp; Xaa at residue 3 is Trp or Bromo Trp; Xaa at residue 8 and 27 is Tyr, 1251-Tyr, mono-iodo-Tyr, di- iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 188
Lys Cys Xaa Ser Xaa Gly Thr Xaa Cys Arg Ala His Ser Lys Cys Cys
1 5 10 15
Arg Gly Cys Asp Gin Asn Arg Asn Lys Cys Xaa 20 25
<210> 189
<211> 318
<212> DNA
<213> Conus magus
<400> 189 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcggaca ccaaactctc catgtcgact cgctgcaagg gtacaggaaa accatgcagt 180 58
aggattgcgt ataactgctg caccggttct tgcagatcag gtaaatgtgg ctgatccagt 240 gcctgatctt cccccttctg tgctctatcc tttttctgcc tgagtcctcc ttacctgaga 300 gtggtcatga accactca 318
<210> 190
<211> 71
<212> PRT '
<213> Conus magus
<400> 190
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Ser Met Ser Thr Arg Cys Lys Gly 35 40 45
Thr Gly Lys Pro Cys Ser Arg He Ala Tyr Asn Cys Cys Thr Gly Ser 50 55 60
Cys Arg Ser Gly Lys Cys Gly 65 70
<210> 191
<211> 25
<212> PRT
<213> Conus magus
<220>
<221> PEPTIDE <222> (1)..(25)
<223> Xaa at residue 7 is Pro or Hyp; Xaa at residue 13 is Tyr, 125I-Ty r, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 191
Cys Lys Gly Thr Gly Lys Xaa Cys Ser Arg He Ala Xaa Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 192
<211> 259
<212> DNA
<213> Conus magus
<400> 192 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aagtcggaca ccaaactctc catgttaact ttgcgctgcg catcttacgg aaaaccttgt 180 ggtatttaca acgactgctg caatacatgc gatccagcca gaaagacatg tacgtagctg 240 atccggcgtc tgatcttcc 259
<210> 193 <211> 72 <212> PRT 59
<213> Conus magus
<400> 193
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Lys Ser Asp Thr Lys Leu Ser Met Leu Thr Leu Arg Cys Ala 35 40 45
Ser Tyr Gly Lys Pro Cys Gly He Tyr Asn Asp Cys Cys Asn Thr Cys 50 55 60
Asp Pro Ala Arg Lys Thr Cys Thr 65 70
<210> 194
<211> 26
<212> PRT
<213> Conus magus
<220>
<221> PEPTIDE <222> (1) .. (26)
<223> Xaa at residue 7 and 20 is Pro or Hyp; Xaa at residue 4 and 11 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-pho spho-Ty
<400> 194
Cys Ala Ser Xaa Gly Lys Xaa Cys Gly He Xaa Asn Asp Cys Cys Asn
1 5 10 15
Thr Cys Asp Xaa Ala Arg Lys Thr Cys Thr 20 25
<210> 195
<211> 254
<212> DNA
<213> Conus magus
<400> 195 gaattttcag catcaccaaa accatcatca aaatgaaact gacgtgtgtg gtgatcgtcg 60 ccgtgctgct cctgacggcc tgtcaactca tcacagctga tgactccaga ggtacgcaga 120 agcatcgtgc cctgaggtcg gacaccaaac tctccatgtc aactcgctgc aagggtaaag 180 gagcatcatg tcataggact tcgtatgact gctgcaccgg ttcttgcaac agaggtaaat 240 ttggctgatc cgcc 254
<210> 196
<211> 71
<212> PRT
<213> Conus magus
<400> 196
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30 60
Ala Leu Arg Ser Asp Thr Lys Leu Ser Met Ser Thr Arg Cys Lys Gly 35 40 45
Lys Gly Ala Ser Cys His Arg Thr Ser Tyr Asp Cys Cys Thr Gly Ser 50 55 60
Cys Asn Arg Gly Lys Phe Gly 65 70
<210> 197
<211> 25
<212> PRT
<213> Conus magus
<220>
<221> PEPTIDE <222> (1).. (25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 197
Cys Lys Gly Lys Gly Ala Ser Cys His Arg Thr Ser Xaa Asp Cys Cys
1 5 10 15
Thr Gly Ser Cys Asn Arg Gly Lys Cys 20 25
<210> 198
<211> 358
<212> DNA
<213> Conus miles
<400> 198 ggatccatga aactgacgtg cgtggtgatc atcgccatgc tgttcctgac agcctatcaa 60 ctcgctacag ctgcgagcta cgccaaaggt aaacagaagc atcgtgctct gaggccagct 120 gacaaacacc tcaggttgac caagcgttgc aatgatcgcg gtggaggttg cagtcaacat 180 cctcactgct gcggtggaac ttgcaataag cttattggcg tatgtctgta aagctggtct 240 gccgtctgat attccctttc tgtgcttcat cctcttttgc ctgagtcatc catacctgtg 300 aatggttaag agccactcaa tacctattcc tctgggggct tcagaggaac tactttac 358
<210> 199
<211> 74
<212> PRT
<213> Conus miles
<400> 199
Met Lys Leu Thr Cys Val Val He He Ala Met Leu Phe Leu Thr Ala
1 5 10 15
Tyr Gin Leu Ala Thr Ala Ala Ser Tyr Ala Lys Gly Lys Gin Lys His 20 25 30
Arg Ala Leu Arg Pro Ala Asp Lys His Leu Arg Leu Thr Lys Arg Cys 35 40 45
Asn Asp Arg Gly Gly Gly Cys Ser Gin His Pro His Cys Cys Gly Gly 50 55 60
Thr Cys Asn Lys Leu He Gly Val Cys Leu 65 70 61
<210> 200
<211> 27
<212> PRT
<213> Conus arenatus
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa at residue 12 is Pro or Hyp
<400> 200
Cys Asn Asp Arg Gly Gly Gly Cys Ser Gin His Xaa His Cys Cys Gly
1 5 10 15
Gly Thr Cys Asn Lys Leu He Gly Val Cys Leu 20 25
<210> 201
<211> 292
<212> DNA
<213> Conus monachus
<400> 201 accaaaacca tcatcaaaat gaaactgacg agtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcggaca ccaaactctc catatcgact cgctgcaagt ctacaggaaa atcatgcagt 180 aggattgcgt ataactgctg caccggttct tgcagatcag gtaaatgtgg ctgatccagc 240 gcctgatctt cccccttctg tgctctatcc ttttctgcct gagtcctcct ta 292
<210> 202
<211> 71
<212> PRT
<213> Conus monachus
<400> 202
Met Lys Leu Thr Ser Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Ser He Ser Thr Arg Cys Lys Ser 35 40 45
Thr Gly Lys Ser Cys Ser Arg He Ala Tyr Asn Cys Cys Thr Gly Ser 50 55 60
Cys Arg Ser Gly Lys Cys Gly 65 70
<210> 203
<211> 25
<212> PRT
<213> Conus monachus
<220>
<221> PEPTIDE <222> (1) .. (25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty 62
<400> 203
Cys Lys Ser Thr Gly Lys Ser Cys Ser Arg He Ala Xaa Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 204
<211> 258
<212> DNA
<213> Conus monachus
<400> 204 accaaaacca tcatcaaaat gaaactgacg agtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcggaca ccaacctctc catgtcgact cgctgcaagg gtaaaggatc ttcatgtagt 180 aggaccatgt ataactgctg caccggttct tgcaacagag gtaaatgtgg ctgatccagc 240 gcctgatctt cccccttc 258
<210> 205
<211> 71
<212> PRT
<213> Conus monachus
<400> 205
Met Lys Leu Thr Ser Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 ■ 30
Ala Leu Arg Ser Asp Thr Asn Leu Ser Met Ser Thr Arg Cys Lys Gly 35 40 45
Lys Gly Ser Ser Cys Ser Arg Thr Met Tyr Asn Cys Cys Thr Gly Ser 50 55 60
Cys Asn Arg Gly Lys Cys Gly 65 70
<210> 206
<211> 25
<212> PRT
<213> Conus monachus
<220>
<221> PEPTIDE <222> (1) .. (25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 206
Cys Lys Gly Lys Gly Ser Ser Cys Ser Arg Thr Met Xaa Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Asn Arg Gly Lys Cys 20 25
<210> 207 <211> 258 63
<212> DNA
<213> Conus obscurus
<400> 207 ctctctctct ctctgctgga caggtcgcct ccctgcatga aaggcggatc gtcatgccgc 60 ggtactacgg gagtctgttg cggtttttgc agtgatttcg gctataaatg tagggactat 120 ccccaaaact gatcttcccc cttctgtgct ctatcctttt ctgtccgagt cctcctgacc 180 tgagagtggt catgaaccac tcatcaccta cccctctggg gcttcacagg atctacattg 240 aaataaaagc cgcattgc 258
<210> 208
<211> 39
<212> PRT
<213> Conus obscurus
<400> 208
Leu Leu Asp Arg Ser Pro Pro Cys Met Lys Gly Gly Ser Ser Cys Arg
1 5 10 15
Gly Thr Thr Gly Val Cys Cys Gly Phe Cys Ser Asp Phe Gly Tyr Lys 20 25 30
Cys Arg Asp Tyr Pro Gin Asn 35
<210> 209
<211> 35
<212> PRT
<213> Conus obscurus
<220>
<221> PEPTIDE
<222> (1) .. (35)
<223> Xaa at residue 2, 3 and 33 is Pro or Hyp; Xaa at residue 27 and 3
2 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O
-phospho-Ty
<400> 209
Ser Xaa Xaa Cys Met Lys Gly Gly Ser Ser Cys Arg Gly Thr Thr Gly
1 5 10 15
Val Cys Cys Gly Phe Cys Ser Asp Phe Gly Xaa Lys Cys Arg Asp Xaa 20 25 30
Xaa Gin Asn 35
<210> 210
<211> 259
<212> DNA
<213> Conus obscurus
<400> 210 ctctctctct ctctgctgga caggtcgact cgctgcttgc ctgacggaac gtcttgcctt 60 tttagtagga tcagatgctg cggtacttgc agttcaatct taaagtcatg tgtgagctga 120 tccagcggtt gatcttcctc cctctgtgct ccatcctttt ctgcctgagt tctccttacc 180 tgagagtggt catgaaccac tcatcaccta ctcttctgga ggcttcagag gagctacatt 240 64 gaaataaaag ccgcattgc 259
<210> 211
<211> 32
<212> PRT
<213> Conus obscurus
<400> 211
Arg Ser Thr Arg Cys Leu Pro Asp Gly Thr Ser Cys Leu Phe Ser Arg
1 5 10 15
He Arg Cys Cys Gly Thr Cys Ser Ser He Leu Lys Ser Cys Val Ser 20 25 30
<210> 212
<211> 28
<212> PRT
<213> Conus monachus
<220>
<221> PEPTIDE
<222> (1)..(28)
<223> Xaa at residue 3 is Pro or Hyp
<400> 212
Cys Leu Xaa Asp Gly Thr Ser Cys Leu Phe Ser Arg He Arg Cys Cys
1 5 10 15
Gly Thr Cys Ser Ser He Leu Lys Ser Cys Val Ser 20 25
<210> 213
<211> 330
<212> DNA
<213> Conus pulicarius
<220>
<221> misc_feature
<222> (1)..(330)
<223> n may be any nucleotide
<400> 213 atgaaactga cgtgtgtggt gatcatcgcc gtgctgttcc tgacggcctg tcaactcatt 60 acagctgaga cttactccag aggtaagcag aagcaccgtg ctttgaggtc aactgacaaa 120 aactccaagt tgactaggca gtgctcgcct aacggtggat cttgttctcg tcattttcac 180 tgctgcagcc tctattgcaa taaaaatact ggcgtatgta ttgcaaccta atacccgtgt 240 gtggtcatga accactcaat accctctcct ctggaggctt cagaggaact gcattgaaat 300 aaaactgcat tgcnttgacc aaaaaaaaaa 330
<210> 214
<211> 76
<212> PRT
<213> Conus pulicarius
<400> 214
Met Lys Leu Thr Cys Val Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Thr Tyr Ser Arg Gly Lys Gin Lys His 20 25 30 65
Arg Ala Leu Arg Ser Thr Asp Lys Asn Ser Lys Leu Thr Arg Gin Cys 35 40 45
Ser Pro Asn Gly Gly Ser Cys Ser Arg His Phe His Cys Cys Ser Leu 50 55 60
Tyr Cys Asn Lys Asn Thr Gly Val Cys He Ala Thr 65 70 75
<210> 215
<211> 30
<212> PRT
<213> Conus pulicarius
<220>
<221> PEPTIDE
<222> (1)..(30)
<223> Xaa at residue 1 is Gin or pyro-Glu; Xaa at residue 4 is Pro or H yp; Xaa at residue 19 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Ty r, O-sulpho-Tyr or O-phospho-Ty
<400> 215
Xaa Cys Ser Xaa Asn Gly Gly Ser Cys Ser Arg His Phe His Cys Cys
1 5 10 15
Ser Leu Xaa Cys Asn Lys Asn Thr Gly Val Cys He Ala Thr 20 25 30
<210> 216
<211> 282
<212> DNA
<213> Conus purpurascens
<400> 216 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgttcc tgacggcctg tcaactcatc 60 acagctgatg actccagacg tacgcagaag catcgtgccc tgaggtcgac caccaaaggc 120 gccacgtcga atcgcccctg caagacaccc ggacgaaaat gttttccgca tcagaaggac 180 tgctgcggtc gagcgtgcat catcacaata tgtccctgat cttccccctt ctgtgctgta 240 tccttttctg cctgagtctc cttacctgag agtggtcatg aa 282
<210> 217
<211> 72
<212> PRT
<213> Conus purpurascens
<400> 217
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Arg Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys Gly Ala Thr Ser Asn Arg Pro Cys Lys 35 40 45
Thr Pro Gly Arg Lys Cys Phe Pro His Gin Lys Asp Cys Cys Gly Arg 50 55 60
Ala Cys He He Thr He Cys Pro 65 70 66
<210> 218
<211> 27
<212> PRT
<213> Conus purpurascens
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa at residue 1, 5, 11 and 27 is Pro or Hyp
<400> 218
Xaa Cys Lys Thr Xaa Gly Arg Lys Cys Phe Xaa His Gin Lys Asp Cys
1 5 10 15
Cys Gly Arg Ala Cys He He Thr He Cys Xaa 20 25
<210> 219
<211> 340
<212> DNA
<213> Conus purpurascens
<400> 219 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcgacca ccaaactctt cacgtcgaaa agctgcaagc ttcccggagc atattgtaat 180 gcagaagatt atgactgctg ccttagatgc aaagttggag gtacatgtgg ctgatccagt 240 gcctgatctt cccccttctg tgctctatcc ttttctgcct gagtcctcct tacctaagag 300 tggtcatgaa ccactcatca ccttctcctc tggaggcttc 340
<210> 220
<211> 71
<212> PRT
<213> Conus purpurascens
<400> 220
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys Leu Phe Thr Ser Lys Ser Cys Lys Leu 35 40 45
Pro Gly Ala Tyr Cys Asn Ala Glu Asp Tyr Asp Cys Cys Leu Arg Cys 50 55 60
Lys Val Gly Gly Thr Cys Gly 65 70
<210> 221
<211> 26
<212> PRT
<213> Conus purpurascens
<220>
<221> PEPTIDE 67
<222> (1) .. (26)
<223> Xaa at residue 12 is Glu or gamma-carboxy Glu; Xaa at residue 5 i s Pro or Hyp; Xaa at residue 8 and 14 is Tyr, 1251-Tyr, mono-iodo -Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 221
Ser Cys Lys Leu Xaa Gly Ala Xaa Cys Asn Ala Xaa Asp Xaa Asp Cys
1 5 10 15
Cys Leu Arg Cys Lys Val Gly Gly Thr Cys 20 25
<210> 222
<211> 317
<212> DNA
<213> Conus purpurascens
<400> 222 atgaaactga cgtgtgtggt gatcgtcgcc gtgctgttcc tgacggcctg tcaactcatc 60 acagctgatg actccagacg tacgcagaag catcgtgccc tgaggtcgac caccaaacgc 120 gccacgtcga atcgcccctg caagaaaacc ggacgaaaat gttttccgca tcagaaggac 180 tgctgcggtc gagcgtgcat catcacaata tgtccctgat cttccccctt ctgtgctgta 240 tccttttctg cctgagtcct ccttacctga gagtggtcat gaaccactca tcaccttctc 300 ctctggaggc ttcagag 317
<210> 223
<211> 72
<212> PRT
<213> Conus purpurascens
<400> 223
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Arg Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys Arg Ala Thr Ser Asn Arg Pro Cys Lys 35 40 45
Lys Thr Gly Arg Lys Cys Phe Pro His Gin Lys Asp Cys Cys Gly Arg 50 55 60
Ala Cys He He Thr He Cys Pro 65 70
<210> 224
<211> 27
<212> PRT
<213> Conus purpurascens
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa at residue 1, 11 and 27 is Pro or Hyp
<400> 224
Xaa Cys Lys Lys Thr Gly Arg Lys Cys Phe Xaa His Gin Lys Asp Cys
1 5 10 15 68
Cys Gly Arg Ala Cys He He Thr He Cys Xaa 20 25
<210> 225
<211> 328
<212> DNA
<213> Conus radiatus
<400> 225 gctgatgcct gatcttcatc gttcttccct gtctcctttg gcatcaccaa aaccatcatc 60 aaaatgaaac tgacgtgtgt ggtgatcgtc gccgtgctgg tcctgacggc ctgtcaactc 120 atcacagctg atgactccag aggtatgcag aaacatcatg ccctggggtc gatcagcagt 180 ctctttaagt cgacccgtca tggctgcaaa cccctcaaac gtcgttgttt caatgataaa 240 gaatgctgca gcaaattttg caattcagtc cgaaagcagt gtggataaat ggctaaaaaa 300 ctgaataaaa gccgcattgc aaaaaaaa 328
<210> 226
<211> 74
<212> PRT
<213> Conus radiatus
<400> 226
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Val Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Met Gin Lys His His 20 25 30
Ala Leu Gly Ser He Ser Ser Leu Phe Lys Ser Thr Arg His Gly Cys 35 40 45
Lys Pro Leu Lys Arg Arg Cys Phe Asn Asp Lys Glu Cys Cys Ser Lys 50 55 60
Phe Cys Asn Ser Val Arg Lys Gin Cys Gly 65 70
<210> 227
<211> 28
<212> PRT
<213> Conus radiatus
<220>
<221> PEPTIDE <222> (1)..(28)
<223> Xaa at residue 15 is Glu or gamma-carboxy Glu; Xaa at residue 5 i s Pro or Hy
<400> 227
His Gly Cys Lys Xaa Leu Lys Arg Arg Cys Phe Asn Asp Lys Xaa Cys
1 5 10 15
Cys Ser Lys Phe Cys Asn Ser Val Arg Lys Gin Cys 20 25
<210> 228
<211> 250
<212> DNA
<213> Conus radiatus 69
<400> 228 gaaatgaaac tgacgtgtgt ggtgatcgtc gccgtgctgg tcctgacggc ctgtcaactc 60 atcacagctg atgactccag aggtatgcag aaacatcatg ccctggggtc gatcagcagt 120 ctctttaagt cgacccgtcg tggctgcaaa cccctcaaac gtcgttgttt caatgataaa 180 gaatgctgca gcaaattttg caattcagtc cgaaaccagt gtggataaat ggctaaaaac 240 tgaataaaag 250
<210> 229
<211> 74
<212> PRT
<213> Conus radiatus
<400> 229
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Val Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Met Gin Lys His His 20 25 30
Ala Leu Gly Ser He Ser Ser Leu Phe Lys Ser Thr Arg Arg Gly Cys 35 40 45
Lys Pro Leu Lys Arg Arg Cys Phe Asn Asp Lys Glu Cys Cys Ser Lys 50 55 60
Phe Cys Asn Ser Val Arg Asn Gin Cys Gly 65 70
<210> 230
<211> 28
<212> PRT
<213> Conus radiatus
<220>
<221> PEPTIDE <222> (1) .. (28)
<223> Xaa at residue 15 is Glu or gamma-carboxy Glu; Xaa at residue 5 i s Pro or Hy
<400> 230
Arg Gly Cys Lys Xaa Leu Lys Arg Arg Cys Phe Asn Asp Lys Xaa Cys
1 5 10 15
Cys Ser Lys Phe Cys Asn Ser Val Arg Asn Gin Cys 20 25
<210> 231
<211> 435
<212> DNA
<213> Conus radiatus
<400> 231 ggaattccgc ttgcacggcg aacctgactt catctttctt ccctgcctcc tttggcatca 60 ccaaaaccat catcaaaatg aaactgacgt gtgtggtgat cgtcgccgtg ctggtcctga 120 cggcctgtca actcatcaca gctgatgact ccagaggtat gcagaagcat catgccctga 180 ggtcgatcac caaactctcc ctgtcgactc gctgcaaacc tcccggatca ccatgtagag 240 tttcttcgta taactgctgc tcttcttgca aatcatacaa caagaaatgt ggctgaactt 300 70
ccccttctgt gctctatcct tttcctgccc gagtcctcca tacctgagag tagtcatgaa 360 ccactgatta cctactcctc tggagggcct cagaggagct actttgaaat aaaagcccgc 420 attgcaaaaa aaaaa 435
<210> 232
<211> 72
<212> PRT
<213> Conus radiatus
<400> 232
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Val Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Met Gin Lys His His 20 25 30
Ala Leu Arg Ser He Thr Lys Leu Ser Leu Ser Thr Arg Cys Lys Pro 35 40 45
Pro Gly Ser Pro Cys Arg Val Ser Ser Tyr Asn Cys Cys Ser Ser Cys 50 55 60
Lys Ser Tyr Asn Lys Lys Cys Gly 65 70
<210> 233
<211> 27
<212> PRT
<213> Conus radiatus
<220>
<221> PEPTIDE <222> (1)..(27)
<223> Xaa at residue 3, 4 and 7 is Pro or Hyp; Xaa at residue 13 and 22 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or 0- phospho-Ty
<400> 233
Cys Lys Xaa Xaa Gly Ser Xaa Cys Arg Val Ser Ser Xaa Asn Cys Cys
1 5 10 15
Ser Ser Cys Lys Ser Xaa Asn Lys Lys Cys Gly 20 25
<210> 234
<211> 392
<212> DNA
<213> Conus rattus
<400> 234 ggatccatga aactgacgtg catggtgatc atcgccgtgc tgttcctgac agcctgtcaa 60 ttcgatacag ctgcgagcta cgacaaaggt aagcagaaac ctcctactct gaggccagct 120 gacaaacaca tcaggttgac caagcgttgc aatgctcgca atgatggttg cagtcaacat 180 tctcaatgct gcagtggatc ttgcaataag actgcaggcg tatgtctgta aagctggtct 240 gccgtctgat attccctttc tgtgctttat cctcttttgc ctgagtcatc catacctgtg 300 aatggttaag agccactcaa tacctactcc tctgggggct tcagaggaac tacattaaat 360 71 aaagccacat tgcaaaaaaa aaaaaaaaaa aa 392
<210> 235
<211> 74
<212> PRT
<213> Conus rattus
<400> 235
Met Lys Leu Thr Cys Met Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Phe Asp Thr Ala Ala Ser Tyr Asp Lys Gly Lys Gin Lys Pro 20 25 30
Pro Thr Leu Arg Pro Ala Asp Lys His He Arg Leu Thr Lys Arg Cys 35 40 45
Asn Ala Arg Asn Asp Gly Cys Ser Gin His Ser Gin Cys Cys Ser Gly 50 55 60
Ser Cys Asn Lys Thr Ala Gly Val Cys Leu 65 70
<210> 236
<211> 27
<212> PRT
<213> Conus rattus
<400> 236
Cys Asn Ala Arg Asn Asp Gly Cys Ser Gin His Ser Gin Cys Cys Ser
1 5 10 15
Gly Ser Cys Asn Lys Thr Ala Gly Val Cys Leu 20 25
<210> 237
<211> 395
<212> DNA
<213> Conus rattus
<400> 237 ggatccatga aactgacgtg cgtggtgatc atcgccgtgc tgttcctgac agcctgtcaa 60 ctcgatgcag ctgcgagcta cgacaaaggt aagcagaaac ctcctactct gaggccagct 120 gacaaacact tcaggttgat caagcgttgc aatgctcgca atagtggttg cagtcaacat 180 cctcaatgct gcagtggatc ttgcaataag actgcaggcg tatgtctgta aagctggtct 240 gccgtctgat attccctttc tgtgctttat cctcttttgc ctgagtcatc catacctgtg 300 aatggttaag agccactcaa tacctactcc tctgggggct tcagaggaac tacattaaat 360 aaagccacat tgcaacgaaa aaaaaaaaaa aaaaa 395
<210> 238
<211> 74
<212> PRT
<213> Conus rattus
<400> 238
Met Lys Leu Thr Cys Val Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu Asp Ala Ala Ala Ser Tyr Asp Lys Gly Lys Gin Lys Pro 72
20 25 30
Pro Thr Leu Arg Pro Ala Asp Lys His Phe Arg Leu He Lys Arg Cys 35 40 45
Asn Ala Arg Asn Ser Gly Cys Ser Gin His Pro Gin Cys Cys Ser Gly 50 55 60
Ser Cys Asn Lys Thr Ala Gly Val Cys Leu 65 70
<210> 239
<211> 27
<212> PRT
<213> Conus rattus
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa at residue 12 is Pro or Hyp
<400> 239
Cys Asn Ala Arg Asn Ser Gly Cys Ser Gin His Xaa Gin Cys Cys Ser
1 5 10 15
Gly Ser Cys Asn Lys Thr Ala Gly Val Cys Leu 20 25
<210> 240
<211> 390
<212> DNA
<213> Conus rattus
<400> 240 ggatccatga aactgacgtg tgtggtgatc atcgccgtgc tgttcctgac agcctgtcaa 60 ttcgatacag ctgcgagcta cgacaaaggt aagcagaaac ctcctactct gaggccagct 120 gacaaacact tcaggttgat caagcgttgc aatgctcgca atagtggttg cagtcaacat 180 cctcaatgct gcagtggatc ttgcaataag actttgggcg tatgtctgta aagctggtct 240 gccgtctgat attccctttc tgtgctttat cctcttttgc ctgagtcatc catacctgtg 300 aatggttaag agccactcaa tacctactcc tctgggggct tcagaggaac tacattaaat 360 aaagccacat tgaaaaaaaa aaaaaaaaaa 390
<210> 241
<211> 74
<212> PRT
<213> Conus rattus
<400> 241
Met Lys Leu Thr Cys Val Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Phe Asp Thr Ala Ala Ser Tyr Asp Lys Gly Lys Gin Lys Pro 20 25 30
Pro Thr Leu Arg Pro Ala Asp Lys His Phe Arg Leu He Lys Arg Cys 35 40 45
Asn Ala Arg Asn Ser Gly Cys Ser Gin His Pro Gin Cys Cys Ser Gly 50 55 60 73
Ser Cys Asn Lys Thr Leu Gly Val Cys Leu 65 70
<210> 242
<211> 27
<212> PRT
<213> Conus rattus
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa at residμe 12 is Pro or Hyp
<400> 242
Cys Asn Ala Arg Asn Ser Gly Cys Ser Gin His Xaa Gin Cys Cys Ser
1 5 10 15
Gly Ser Cys Asn Lys Thr Leu Gly Val Cys Leu 20 25
<210> 243
<211> 379
<212> DNA
<213> Conus stercusmuscarum
<400> 243 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcgaaga ccaaactctc catgtcgact cgctgcaaga gtaaaggagc aaaatgttca 180 aggcttatgt atgactgctg cagcggttct tgcagcggct acacaggtag atgtggctga 240 tccagcgcct gatcttcccc cttctgtgct ctatcctttt ctgcctgggt cctccttacc 300 tgagagtggt catgaaccac tcatcaccta ctcctctgga ggcctcagag gagttacaat 360 gaaataaaag ccgcattgc 379
<210> 244
<211> 73
<212> PRT
<213> Conus stercusmuscarum
<400> 244
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Lys Thr Lys Leu Ser Met Ser Thr Arg Cys Lys Ser 35 40 45
Lys Gly Ala Lys Cys Ser Arg Leu Met Tyr Asp Cys Cys Ser Gly Ser 50 55 60
Cys Ser Gly Tyr Thr Gly Arg Cys Gly 65 70
<210> 245 <211> 27 <212> PRT 74
<213> Conus stercusmuscarum
<220>
<221> PEPTIDE <222> (1) .. (27)
<223> Xaa at residue 13 and 23 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo -Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 245
Cys Lys Ser Lys Gly Ala Lys Cys Ser Arg Leu Met Xaa Asp Cys Cys
1 5 10 15
Ser Gly Ser Cys Ser Gly Xaa Thr Gly Arg Cys 20 25
<210> 246
<211> 35
<212> PRT
<213> Conus stercusmuscarum
<220>
<221> PEPTIDE <222> (1)..(35)
<223> Xaa at residue 33 is Pro or Hyp; Xaa at residue 10, 21, 24 and 32 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O -phospho-Ty
<400> 246
Thr Thr Ser Cys Met Gin Ala Gly Ser Xaa Cys Gly Ser Thr Thr Arg
1 5 10 15
He Cys Cys Gly Xaa Cys Ala Xaa Phe Gly Lys Lys Cys He Asp Xaa 20 25 30
Xaa Ser Asn 35
<210> 247
<211> 380
<212> DNA
<213> Conus stercusmuscarum
<400> 247 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acgacctgtc aactcatcac agctgatgac tccagaggta cgcaggagca tcgtgccctg 120 aggtcgaaga ccaaactctc catgttaact ttgcgctgcg catcttacgg aaaaccttgt 180 ggtattgaca acgactgctg caatgcatgc gatccagcca gaaatatatg tacgtagctg 240 atccggcgtc tgatcttccc ccttctgtgc tctatccttt tctgcctgag tcctccttac 300 ctgagagtgg tcatgaacca ctcatcatct actctcctgg aggcctcaga ggagctacaa 360 tgaaataaaa gccgcattgc 380
<210> 248
<211> 72
<212> PRT
<213> Conus stercusmuscarum
<400> 248
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Thr
1 5 10 15 75
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Glu His Arg 20 25 30
Ala Leu Arg Ser Lys Thr Lys Leu Ser Met Leu Thr Leu Arg Cys Ala 35 40 45
Ser Tyr Gly Lys Pro Cys Gly He Asp Asn Asp Cys Cys Asn Ala Cys 50 55 60
Asp Pro Ala Arg Asn He Cys Thr 65 70
<210> 249
<211> 26
<212> PRT
<213> Conus stercusmuscarum
<220>
<221> PEPTIDE <222> (1)..(26)
<223> Xaa at residue 7 and 20 is Pro or Hyp; Xaa at residue4 is Tyr, 1 251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 249
Cys Ala Ser Xaa Gly Lys Xaa Cys Gly He Asp Asn Asp Cys Cys Asn
1 5 10 15
Ala Cys Asp. Xaa Ala Arg Asn He Cys Thr 20 25
<210> 250
<211> 388
<212> DNA
<213> Conus stercusmuscarum
<400> 250 ggatccatga aactgacgtg tgtggtgatt gtcgccgtgc tgctcctgac ggcctgtcaa 60 ctcatcacag ctgatgactc cagaggtacg caggagcatc gtgccctgag gtcgaagacc 120 aaactctcca tgttaacttt gcgctgcgta tcttacggaa aaccttgtgg tattgacaac 180 gactgctgca atgcatgcga tccagccaga aatatatgta cgtagctgat ccggcgtctg 240 atcttccccc ttctgtgctc tatccttttc tgcctgggtc ctccttacct gagagtggtc 300 atgaaccact catcacctac tcctctggag gcctcagagg agttacaatg aaataaaagc 360 cgcattgcaa aaaaaaaaaa aaaaaaaa 388
<210> 251
<211> 72
<212> PRT
<213> Conus stercusmuscarum
<400> 251
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 ' 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Glu His Arg 20 25 30
Ala Leu Arg Ser Lys Thr Lys Leu Ser Met Leu Thr Leu Arg Cys Val 76
35 40 45
Ser Tyr Gly Lys Pro Cys Gly He Asp Asn Asp Cys Cys Asn Ala Cys 50 55 60
Asp Pro Ala Arg Asn He Cys Thr 65 70
<210> 252
<211> 26
<212> PRT
<213> Conus stercusmuscarum
<220>
<221> PEPTIDE <222> (1) .. (26)
<223> Xaa at residue 7 and 20 is Pro or Hyp; Xaa at residue 4 is Tyr, 1 251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 252
Cys Val Ser Xaa Gly Lys Xaa Cys Gly He Asp Asn Asp Cys Cys Asn
1 5 10 15
Ala Cys Asp Xaa Ala Arg Asn He Cys Thr 20 25
<210> 253
<211> 264
<212> DNA
<213> Conus striatus
<400> 253 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgttccctg 120 aggtcgacca ccaaagtctc caaggcgact gactgcattg aagccggaaa ttattgcgga 180 cctactgtta tgaaaatctg ctgcggcttt tgcagtccat acagcaaaat atgtatgaac 240 tatcccaaaa attgatcttc cccc 264
<210> 254
<211> 78
<212> PRT
<213> Conus striatus
<400> 254
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ser Leu Arg Ser Thr Thr Lys Val Ser Lys Ala Thr Asp Cys He Glu 35 40 45
Ala Gly Asn Tyr Cys Gly Pro Thr Val Met Lys He Cys Cys Gly Phe 50 55 60
Cys Ser Pro Tyr Ser Lys He Cys Met Asn Tyr Pro Lys Asn 65 70 75 77
<210> 255
<211> 36
<212> PRT
<213> Conus striatus
<220>
<221> PEPTIDE
<222> (1) .. (36)
<223> Xaa at residue 6 is Glu or gamma-carboxy Glu; Xaa at residue 13, 25 and 34 is Pro or Hyp; Xaa at residue 10, 26 and 33 is Tyr, 125 I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 255
Ala Thr Asp Cys He Xaa Ala Gly Asn Xaa Cys Gly Xaa Thr Val Met
1 5 10 15
Lys He Cys Cys Gly Phe Cys Ser Xaa Xaa Ser Lys He Cys Met Asn 20 25 30
Xaa Xaa Lys Asn 35
<210> 256
<211> 233
<212> DNA
<213> Conus striatus
<400> 256 gtcgactcgc tgcaagctta aaggacaatc atgtcgtagg actatgtatg actgctgcag 60 ciggttcttgc ggcaggagag gtaaatgtgg ctgatccagc gcctgatctc cccccttctg 120 tgctctatcc ttttctgcct gggtcctcct tacctgagag tggtcatgaa ccactcatca 180 cctactcctc tggaggcctc agaggagcta caatgaaata aaagccgcat tgc 233
<210> 257
<211> 30
<212> PRT
<213> Conus striatus
<400> 257
Ser Thr Arg Cys Lys Leu Lys Gly Gin Ser Cys Arg Arg Thr Met Tyr
1 5 10 15
Asp Cys Cys Ser Gly Ser Cys Gly Arg Arg Gly Lys Cys Gly 20 25 30
<210> 258
<211> 26
<212> PRT
<213> Conus striatus
<220>
<221> PEPTIDE <222> (1)..(26)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 258
Cys Lys Leu Lys Gly Gin Ser Cys Arg Arg Thr Met Xaa Asp Cys Cys
1 5 10 15
Ser Gly Ser Cys Gly Arg Arg Gly Lys Cys 20 25 78
<210> 259
<211> 310
<212> DNA
<213> Conus striatus
<400> 259 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcagaagca tcgtgccctg 120 aggtcggaca ccaaactctc catgtcgact cgctgcaagg ctgcaggaaa atcatgcagt 180 aggattgcgt ataactgctg caccggttct tgcagatcag gtaaatgcgg ctgatccagc 240 gcctgatctt cccccttctg tgctctatcc tttctgcctg agtcctctta cctgagagtg 300 gtcatgaacc 310
<210> 260
<211> 71
<212> PRT
<213> Conus striatus
<400> 260
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala 1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Ser Met Ser Thr Arg Cys Lys Ala 35 40 45
Ala Gly Lys Ser Cys Ser Arg He Ala Tyr Asn Cys Cys Thr Gly Ser 50 55 60
Cys Arg Ser Gly Lys Cys Gly 65 70
<210> 261
<211> 25
<212> PRT
<213> Conus striatus
<220>
<221> PEPTIDE <222> (1) .. (25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 261
Cys Lys Ala Ala Gly Lys Ser Cys Ser Arg He Ala Xaa Asn Cys Cys
1 " 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 262
<211> 256
<212> DNA
<213> Conus striatus
<400> 262 79 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc aactcatcac agctgatgac tccagaggta cgcaggagca tcgtgccctg 120 aggtcggaca ccaaactctc catgttaact ttgcgctgcg aatcttacgg aaaaccttgt 180 ggtatttaca acgactgctg caatgcatgc gatccagcca aaaagacatg tacgtagctg 240 atccggcgtc tgatct 256
<210> 263
<211> 72
<212> PRT
<213> Conus striatus
<400> 263
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Glu His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Ser Met Leu Thr Leu Arg Cys Glu 35 40 45
Ser Tyr Gly Lys Pro Cys Gly He Tyr Asn Asp Cys Cys Asn Ala Cys 50 55 60
Asp Pro Ala Lys Lys Thr Cys Thr 65 70
<210> 264
<211> 26
<212> PRT
<213> Conus striatus
<220>
<221> PEPTIDE
<222> (1) .. (26)
<223> Xaa at residue 2 is Glu or gamma-carboxy Glu; Xaa at residue 7 an d 20 is Pro or Hyp; Xaa at residue 4 and 11 is Tyr, 1251-Tyr, mon o-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 264
Cys Xaa Ser Xaa Gly Lys Xaa Cys Gly He Xaa Asn Asp Cys Cys Asn
1 5 10 15
Ala Cys Asp Xaa Ala Lys Lys Thr Cys Thr 20 25
<210> 265
<211> 229
<212> DNA
<213> Conus striatus
<400> 265 tctaggtcct ccggcagccc ctgtggtgtt actagtatat gctgtggtag atgctatagg 60 ggtaaatgta cgtagctcat cgggcgtctg atcttccccc ttctgtgctc catccttttc 120 tgcctgagtc ctσcttacct gagagtggtc gtgaaccact catcgcctac tcctctggag 180 gcttcagagg ggctacacta aaataaaagc tatattgcaa tgaaaaaaa 229 80
<210> 266
<211> 24
<212> PRT
<213> Conus striatus
<400> 266
Cys Arg Ser Ser Gly Ser Pro Cys Gly Val Thr Ser He Cys Cys Gly
1 5 10 15
Arg Cys Tyr Arg Gly Lys Cys Thr 20
<210> 267
<211> 24
<212> PRT
<213> Conus striatus
<220>
<221> PEPTIDE <222> (1)..(24)
<223> Xaa at residue 7 is Pro or Hyp; Xaa at residue 19 is Tyr, 125I-Ty r, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 267
Cys Arg Ser Ser Gly Ser Xaa Cys Gly Val Thr Ser He Cys Cys Gly
1 5 10 15
Arg Cys Xaa Arg Gly Lys Cys Thr 20
<210> 268
<211> 26
<212> PRT
<213> Conus striatus
<220>
<221> PEPTIDE <222> (1) .. (26)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 268
Cys Lys Leu Lys Gly Gin Ser Cys Arg Lys Thr Ser Xaa Asp Cys Cys
1 5 10 15
Ser Gly Ser Cys Gly Arg Ser Gly Lys Cys 20 25
<210> 269
<211> 292
<212> DNA
<213> Conus striolatus
<400> 269 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgtctt gctgctcctg 60 acgacctgtc gtctcatcac agctgatgac tccagaggta cgcagaagca tcgttccctg 120 aggtcgacta ctaaagtctc catgtcgact cgctgcaagg gtaaaggagc atcatgtctt 180 aggactgcgt atgactgctg caccggttct tgcaacagag gtagatgtgg ctgatccagc 240 gtctgatctt cccccttctg tgctctatcc ttttctgctt gagtcctcct ta 292 81
<210> 270
<211> 71
<212> PRT
<213> Conus striolatus
<400> 270
Met Lys Leu Thr Cys Val Val He Val Val Leu Leu Leu Leu Thr Thr
1 5 10 15
Cys Arg Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ser Leu Arg Ser Thr Thr Lys Val Ser Met Ser Thr Arg Cys Lys Gly 35 40 45
Lys Gly Ala Ser Cys Leu Arg Thr Ala Tyr Asp Cys Cys Thr Gly Ser 50 55 60
Cys Asn Arg Gly Arg Cys Gly 65 70
<210> 271
<211> 25
<212> PRT
<213> Conus striolatus
<220>
<221> PEPTIDE <222> (1)..(25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, 0 -sulpho-Tyr or O-phospho-Ty
<400> 271
Cys Lys Gly Lys Gly Ala Ser Cys Leu Arg Thr Ala Xaa Asp Cys Cys
1 5 10 15
Thr Gly Ser Cys Asn Arg Gly Arg Cys 20 25
<210> 272
<211> 259
<212> DNA
<213> Conus striolatus
<400> 272 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt tctgctgacg 60 gcgtgtcaac tcatcacagc tgaggactcc agaggtacac agaagcatcg taccctgagg 120 tcgaccgtca gacgctccaa gtccgagttg actacgagat gcaggccttc aggatccaac 180 tgtggtaata ttagtatctg ctgtggtaga tgcgttaaca gaagatgtac gtagctcatc 240 gggcgtctga tctttcccc 259
<210> 273
<211> 71
<212> PRT
<213> Conus striolatus
<400> 273
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Thr Ala Cys
1 5 10 15
Gin Leu He Thr Ala Glu Asp Ser Arg Gly Thr Gin Lys His Arg Thr 82
20 25 30
Leu Arg Ser Thr Val Arg Arg Ser Lys Ser Glu Leu Thr Thr Arg Cys 35 40 45
Arg Pro Ser Gly Ser Asn Cys Gly Asn He Ser He Cys Cys Gly Arg 50 55 60
Cys Val Asn Arg Arg Cys Thr 65 70
<210> 274
<211> 24
<212> PRT
<213> Conus striolatus
<220>
<221> PEPTIDE
<222> (1) .. (24)
<223> Xaa at residue 3 is Pro or Hyp
<400> 274
Cys Arg Xaa Ser Gly Ser Asn Cys Gly Asn He Ser He Cys Cys Gly
1 5 10 15
Arg Cys Val Asn Arg Arg Cys Thr 20
<210> 275
<211> 280
<212> DNA
<213> Conus striolatus
<400> 275 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt tctgttcctg 60 acggcgtgtc aactcatcac agctgaggac tccagaggta cacagaagca tcgttccctg 120 aggtcgacta ccaaagtctc caagtcgact agctgcatga aagccgggtc ttattgcgtc 180 gctactacga gaatctgctg cggttattgc gcttatttcg gcaaaatatg tattgactat 240 cccaaaaact gatcttcccc ctactgtgct ctatcctttt 280
<210> 276
<211> 77
<212> PRT
<213> Conus striolatus
<400> 276
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Asp Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ser Leu Arg Ser Thr Thr Lys Val Ser Lys Ser Thr Ser Cys Met Lys 35 40 45
Ala Gly Ser Tyr Cys Val Ala Thr Thr Arg He Cys Cys Gly Tyr Cys 50 55 60
Ala Tyr Phe Gly Lys He Cys He Asp Tyr Pro Lys Asn 65 70 75 83
<210> 277
<211> 35
<212> PRT
<213> Conus striolatus
<220>
<221> PEPTIDE <222> (1) .. (35)
<223> Xaa at residue 33 is Pro or Hyp; Xaa at residue 10, 21, 24 and 32 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or 0- phospho-Ty
<400> 277
Ser Thr Ser Cys Met Lys Ala Gly Ser Xaa Cys Val Ala Thr Thr Arg
1 5 10 15
He Cys Cys Gly Xaa Cys Ala Xaa Phe Gly Lys He Cys He Asp Xaa 20 25 30
Xaa Lys Asn 35
<210> 278
<211> 174
<212> DNA
<213> Conus textile
<400> 278 gttgactcgg tactgcacgc ctcatggagg acattgtggt tatcataatg actgctgcag 60 tcatcaatgc aatataaaca gaaataaatg tgagtagctg atctggcatc tgatctgtgc 120 tcgtccttac ctgagagtgg tcatgaacca ctcatcacct actcctctgg aggc 174
<210> 279
<211> 31
<212> PRT
<213> Conus textile
<400> 279
Leu Thr Arg Tyr Cys Thr Pro His Gly Gly His Cys Gly Tyr His Asn
1 5 10 15
Asp Cys Cys Ser His Gin Cys Asn He Asn Arg Asn Lys Cys Glu 20 25 30
<210> 280
<211> 28
<212> PRT
<213> Conus textile
<220>
<221> PEPTIDE
<222> (1)..(28)
<223> Xaa at residue 28 is Glu or gamma-carboxy Glu; Xaa at residue 4 i s Pro or Hyp; Xaa at residue 1 and 11 is Tyr, 1251-Tyr, mono-iodo -Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 280
Xaa Cys Thr Xaa His Gly Gly His Cys Gly Xaa His Asn Asp Cys Cys
1 5 10 15
Ser His Gin Cys Asn He Asn Arg Asn Lys Cys Xaa 20 25 84
<210> 281
<211> 28
<212> PRT
<213> Conus textile
<220>
<221> PEPTIDE
<222> (1) .. (28)
<223> Xaa at residue 28 is Glu or gamma-carboxy Glu; Xaa at residue 4 i s Pro or Hyp; Xaa at residue 1 and 11 is Tyr, 1251-Tyr, mono-iodo -Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 281
Xaa Cys Thr Xaa Xaa Gly Gly His Cys Gly Xaa His Asn Asp Cys Cys
1 5 10 15
Ser His Gin Cys Asn He Asn Arg Asn Lys Cys Xaa 20 25
<210> 282
<211> 379
<212> DNA
<213> Conus tulipa
<400> 282 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcatcac agctctgcac tccagaggta cgcagaagca tcgtgccctg 120 gggcggacca ccaaactσac cttgtσgact cgctgcaaat cacccggatc tccatgttca 180 ccgactagtt ataattgctg ctggtcttgc agtccataca gaaaaaaatg taggggctaa 240 tccagcgcct gattttcccc cttctgtgct ctattccttt ctgcctgagt cctccttacc 300 tgaaagtggt catgaaccac tcatcaccta cttctctgga ggcttcggag gagctacatt 360 gaaataaaag ccgcattgc 379
<210> 283
<211> 73
<212> PRT
<213> Conus tulipa
<400> 283
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Leu His Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Gly Arg Thr Thr Lys Leu Thr Leu Ser Thr Arg Cys Lys Ser 35 40 45
Pro Gly Ser Pro Cys Ser Pro Thr Ser Tyr Asn Cys Cys Trp Ser Cys 50 55 60
Ser Pro Tyr Arg Lys Lys Cys Arg Gly 65 70
<210> 284
<211> 27
<212> PRT
<213> Conus tulipa 85
<220>
<221> PEPTIDE
<222> (1)..(27)
<223> Xaa at residue 3, 7, 10 and 21 is Pro or Hyp; Xaa at residue 17 i s Trp or Bromo Trp; Xaa at residue 13 and 22 is Tyr, 1251-Tyr, mo no-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 284
Cys Lys Ser Xaa Gly Ser Xaa Cys Ser Xaa Thr Ser Xaa Asn Cys Cys
1 5 10 15
Xaa Ser Cys Ser Xaa Xaa Arg Lys Lys Cys Arg 20 25
<210> 285
<211> 379
<212> DNA
<213> Conus tulipa
<400> 285 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcatcac agctctgcac tccagaggta cgcagaagca tcgtgccctg 120 gggtcgacca ccaaactcac cttgtcgact cgctgcttgt cacccggatc ttcatgttca 180 ccgactagtt ataattgctg caggtcttgc aatccataca gcagaaaatg taggggctaa 240 tccagcgcct gatcttcccc cttctgtgct ctattccttt ctgcctgagt cctccttacc 300 tgaaagtggt catgaaccac tcatcaccta cttctctgga ggcttcggag gagctacatt 360 gaaataaaag ccgcattgc 379
<210> 286
<211> 73
<212> PRT
<213> Conus tulipa
<400> 286
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Leu His Ser Arg Gly Thr Gin Lys His Arg 20 25 30
Ala Leu Gly Ser Thr Thr Lys Leu Thr Leu Ser Thr Arg Cys Leu Ser 35 40 45
Pro Gly Ser Ser Cys Ser Pro Thr Ser Tyr Asn Cys Cys Arg Ser Cys 50 55 60
Asn Pro Tyr Ser Arg Lys Cys Arg Gly 65 70
<210> 287
<211> 27
<212> PRT
<213> Conus tulipa
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa at residue 4, 10 and 21 is Pro or Hyp; Xaa at residue 13 and 86
22 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 287
Cys Leu Ser Xaa Gly Ser Ser Cys Ser Xaa Thr Ser Xaa Asn Cys Cys
1 5 10 15
Arg Ser Cys Asn Xaa Xaa Ser Arg Lys Cys Arg 20 25
<210> 288
<211> 401
<212> DNA
<213> Conus viola
<400> 288 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcattac agctgatgac tccagaggta cgcagttgca tcgtgccctg 120 aggaaggcca ccaaactccc cgtgtcgact cgctgcatta ctttaggaac acgatgtaag 180 gttccgagtc aatgctgcag atcttcttgc aagaacggtc gttgtgctcc atcccctgaa 240 gaatggtaaa tgtggctgat ccagcgcctg atcttccccc ttctgactgt ctccgacctt 300 ttctgcctga gtcctcctta cctgagaggt gtcatgaacc actcatcacc tactcccctg 360 gaagcttcag aggagctaca ttgaaataaa agccgcattg c 401
<210> 289
<211> 76
<212> PRT
<213> Conus viola
<400> 289
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Leu His Arg 20 25 30
Ala Leu Arg Lys Ala Thr Lys Leu Pro Val Ser Thr Arg Cys He Thr 35 40 45
Leu Gly Thr Arg Cys Lys Val Pro Ser Gin Cys Cys Arg Ser Ser Cys 50 55 60
Lys Asn Gly Arg Cys Ala Pro Ser Pro Glu Glu Trp 65 70 75
<210> 290
<211> 31
<212> PRT
<213> Conus viola
<220>
<221> PEPTIDE
<222> (1) .. (31)
<223> Xaa at residue 29 and 30 is Glu or gamma-carboxy Glu; Xaa at resi due 11, 26 and 28 is Pro or Hyp; Xaa at residue 31 is Trp or Brom o Tr
<400> 290
Cys He Thr Leu Gly Thr Arg Cys Lys Val Xaa Ser Gin Cys Cys Arg 87
1 5 10 15
Ser Ser Cys Lys Asn Gly Arg Cys Ala Xaa Ser Xaa Xaa Xaa Xaa 20 25 30
<210> 291
<211> 372
<212> DNA
<213> Conus viola
<400> 291 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcattat agctggggac tccagaggta cgcagttgca tcgtgccctg 120 aggaaggcca ccaaactctc cgtgtcgact cgctgcaaga gtagaggatc atcatgtcgt 180 aggacttcgt atgactgctg cacgggttct tgcagaaatg gtaaatgtgg ctgatccagc 240 gcctgatctt cccccttctg tgctccatcc ttttctgcct gagtcctcct tacctgagag 300 tgggcatgaa ccactcatca cctactccct ggaagcttca gaggagctac attgaaataa 360 aagccgcatt gc 372
<210> 292
<211> 71
<212> PRT
<213> Conus viola
<400> 292
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He He Ala Gly Asp Ser Arg Gly Thr Gin Leu His Arg 20 25 ' 30
Ala Leu Arg Lys Ala Thr Lys Leu Ser Val Ser Thr Arg Cys Lys Ser 35 40 45
Arg Gly Ser Ser Cys Arg Arg Thr Ser Tyr Asp Cys Cys Thr Gly Ser 50 55 ' 60
Cys Arg Asn Gly Lys Cys Gly 65 70
<210> 293
<211> 25
<212> PRT
<213> Conus viola
<220>
<221> PEPTIDE <222> (1)..(25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 293
Cys Lys Ser Arg Gly Ser Ser Cys Arg Arg Thr Ser Xaa Asp Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Asn Gly Lys Cys 20 25 88
<210> 294
<211> 380
<212> DNA
<213> Conus viola
<400> 294 accaaaacca tcatcaaaat gaaactgacg tgtgtggcga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcattac agctgaagac tccagaggta cgcatgagca tcttgccctg 120 aagtcgacct ccaaagtctc caagtcgact agctgcatgg aagccagatc ttattgcgga 180 cctgctacta cgaaaatctg ctgcgatttt tgcagtccat tcagcgatag atgtatgaac 240 aatcccaaca attgatcttc ccccttgtgt gctccatctt ttctgcctga gtcctcctta 300 cctgagagtg gtcatgaacc actcatcacc tactcctctg gaggcttcag aggagttaca 360 ttgaaataaa agccgcatgc 380
<210> 295
<211> 78
<212> PRT
<213> Conus viola
<400> 295
Met Lys Leu Thr Cys Val Ala He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Asp Ser Arg Gly Thr His Glu His Leu 20 25 30
Ala Leu Lys Ser Thr Ser Lys Val Ser Lys Ser Thr Ser Cys Met Glu 35 40 45
Ala Arg Ser Tyr Cys Gly Pro Ala Thr Thr Lys He Cys Cys Asp Phe 50 55 60
Cys Ser Pro Phe Ser Asp Arg Cys Met Asn Asn Pro Asn Asn 65 70 75
<210> 296
<211> 36
<212> PRT
<213> Conus viola
<220>
<221> PEPTIDE
<222> (1)..(36)
<223> Xaa at residue6 is Glu or gamma-carboxy Glu; Xaa at residue 13, 25 and 34 is Pro or Hyp; Xaa at residue 10 is Tyr, 1251-Tyr, mono -iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 296
Ser Thr Ser Cys Met Xaa Ala Arg Ser Xaa Cys Gly Xaa Ala Thr Thr
1 5 10 15
Lys He Cys Cys Asp Phe Cys Ser Xaa Phe Ser Asp Arg Cys Met Asn 20 25 30
Asn Xaa Asn Asn 35
<210> 297 <211> 373 89
<212> DNA
<213> Conus viola
<400> 297 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgctcctg 60 acggcctgtc agctcattac agctgaggac tccagaggta cgcagttgca tcgtgccctg 120 aggaagacca ccaaactctc cttgtcgact cgctgcaagg gtccaggagc catatgtata 180 aggattgcgt ataactgctg caagtattct tgcggaaatg gtaaatgtgg ctgatccagc 240 gcctgatctt cccccttgtg tgctccatcc tttttctgcc tgagtcctcc ttacctgaga 300 gtggtcatga accactcatc acctactcct ctggaggctt cagaggagct acattgaaat 360 aaaagccgca tgc 373
<210> 298
<211> 71
<212> PRT
<213> Conus viola
<400> 298
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Asp Ser Arg Gly Thr Gin Leu His Arg 20 25 30
Ala Leu Arg Lys Thr Thr Lys Leu Ser Leu Ser Thr Arg Cys Lys Gly 35 40 45
Pro Gly Ala He Cys He Arg He Ala Tyr Asn Cys Cys Lys Tyr Ser 50 55 60
Cys Gly Asn Gly Lys Cys Gly 65 70
<210> 299
<211> 25
<212> PRT
<213> Conus viola
<220>
<221> PEPTIDE <222> (1)..(25)
<223> Xaa at residue 3 is Pro or Hyp; Xaa at residue 13 and 18 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-T y
<400> 299
Cys Lys Gly Xaa Gly Ala He Cys He Arg He Ala Xaa Asn Cys Cys
1 5 10 15
Lys Xaa Ser Cys Gly Asn Gly Lys Cys 20 25
<210> 300
<211> 353
<212> DNA
<213> Conus viola
<400> 300 accaaaacca tcatcaaaat gaaactgacg tgtgtggtga tcgtcgccgt gctgttcctg 60 90
acggcctgtc aattcatcac agctgatgac tccagaagta cgcagaagca tcgtgccctg 120 aggtcgacca ccaaacactt tatgttgact tggtactgca cgccttatgg aggacattgt 180 ggttattata atgactgctg cagtcatcaa tgcaatataa acagaaataa atgtgagtag 240 ctgatccggc atctgatctg tgctcgccct aacctgagag tggtcatgaa ccactcatca 300 tctactcctc tggaggcttc agaggagcta catggaaata aaagccgcat tgc 353
<210> 301
<211> 73
<212> PRT
<213> Conus viola
<400> 301
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Phe He Thr Ala Asp Asp Ser Arg Ser Thr Gin Lys His Arg 20 25 30
Ala Leu Arg Ser Thr Thr Lys His Phe Met Leu Thr Trp Tyr Cys Thr 35 40 45
Pro Tyr Gly Gly His Cys Gly Tyr Tyr Asn Asp Cys Cys Ser His Gin 50 55 60
Cys Asn He Asn Arg Asn Lys Cys Glu 65 70
<210> 302
<211> 28
<212> PRT
<213> Conus viola
<220>
<221> PEPTIDE
<222> (1) .. (28)
<223> Xaa at residue 28 is Glu or gamma-carboxy Glu; Xaa at residue 4 i s Pro or Hyp; Xaa at residue 1, 5, 11 and 12 is Tyr, 1251-Tyr, mo no-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 302
Xaa Cys Thr Xaa Xaa Gly Gly His Cys Gly Xaa Xaa Asn Asp Cys Cys
1 5 10 15
Ser His Gin Cys Asn He Asn Arg Asn Lys Cys Xaa 20 25
<210> 303
<211> 294
<212> DNA
<213> Conus pulicarius
<400> 303 ggatccatga aactgacgtg cgtggtgatt atcgccgtgc tgttcctgac ggcctgtcaa 60 ctcattacag ctgagactta ctccagaggt aagcagatgc accgtgctct gaggtcaact 120 gacaaaaact ccaagttgac cagggaatgc acacctccag atggagcttg tggtttacct 180 acacactgct gcgggttttg cgatatggca aacaacagat gtctgtaaag cgtctgatat 240 91 tccccttctg tgctctatcc tctttggcct gagtcatcca tacctgtgct cgag 294
<210> 304
<211> 73
<212> PRT
<213> Conus pulicarius
<400> 304
Met Lys Leu Thr Cys Val Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Glu Thr Tyr Ser Arg Gly Lys Gin Met His 20 25 30
Arg Ala Leu Arg Ser Thr Asp Lys Asn Ser Lys Leu Thr Arg Glu Cys 35 40 45
Thr Pro Pro Asp Gly Ala Cys Gly Leu Pro Thr His Cys Cys Gly Phe 50 55 60
Cys Asp Met Ala Asn Asn Arg Cys Leu 65 70
<210> 305
<211> 27
<212> PRT
<213> Conus pulicarius
<220>
<221> PEPTIDE <222> (1)..(27)
<223> Xaa at residue 1 is Glu or gamma-carboxy Glu; Xaa at residue 4, 5 and 12 is Pro or Hy
<400> 305
Xaa Cys Thr Xaa Xaa Asp Gly Ala Cys Gly Leu Xaa Thr His Cys Cys
1 5 10 15
Gly Phe Cys Asp Met Ala Asn Asn Arg Cys Leu 20 25
<210> 306
<211> 294
<212> DNA
<213> Conus pulicarius
<400> 306 ggatccatga aactgacgtg cgtggtgatt atcgccgtgc tgttcctgac ggcctgtcaa 60 ctcattacag ctgagactta ctccagaggt aagcagatgc accgtgctct gaggtcaact 120 gacaaaaact cccagttgac cagggaatgc acacctccag gtggagcttg tggtttacct 180 acacactgct gcgggttttg cgatatggca aacaacagat gtctgtaaag cgtctgatat 240 tccccttctg tgctctatcc tctttggcct gagtcatcca tacctgtgct cgag 294
<210> 307
<211> 73
<212> PRT
<213> Conus pulicarius
<400> 307
Met Lys Leu Thr Cys Val Val He He Ala Val Leu Phe Leu Thr Ala
1 5 10 15 92
Cys Gin Leu He Thr Ala Glu Thr Tyr Ser Arg Gly Lys Gin Met His 20 25 30
Arg Ala Leu Arg Ser Thr Asp Lys Asn Ser Gin Leu Thr Arg Glu Cys 35 40 45
Thr Pro Pro Gly Gly Ala Cys Gly Leu Pro Thr His Cys Cys Gly Phe 50 55 60
Cys Asp Met Ala Asn Asn Arg Cys Leu 65 70
<210> 308
<211> 27
<212> PRT
<213> Conus pulicarius
<220>
<221> PEPTIDE <222> (1) .. (27)
<223> Xaa at residue 1 is Glu or gamma-carboxy Glu; Xaa at residue 4, 5 and 12 is Pro or Hy
<400> 308
Xaa Cys Thr Xaa Xaa Gly Gly Ala Cys Gly Leu Xaa Thr His Cys Cys
1 5 10 15
Gly Phe Cys Asp Met Ala Asn Asn Arg Cys Leu 20 25
<210> 309
<211> 307
<212> DNA
<213> Conus rattus
<400> 309 ggatccatga aactgacgtg tgtggtgatc atcgccgtgc tgttcctggc agcctgtcaa 60 cctgttacaa ctgagacttt ctccagaggt aaggagaagc gtcgtgctct gaggtcaact 120 gacggcaact cccggttgac cagggcatgc acgcctgaag gtggagcctg tagtagtggg 180 cgtcactgct gcggcttttg cgataacgtg tcccacacgt gctatggtga aacaccatct 240 ctccactgat gtttcccctt ctgtgctcta tcttcttttg cctgagtcat ccatacctgt 300 gctcgag 307
<210> 310
<211> 80
<212> PRT
<213> Conus rattus
<400> 310
Met Lys Leu Thr Cys Val Val He He Ala Val Leu Phe Leu Ala Ala
1 5 10 15
Cys Gin Pro Val Thr Thr Glu Thr Phe Ser Arg Gly Lys Glu Lys Arg 20 25 30
Arg Ala Leu Arg Ser Thr Asp Gly Asn Ser Arg Leu Thr Arg Ala Cys 35 40 45
Thr Pro Glu Gly Gly Ala Cys Ser Ser Gly Arg His Cys Cys Gly Phe 93
50 55 60
Cys Asp Asn Val Ser His Thr Cys Tyr Gly Glu Thr Pro Ser Leu His 65 70 75 80
<210> 311
<211> 34
<212> PRT
<213> Conus rattus
<220>
<221> PEPTIDE
<222> (1)..(34)
<223> Xaa at residue 5 and 29 is Glu or gamma-carboxy Glu; Xaa at resid ue 4 and 31 is Pro or Hyp; Xaa at residue 27 is Tyr, 1251-Tyr, mo no-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty
<400> 311
Ala Cys Thr Xaa Xaa Gly Gly Ala Cys Ser Ser Gly Arg His Cys Cys
1 5 10 15
Gly Phe Cys Asp Asn Val Ser His Thr Cys Xaa Gly Xaa Thr Xaa Ser 20 25 30
Leu His
<210> 312
<211> 342
<212> DNA
<213> Conus stercusmuscarum
<220>
<221> misc_feature
<222> (1) .. (342)
<223> n may be any nucleotide
<400> 312 agatccatga aactgacgtg cgtggtgatc gtcgccgtgc tgctcctgac ggcctgtcaa 60 ctcatcacag ctgatgactc cagaggtacg caggagcatc gtgccctgag gtcggacacc 120 aaactcccca tatcgactcg ctgcaagggt aaaggagcat catgtcataa gactatgtat 180 gactgctgca gcggttcctg caccagaggt agatgtggct gatccagcgc ctgatcttcc 240 cccttctgtg ctctatcctt ttctgcctga gtcatcatac ctgtgctcga gcgttactag 300 tggatccgag ctcggtacca agcttggcgt aatcataaaa nc 342
<210> 313
<211> 71
<212> PRT
<213> Conus stercusmuscarum
<400> 313
Met Lys Leu Thr Cys Val Val He Val Ala Val Leu Leu Leu Thr Ala
1 5 10 15
Cys Gin Leu He Thr Ala Asp Asp Ser Arg Gly Thr Gin Glu His Arg 20 25 30
Ala Leu Arg Ser Asp Thr Lys Leu Pro He Ser Thr Arg Cys Lys Gly 35 40 45 94
Lys Gly Ala Ser Cys His Lys Thr Met Tyr Asp Cys Cys Ser Gly Ser 50 55 60
Cys Thr Arg Gly Arg Cys Gly 65 70
<210> 314
<211> 25
<212> PRT
<213> Conus stercusmuscarum
<220>
<221> PEPTIDE <222> (1) .. (25)
<223> Xaa at residue 13 is Tyr, 1251-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O -sulpho-Tyr or O-phospho-Ty
<400> 314
Cys Lys Gly Lys Gly Ala Ser Cys His Lys Thr Met Xaa Asp Cys Cys
1 5 10 15
Ser Gly Ser Cys Thr Arg Gly Arg Cys 20 '25
<210> 315
<211> 33
<212> PRT
<213> Conus arenatus
<400> 315
Gin Cys Ser Ala Asn Gly Gly Ser Cys Thr Arg His Phe His Cys Cys
1 5 10 15
Ser Leu Tyr Cys Asn Lys Asp Ser Ser Val Cys Val Ala Thr Ser Tyr 20 25 30
Pro
<210> 316
<211> 28
<212> PRT
<213> Conus arenatus
<400> 316
Thr Cys Asn Thr Pro Thr Glu Tyr Cys Thr Leu His Arg His Cys Cys
1 5 10 15
Ser Gly Tyr Cys His Lys Thr He Gin Ala Cys Ser 20 25
<210> 317
<211> 33
<212> PRT
<213> Conus arenatus
<400> 317
Gin Cys Thr Pro Asn Gly Gly Ser Cys Ser Arg His Phe His Cys Cys
1 5 10 15
Ser Leu Tyr Cys Asn Lys Ser Thr Gly Val Cys He Ala Thr Ser Tyr 20 25 30
Pro 95
<210> 318
<211> 33
<212> PRT
<213> Conus arenatus
<400> 318
Gin Cys Thr Pro Asn Gly Gly Ser Cys Ser Arg His Phe His Cys Cys
1 5 10 15
Ser Leu Tyr Cys Asn Lys Ser Thr Gly Val Cys He Ala Thr Ser Tyr 20 25 30
Pro
<210> 319
<211> 27
<212> PRT
<213> Conus arenatus
<400> 319
Glu Cys Thr Pro Pro Gly Gly Ala Cys Gly Leu Pro Thr His Cys Cys
1 5 10 15
Gly Phe Cys Asp Thr Ala Asn Asn Arg Cys Leu 20 25
<210> 320
<211> 28
<212> PRT
<213> Conus arenatus
<400> 320
Thr Cys Asn Thr Pro Thr Glu Tyr Cys Thr Leu His Gin His Cys Cys
1 5 10 15
Ser Gly His Cys His Lys Thr He Gin Ala Cys Ala 20 25
<210> 321
<211> 30
<212> PRT
<213> Conus arenatus
<400> 321
Gin Cys Ser Pro He Gly Gly Tyr Cys Thr Leu His He His Cys Cys
1 5 10 15
Ser Asn His Cys He Lys Pro He Gly Arg Cys Val Ala Thr 20 25 30
<210> 322
<211> 30
<212> PRT
<213> Conus arenatus
<400> 322
Gin Cys Leu Pro Asn Gly Gly Tyr Cys Thr Leu His He His Cys Cys
1 5 10 15
Ser Asp His Cys He Lys Pro He Asp Arg Cys Val Ala Thr 20 25 30 96
<210> 323
<211> 25
<212> PRT
<213> Conus aurisiacus
<400> 323
Cys Lys Gly Lys Gly Lys Pro Cys Ser Arg He Ser Tyr Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 324
<211> 32
<212> PRT
<213> Conus aurisiacus
<400> 324
Cys Met Glu Ala Gly Ser Tyr Cys Gly Ser Thr Thr Arg He- Cys Cys
1 5 10 15
Gly Phe Cys Ala Tyr Phe Gly Lys Lys Cys He Asp Tyr Pro Ser Asn 20 25 30
<210> 325
<211> 25
<212> PRT
<213> Conus aurisiacus
<400> 325
Cys Lys Ala Lys Gly Lys Pro Cys Ser Arg He Ala Tyr Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 326
<211> 26
<212> PRT
<213> Conus aurisiacus
<400> 326
Cys Ala Ser Tyr Gly Lys Pro Cys Gly He Asp Asn Asp Cys Cys Asn
1 5 10 15
Ala Cys Asp Pro Gly Arg Asn He Cys Thr 20 25
<210> 327
<211> 36
<212> PRT
<213> Conus bullatus
<400> 327
Ser Thr Ser Cys Met Glu Ala Gly Ser Tyr Cys Gly Pro Ala Thr Thr
1 5 10 15
Lys He Cys Cys Asp Phe Cys Ser Pro Phe Ser Asp Arg Cys Met Asn 20 25 30
Asn Pro Asn Asn 35
<210> 328 <211> 31 97
<212> PRT
<213> Conus bullatus
<400> 328
Cys He Thr Pro Gly Thr Arg Cys Lys Val Pro Ser Gin Cys Cys Arg
1 5 10 15
Gly Pro Cys Lys Asn Gly Arg Cys Thr Pro Ser Pro Ser Glu Trp 20 25 30
<210> 329
<211> 26
<212> PRT
<213> Conus bullatus
<400> 329
Cys Ala Thr Tyr Gly Lys Pro Cys Gly He Gin Asn Asp Cys Cys Asn
1 5 10 15
Thr Cys Asp Pro Ala Arg Arg Thr Cys Thr 20 25
<210> 330
<211> 25
<212> PRT
<213> Conus bullatus
<400> 330
Cys Lys Gly Pro Gly Ala Ser Cys He Arg He Ala Tyr Asn Cys Cys
1 5 10 15
Lys Tyr Ser Cys Arg Asn Gly Lys Cys 20 25
<210> 331
<211> 36
<212> PRT
<213> Conus bullatus
<400> 331
Ser Thr Ser Cys Met Ala Ala Gly Ser Tyr Cys Gly Pro Ala Thr Thr
1 5 10 15
Asn He Cys Cys Asp Phe Cys Ser Pro Phe Ser Asp Arg Cys Met Lys 20 25 30
Lys Pro Asn Asn 35
<210> 332
<211> 25
<212> PRT
<213> Conus bullatus
<400> 332
Cys Lys Ser Lys Gly Ser Ser Cys His Arg Thr Ser Tyr Asp Cys Cys
1 - 5 10 15
Thr Gly Ser Cys Arg Asn Gly Arg Cys 20 25
<210> 333 <211> 25 <212> PRT 98
<213> Conus catus
<400> 333
Cys Lys Ser Thr Gly Ala Ser Cys Arg Arg Thr Ser Tyr Asp Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Arg Cys 20 25
<210> 334
<211> 25
<212> PRT
<213> Conus catus
<400> 334
Cys Gin Gly Arg Gly Ala Ser Cys Arg Lys Thr Met Tyr Asn Cys Cys
1 5 10 15
Ser Gly Ser Cys Asn Arg Gly Ser Cys 20 25
<210> 335
<211> 28
<212> PRT
<213> Conus catus
<400> 335
Cys Leu Pro Ala Gly Glu Ser Cys Leu Phe Ser Arg He Arg Cys Cys
1 5 10 15
Gly Thr Cys Ser Ser Val Leu Lys Ser Cys Val Ser 20 25
<210> 336
<211> 25
<212> PRT
<213> Conus catus
<400> 336
Cys Gin Gly Arg Gly Gly Pro Cys Thr Lys Ala Val Phe Asn Cys Cys
1 5 10 15
Ser Gly Ser Cys Asn Arg Gly Arg Cys 20 25
<210> 337
<211> 26
<212> PRT
<213> Conus catus
<400> 337
Cys Ala Thr Tyr Gly Lys Pro Cys Gly He Gin Asn Asp Cys Cys Asn
1 5 10 15
Thr Cys Asp Pro Ala Arg Lys Thr Cys Thr 20 25
<210> 338
<211> 25
<212> PRT
<213> Conus catus
<400> 338
Cys Arg Gly Arg Gly Gly Pro Cys Thr Lys Ala Met Phe Asn Cys Cys
1 5 10 15 99
Ser Gly Ser Cys Asn Arg Gly Arg Cys 20 25
<210> 339
<211> 33
<212> PRT
<213> Conus caracteristicus
<400> 339
Gin Cys Ser Ala Asn Gly Gly Ser Cys Thr Arg His Phe His Cys Cys
1 5 10 15
Ser Leu Tyr Cys Asn Lys Asp Ser Ser Val Cys Val Ala Thr Ser Tyr 20 25 30
Pro
<210> 340
<211> 26
<212> PRT
<213> Conus consors
<400> 340
Cys Ala Ser Tyr Gly Lys Pro Cys Gly He Asp Asn Asp Cys Cys Asn
1 5 10 15
Thr Cys Asp Pro Ala Arg Lys Thr Cys Thr 20 25
<210> 341
<211> 25
<212> PRT
<213> Conus consors
<400> 341
Cys Lys Gly Thr Gly Lys Pro Cys Ser Arg He Ala Tyr Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 342
<211> 36
<212> PRT
<213> Conus consors
<400> 342
Ala Thr Asp Cys He Glu Ala Gly Asn Tyr Cys Gly Pro Thr Val Met
1 5 10 15
Lys He Cys Cys Gly Phe Cys Ser Pro Tyr Ser Lys He Cys Met Asn 20 25 30
Tyr Pro Gin Asn 35
<210> 343
<211> 27
<212> PRT
<213> Conus catus
<400> 343
Cys Lys Gly Lys Gly Ala Ser Cys Thr Arg Leu Met Tyr Asp Cys Cys 100
1 5 10 15
His Gly Ser Cys Ser Ser Ser Lys Gly Arg Cys 20 25
<210> 344
<211> 25
<212> PRT
<213> Conus consors
<400> 344
Cys Lys Gly Lys Gly Ala Ser Cys His Arg Thr Ser Tyr Asp Cys Cys
1 5 10 15
Thr Gly Ser Cys Asn Arg Gly Lys Cys 20 25
<210> 345
<211> 26
<212> PRT
<213> Conus consors
<400> 345
Cys Ala Ser Tyr Gly Lys Pro Cys Gly He Tyr Asn Asp Cys Cys Asn
1 5 10 15
Thr Cys Asp Pro Ala Arg Lys Thr Cys Thr 20 25
<210> 346
<211> 25
<212> PRT
<213> Conus consors
<400> 346
Cys Lys Gly Thr Gly Lys Pro Cys Ser Arg Val Ala Tyr Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 347
<211> 35
<212> PRT
<213> Conus consors
<400> 347
Ser Thr Ser Cys Met Lys Ala Gly Ser Tyr Cys Arg Ser Thr Thr Arg
1 5 10 15
Thr Cys Cys Gly Tyr Cys Ala Tyr Phe Gly Lys Phe Cys He Asp Phe 20 25 30
Pro Ser Asn 35
<210> 348
<211> 25
<212> PRT
<213> Conus circumcisus
<400> 348
Cys Lys Gly Lys Gly Ala Ser Cys Arg Lys Thr Met Tyr Asn Cys Cys
1 5 10 15 101
Ser Gly Ser Cys Ser Asn Gly Arg Cys 20 25
<210> 349
<211> 35
<212> PRT
<213> Conus circumcisus
<400> 349
Ser Thr Ser Cys Met Glu Ala Gly Ser Tyr Cys Arg Ser Thr Thr Arg
1 5 10 15
Thr Cys Cys Gly Tyr Cys Ser Tyr Phe Ser Lys Lys Cys He Asp Phe 20 25 30
Pro Ser Asn 35
<210> 350
<211> 27
<212> PRT
<213> Conus circumcisus
<400> 350
Cys Lys Ser Lys Gly Ala Lys Cys Ser Arg Leu Met Tyr Asp Cys Cys
1 5 10 15
Ser Gly Ser Cys Ser Arg Tyr Ser Gly Arg Cys 20 25
<210> 351
<211> 35
<212> PRT
<213> Conus circumcisus
<400> 351
Ser Thr Gly Cys Met Lys Ala Gly Ser Tyr Cys Arg Ser Thr Thr Arg
1 5 10 15
Thr Cys Cys Gly Tyr Cys Ala Tyr Phe Gly Lys Lys Cys He Asp Tyr 20 25 30
Pro Ser Asn 35
<210> 352
<211> 28
<212> PRT
<213> Conus dalli
<400> 352
Ser Cys Thr Pro Pro Gly Gly Pro Cys Gly Tyr Tyr Asn Asp Cys Cys
1 5 10 15
Ser His Gin Cys Asn He Ser Arg Asn Lys Cys Glu 20 25
<210> 353
<211> 25
<212> PRT
<213> Conus distans
<220>
<221> PEPTIDE 102
<222> (1) .. (25) <223> Xaa is Hyp
<400> 353
Cys Glu Asp Xaa Gly Glu Xaa Cys Gly Ser Asp His Ser Cys Cys Gly
1 5 10 15
Gly Ser Cys Asn His Asn Val Cys Ala 20 25
<210> 354
<211> 27
<212> PRT
<213> Conus ermineus
p Cys
Figure imgf000184_0001
Cys Asn Lys Thr Cys Thr Arg Ser Lys Cys Pro 20 25
<210> 355
<211> 27
<212> PRT
<213> Conus ermineus
<400> 355
Ala Cys Trp Ser Ser Gly Thr Pro Cys Gly Thr Asp Ser Leu Cys Cys
1 5 10 15
Gly Gly Cys Asn Val Ser Lys Ser Lys Cys Asn 20 25
<210> 356
<211> 27
<212> PRT
<213> Conus geographus
<400> 356
Cys Lys Ser Pro Gly Ser Ser Cys Ser Pro Thr Ser Tyr Asn Cys Cys
1 5 10 15
Arg Ser Cys Asn Pro Tyr Ala Lys Arg Cys Tyr 20 25
<210> 357
<211> 29
<212> PRT
<213> Conus geographus
<400> 357
Cys Lys Ser Pro Gly Thr Pro Cys Ser Arg Gly Met Arg Asp Cys Cys
1 5 10 15
Thr Pro Cys Leu Leu Tyr Ser Asn Lys Cys Arg Arg Tyr 20 25
<210> 358
<211> 30
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species 103
<400> 358
Cys Leu Ser Pro Gly Ser Arg Cys His Lys Thr Met Arg Asn Cys Cys
1 5 10 15
Thr Ser Cys Ser Ser Tyr Lys Gly Lys Cys Arg Pro Arg Lys 20 25 30
<210> 359
<211> 27
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<400> 359
Cys Lys Pro Pro Gly Arg Lys Cys Leu Asn Arg Lys Asn Glu Cys Cys
1 5 10 15
Ser Lys Phe Cys Asn Glu His Leu His Met Cys 20 25
<210> 360
<211> 26
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<400> 360
Cys Lys Pro Pro Arg Arg Lys Cys Leu Lys He Lys Asp Lys Cys Cys
1 5 10 15
Asn Phe Cys Asn Thr His Leu Asn Met Cys 20 25
<210> 361
<211> 28
<212> PRT
<213> Unknown
<220>
<223> unknown Conus species
<400> 361
Cys Ala Gly Pro Gly Thr He Cys Pro Asn Arg Val Cys Cys Gly Tyr
1 5 ' 10 15
Cys Ser Lys Arg Thr His Leu Cys His Ser Arg Thr 20 25
<210> 362
<211> 27
<212> PRT
<213> Conus laterculatus
<400> 362
Lys Cys Trp Pro Ser Gly Ser Tyr Cys Arg Ala Asn Ser Lys Cys Cys
1 5 10 15
Ser Gly Cys Asp Arg Asn Arg Asn Lys Cys Tyr 20 . 25 104
<210> 363
<211> 27
<212> PRT
<213> Conus laterculatus
<400> 363
Cys Leu Pro Pro Gly Ser Tyr Cys Lys Ala Thr Thr Glu Val Cys Cys
1 5 10 15
Ser Ser Cys Leu Gin Phe Ala Gin He Cys Ser 20 25
<210> 364
<211> 30
<212> PRT
<213> Conus lynceus
<400> 364
Cys Lys Ser Pro Gly Ser Pro Cys Ser Val Thr Ser Tyr Asn Cys Cys
1 5 10 15
Thr Phe Cys Ser Ser Tyr Thr Lys Lys Cys Arg Ala Ser Leu 20 25 30
<210> 365
<211> 28
<212> PRT
<213> Conus lynceus
<400> 365
Cys Ala Gly Pro Gly Ala He Cys Pro Asn Arg Val Cys Cys Gly Tyr
1 5 10 15
Cys Ser Lys Arg Thr His Leu Cys His Ser Arg Thr 20 25
<210> 366
<211> 27
<212> PRT
<213> Conus lynceus
<400> 366
Ala Cys Trp Ser Ser Gly Thr Pro Cys Gly Thr Asp Ser Leu Cys Cys
1 5 10 15
Gly Gly Cys Asn Val Ser Lys Ser Lys Cys Asn 20 25
<210> 367
<211> 27
<212> PRT
<213> Conus lynceus
<400> 367
Lys Cys Trp Ser Pro Gly Thr Tyr Cys Arg Ala His Ser Lys Cys Cys
1 5 10 15
Arg Gly Cys Asp Gin Asn Arg Asn Lys Cys Tyr 20 25
<210> 368
<211> 29
<212> PRT
<213> Conus laterculatus 105
<400> 368
Cys Lys Ser Pro Gly Ser Ser Cys Ser Val Ser Met Arg Asn Cys Cys
1 5 10 15
Thr Ser Cys Asn Ser Arg Thr Lys Lys Cys Thr Arg Arg 20 25
<210> 369
<211> 27
<212> PRT
<213> Conus laterculatus
<400> 369
Thr Cys Trp Pro Ser Gly Thr Ala Cys Gly He Asp Ser Asn Cys Cys
1 5 10 15
Ser Gly Cys Asn Val Ser Arg Ser Lys Cys Asn 20 25
<210> 370
<211> 27
<212> PRT
<213> Conus laterculatus
<400> 370
Lys Cys Trp Pro Ser Gly Ser Tyr Cys Arg Ala Asn Ser Lys Cys Cys
1 5 10 15
Ser Gly Cys Asp Arg Asn Arg Ser Lys Cys Asn 20 25
<210> 371
<211> 37
<212> PRT
<213> Conus leopardus
<400> 371
Ser Leu Phe Glu Cys Ala Pro Ser Gly Gly Arg Cys Gly Phe Leu Lys
1 5 10 15
Ser Cys Cys Glu Gly Tyr Cys Asp Gly Glu Ser Thr Ser Cys Val Ser 20 25 30
Gly Pro Tyr Ser He 35
<210> 372
<211> 30
<212> PRT
<213> Conus leopardus
<400> 372
Trp Pro Leu Asp Cys Thr Ala Pro Ser Gin Pro Cys Gly Tyr Phe Pro
1 5 10 15
Arg Cys Cys Gly His Cys Asp Val Arg Arg Val Cys Thr Ser 20 25 30
<210> 373
<211> 31
<212> PRT
<213> Conus leopardus
<400> 373
Cys Met Ser Pro Gly Gly He Cys Gly Asp Phe Gly Asp Cys Cys Glu 106
1 5 10 15
He Cys Asn Val Tyr Gly He Cys Val Ser Asp Leu Pro Gly He 20 25 30
<210> 374
<211> 27
<212> PRT
<213> Conus leopardus
<400> 374
Tyr Cys Ala Pro Pro Gly Gly Ala Cys Gly Phe Phe Asp His Cys Cys
1 5 10 15
Gly Tyr Cys Glu Thr Phe Tyr Asn Thr Cys Arg 20 25
<210> 375
<211> 25
<212> PRT
<213> Conus magus
<400> 375
Cys Lys Gly Thr Gly Lys Pro Cys Ser Arg He Ala Tyr Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 376
<211> 26
<212> PRT
<213> Conus magus
<400> 376
Cys Ala Ser Tyr Gly Lys Pro Cys Gly He Tyr Asn Asp Cys Cys Asn
1 5 10 15
Thr Cys Asp Pro Ala Arg Lys Thr Cys Thr 20 25
<210> 377
<211> 27
<212> PRT
<213> Conus miles
<400> 377
Cys Asn Asp Arg Gly Gly Gly Cys Ser Gin His Pro His Cys Cys Gly
1 5 10 15
Gly Thr Cys Asn Lys Leu He Gly Val Cys Leu 20 25
<210> 378
<211> 25
<212> PRT
<213> Conus monachus
<400> 378
Cys Lys Ser Thr Gly Lys Ser Cys Ser Arg He Ala Tyr Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25 107
<210> 379
<211> 25
<212> PRT
<213> Conus monachus
<400> 379
Cys Lys Gly Lys Gly Ser Ser Cys Ser Arg Thr Met Tyr Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Asn Arg Gly Lys Cys 20 25
<210> 380
<211> 35
<212> PRT
<213> Conus obscurus
<400> 380
Ser Pro Pro Cys Met Lys Gly Gly Ser Ser Cys Arg Gly Thr Thr Gly
1 5 10 15
Val Cys Cys Gly Phe Cys Ser Asp Phe Gly Tyr Lys Cys Arg Asp Tyr 20 25 30
Pro Gin Asn 35
<210> 381
<211> 28
<212> PRT
<213> Conus obscurus
<400> 381
Cys Leu Pro Asp Gly Thr Ser Cys Leu Phe Ser Arg He Arg Cys Cys
1 5 10 15
Gly Thr Cys Ser Ser He Leu Lys Ser Cys Val Ser 20 25
<210> 382
<211> 27
<212> PRT
<213> Conus purpurascens
<220>
<221> PEPTIDE
<222> (1) .. (27)
<223> Xaa is Hyp
<400> 382
Xaa Cys Lys Thr Xaa Gly Arg Lys Cys Phe Xaa His Gin Lys Asp Cys
1 5 10 15
Cys Gly Arg Ala Cys He He Thr He Cys Pro 20 25
<210> 383
<211> 26
<212> PRT
<213> Conus purpurascens
<220>
<221> PEPTIDE
<222> (1) .. (26)
<223> Xaa at residue 5 is Hyp; Xaa at residue 12 is gamma-carboxy-Glu 108
<400> 383
Ser Cys Lys Leu Xaa Gly Ala Tyr Cys Asn Ala Xaa Asp Tyr Asp Cys
1 5 10 15
Cys Leu Arg Cys Lys Val Gly Gly Thr Cys 20 25
<210> 384
<211> 27
<212> PRT
<213> Conus purpurascens
<400> 384
Pro Cys Lys Lys Thr Gly Arg Lys Cys Phe Pro His Gin Lys Asp Cys
1 5 10 15
Cys Gly Arg Ala Cys He He Thr He Cys Pro 20 25
<210> 385
<211> 30
<212> PRT
<213> Conus pulicarius
<400> 385
Gin Cys Ser Pro Asn Gly Gly Ser Cys Ser Arg His Phe His Cys Cys
1 5 10 15
Ser Leu Tyr Cys Asn Lys Asn Thr Gly Val Cys He Ala Thr 20 25 30
<210> 386
<211> 27
<212> PRT
<213> Conus pulicarius
<400> 386
Glu Cys Thr Pro Pro Asp Gly Ala Cys Gly Leu Pro Thr His Cys Cys
1 5 10 15
Gly Phe Cys Asp Met Ala Asn Asn Arg Cys Leu 20 25
<210> 387
<211> 27
<212> PRT
<213> Conus pulicarius
<400> 387
Glu Cys Thr Pro Pro Gly Gly Ala Cys Gly Leu Pro Thr His Cys Cys
1 5 10 15
Gly Phe Cys Asp Met Ala Asn Asn Arg Cys Leu 20 25
<210> 388
<211> 28
<212> PRT
<213> Conus radiatus
<400> 388
His Gly Cys Lys Pro Leu Lys Arg Arg Cys Phe Asn Asp Lys Glu Cys
1 5 10 15 109
Cys Ser Lys Phe Cys Asn Ser Val Arg Lys Gin Cys 20 25
<210> 389
<211> 28
<212> PRT
<213> Conus radiatus
<400> 389
Arg Gly Cys Lys Pro Leu Lys Arg Arg Cys Phe Asn Asp Lys Glu Cys
1 5 10 15
Cys Ser Lys Phe Cys Asn Ser Val Arg Asn Gin Cys 20 25
<210> 390
<211> 27
<212> PRT
<213> Conus rattus
<400> 390
Cys Asn Ala Arg Asn Asp Gly Cys Ser Gin His Ser Gin Cys Cys Ser
1 5 10 15
Gly Ser Cys Asn Lys Thr Ala Gly Val Cys Leu 20 25
<210> 391
<211> 27
<212> PRT
<213> Conus rattus
<400> 391
Cys Asn Ala Arg Asn Ser Gly Cys Ser Gin His Pro Gin Cys Cys Ser
1 5 10 15
Gly Ser Cys Asn Lys Thr Ala Gly Val Cys Leu 20 25
<210> 392
<211> 27
<212> PRT
<213> Conus rattus
<400> 392
Cys Asn Ala Arg Asn Ser Gly Cys Ser Gin His Pro Gin Cys Cys Ser
1 5 10 15
Gly Ser Cys Asn Lys Thr Leu Gly Val Cys Leu 20 25
<210> 393
<211> 34
<212> PRT
<213> Conus rattus
<400> 393
Ala Cys Thr Pro Glu Gly Gly Ala Cys Ser Ser Gly Arg His Cys Cys
1 5 10 15
Gly Phe Cys Asp Asn Val Ser His Thr Cys Tyr Gly Glu Thr Pro Ser 20 25 30
Leu His 110
<210> 394
<211> 36
<212> PRT
<213> Conus striatus
<400> 394
Ala Thr Asp Cys He Glu Ala Gly Asn Tyr Cys Gly Pro Thr Val Met
1 5 10 15
Lys He Cys Cys Gly Phe Cys Ser Pro Tyr Ser Lys He Cys Met Asn 20 25 30
Tyr Pro Lys Asn 35
<210> 395
<211> 26
<212> PRT
<213> Conus striatus
<400> 395
Cys Lys Leu Lys Gly Gin Ser Cys Arg Arg Thr Met Tyr Asp Cys Cys
1 5 10 15
Ser Gly Ser Cys Gly Arg Arg Gly Lys Cys 20 25
<210> 396
<211> 25
<212> PRT
<213> Conus striatus
<400> 396
Cys Lys Ala Ala Gly Lys Ser Cys Ser Arg He Ala Tyr Asn Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Ser Gly Lys Cys 20 25
<210> 397
<211> 26
<212> PRT
<213> Conus striatus
<400> 397
Cys Glu Ser Tyr Gly Lys Pro Cys Gly He Tyr Asn Asp Cys Cys Asn
1 5 10 15
Ala Cys Asp Pro Ala Lys Lys Thr Cys Thr 20 25
<210> 398
<211> 27
<212> PRT
<213> Conus stercusmuscarum
<400> 398
Cys Lys Ser Lys Gly Ala Lys Cys Ser Arg Leu Met Tyr Asp Cys Cys
1 5 10 15
Ser Gly Ser Cys Ser Gly Tyr Thr Gly Arg Cys 20 25 111
<210> 399
<211> 35
<212> PRT
<213> Conus stercusmuscarum
<400> 399
Thr Thr Ser Cys Met Gin Ala Gly Ser Tyr Cys Gly Ser Thr Thr Arg
1 5 10 15
He Cys Cys Gly Tyr Cys Ala Tyr Phe Gly Lys Lys Cys He Asp Tyr 20 25 30
Pro Ser Asn 35
<210> 400
<211> 26
<212> PRT
<213> Conus stercusmuscarum
<400> 400
Cys Ala Ser Tyr Gly Lys Pro Cys Gly He Asp Asn Asp Cys Cys Asn
1 5 10 15
Ala Cys Asp Pro Ala Arg Asn He Cys Thr 20 25
<210> 401
<211> 26
<212> PRT
<213> Conus stercusmuscarum
<400> 401
Cys Val Ser Tyr Gly Lys Pro Cys Gly He Asp Asn Asp Cys Cys Asn
1 5 10 15
Ala Cys Asp Pro Ala Arg Asn He Cys Thr 20 25
<210> 402
<211> 25
<212> PRT
<213> Conus stercusmuscarum
<400> 402
Cys Lys Gly Lys Gly Ala Ser Cys His Lys Thr Met Tyr Asp Cys Cys
1 5 10 15
Ser Gly Ser Cys Thr Arg Gly Arg Cys 20 25
<210> 403
<211> 25
<212> PRT
<213> Conus striolatus
<400> 403
Cys Lys Gly Lys Gly Ala Ser Cys Leu Arg Thr Ala Tyr Asp Cys Cys
1 5 10 15
Thr Gly Ser Cys Asn Arg Gly Arg Cys 20 25
<210> 404 <211> 24 112
<212> PRT
<213> Conus striolatus
<400> 404
Cys Arg Pro Ser Gly Ser Asn Cys Gly Asn He Ser He Cys Cys Gly
1 5 10 15
Arg Cys Val Asn Arg Arg Cys Thr 20
<210> 405
<211> 35
<212> PRT
<213> Conus striolatus
<400> 405
Ser Thr Ser Cys Met Lys Ala Gly Ser Tyr Cys Val Ala Thr Thr Arg
1 5 10 15
He Cys Cys Gly Tyr Cys Ala Tyr Phe Gly Lys He Cys He Asp Tyr 20 25 30
Pro Lys Asn 35
<210> 406
<211> 28
<212> PRT
<213> Conus textile
<400> 406
Tyr Cys Thr Pro His Gly Gly His Cys Gly Tyr His Asn Asp Cys Cys
1 5 10 15
Ser His Gin Cys Asn He Asn Arg Asn Lys Cys Glu 20 25
<210> 407
<211> 31
<212> PRT
<213> Conus viola
<400> 407
Cys He Thr Leu Gly Thr Arg Cys Lys Val Pro Ser Gin Cys Cys Arg
1 5 10 15
Ser Ser Cys Lys Asn Gly Arg Cys Ala Pro Ser Pro Glu Glu Trp 20 25 30
<210> 408
<211> 25
<212> PRT
<213> Conus viola
<400> 408
Cys Lys Ser Arg Gly Ser Ser Cys Arg Arg Thr Ser Tyr Asp Cys Cys
1 5 10 15
Thr Gly Ser Cys Arg Asn Gly Lys Cys 20 25
<210> 409
<211> 36
<212> PRT
<213> Conus viola 113
<400> 409
Ser Thr Ser Cys Met Glu Ala Arg Ser Tyr Cys Gly Pro Ala Thr Thr
1 5 10 15
Lys He Cys Cys Asp Phe Cys Ser Pro Phe Ser Asp Arg Cys Met Asn 20 25 30
Asn Pro Asn Asn 35
<210> 410
<211> 25
<212> PRT
<213> Conus viola
<400> 410
Cys Lys Gly Pro Gly Ala He Cys He Arg He Ala Tyr Asn Cys Cys
1 5 10 15
Lys Tyr Ser Cys Gly Asn Gly Lys Cys 20 25
<210> 411
<211> 28
<212> PRT
<213> Conus viola
<400> 411
Tyr Cys Thr Pro Tyr Gly Gly His Cys Gly Tyr Tyr Asn Asp Cys Cys
1 5 10 15
Ser His Gin Cys Asn He Asn Arg Asn Lys Cys Glu 20 25
<210> 412
<211> 27
<212> PRT
<213> Conus textile
<400> 412
Cys Thr Pro Tyr Gly Gly His Cys Gly Tyr Asn His Asp Cys Cys Ser
1 5 10 15
His Gin Cys Asn He Asn Arg Asn Lys Cys Glu 20 25
<210> 413
<211> 26
<212> PRT
<213> Conus tulipa
<220>
<221> PEPTIDE
<222> (1) .. (26)
<223> Xaa is Hyp
<400> 413
Cys Lys Ser Trp Gly Ser Xaa Cys Ser Xaa Thr Ser Thr Asn Cys Cys
1 5 10 15
Trp Ser Cys Ser Pro Tyr Arg Lys Lys Cys 20 25
PCT/US2001/023041 2000-07-21 2001-07-23 Omega-conopeptides WO2002007675A2 (en)

Priority Applications (4)

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JP2002513413A JP2004512025A (en) 2000-07-21 2001-07-23 Omega-conopeptide
CA002416287A CA2416287A1 (en) 2000-07-21 2001-07-23 Omega-conopeptides
EP01957214A EP1311283A4 (en) 2000-07-21 2001-07-23 Omega-conopeptides
AU2001278982A AU2001278982A1 (en) 2000-07-21 2001-07-23 Omega-conopeptides

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US21961600P 2000-07-21 2000-07-21
US60/219,616 2000-07-21
US26588801P 2001-02-05 2001-02-05
US60/265,888 2001-02-05

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WO2008054171A1 (en) * 2006-11-04 2008-05-08 Anygen Co., Ltd. Omega conotoxins
WO2011032233A1 (en) * 2009-09-21 2011-03-24 The University Of Queensland Novel omega conotoxin peptides

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Publication number Priority date Publication date Assignee Title
JP6977979B2 (en) * 2015-06-09 2021-12-08 国立大学法人大阪大学 Nerve injury treatment or preventive medicine

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US5587454A (en) * 1991-12-30 1996-12-24 Neurex Corporation Omega conopeptide compositions
US5591821A (en) * 1993-07-16 1997-01-07 The University Of Utah Omega-conotoxin peptides
WO1999054350A1 (en) * 1998-04-16 1999-10-28 The University Of Queensland Novel omega conotoxin peptides

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US5591821A (en) * 1993-07-16 1997-01-07 The University Of Utah Omega-conotoxin peptides
WO1999054350A1 (en) * 1998-04-16 1999-10-28 The University Of Queensland Novel omega conotoxin peptides

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008054171A1 (en) * 2006-11-04 2008-05-08 Anygen Co., Ltd. Omega conotoxins
KR101046934B1 (en) 2006-11-04 2011-07-06 광주과학기술원 Novel Omega―Conotoxins
US8673856B2 (en) 2006-11-04 2014-03-18 Anygen Co., Ltd. Omega conotoxins
WO2011032233A1 (en) * 2009-09-21 2011-03-24 The University Of Queensland Novel omega conotoxin peptides
US8765677B2 (en) 2009-09-21 2014-07-01 The University Of Queensland Omega conotoxin peptides

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EP1311283A2 (en) 2003-05-21
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JP2004512025A (en) 2004-04-22
AU2001278982A1 (en) 2002-02-05

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