US20040176278A1 - B-superfamily conotoxins - Google Patents

B-superfamily conotoxins Download PDF

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US20040176278A1
US20040176278A1 US10/838,226 US83822604A US2004176278A1 US 20040176278 A1 US20040176278 A1 US 20040176278A1 US 83822604 A US83822604 A US 83822604A US 2004176278 A1 US2004176278 A1 US 2004176278A1
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substituted
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cys
lys
ser
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Robert Jones
Baldomero Olivera
Maren Watkins
James Garrett
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University of Utah Research Foundation UURF
Cognetix Inc
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University of Utah Research Foundation UURF
Cognetix Inc
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Priority to US11/198,847 priority patent/US7115708B2/en
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Assigned to NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR reassignment NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF UTAH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates

Definitions

  • the present invention is directed to ⁇ -superfamily conotoxin peptides (also referred to as ⁇ -conotoxins), derivatives or pharmaceutically acceptable salts thereof.
  • the present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated ion channels, ligand-gated ion channels and/or receptors.
  • the invention is further directed to nucleic acid sequences encoding the conotoxin peptides 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. When close enough it extends its proboscis and impales the fish hollow harpoon-like tooth containing venom. This immobilizes the fish and enables the cone snail to wind it into its mouth via the tooth at the end of the proboscis.
  • For general information on Conus and their venom see the website address grimwade.biochem.unimelb.
  • Conus species venom appears to contain a unique set of 50-200 peptides.
  • the composition of the venom differs greatly between species and between individual snails within each species, each optimally evolved to paralyse it's prey.
  • the active components of the venom are small peptides toxins, typically 10-30 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 and the ⁇ -conotoxins target the voltage-gated calcium channels (Olivera et al., 1985; Olivera et al., 1990).
  • a linkage has been established between ⁇ -, ⁇ A- & ⁇ -conotoxins and the nicotinic ligand-gated ion channel; co-conotoxins and the voltage-gated calcium channel; ⁇ -conotoxins and the voltage-gated sodium channel; ⁇ -conotoxins and the voltage-gated sodium channel; ⁇ -conotoxins and the voltage-gated potassium channel; conantokins and the ligand-gated glutamate (NMDA) channel.
  • NMDA ligand-gated glutamate
  • Conus peptides which target voltage-gated ion channels include those that delay the inactivation of sodium channels, as well as blockers specific for sodium channels, calcium channels and potassium channels.
  • Peptides that target ligand-gated ion channels include antagonists of NMDA and serotonin receptors, as well as competitive and noncompetitive nicotinic receptor antagonists.
  • Peptides which act on G-protein receptors include neurotensin and vasopressin receptor agonists.
  • the unprecedented pharmaceutical selectivity of conotoxins is at least in part defined by a specific disulfide bond frameworks combined with hypervariable amino acids within disulfide loops (for a review see McIntosh et al., 1998).
  • Conus peptides Due to the high potency and extraordinarily 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 co-conotoxin MVIIA (ziconotide), an N-type calcium channel blocker (see Heading, C., 1999; U.S. Pat. No. 5,859,186).
  • co-conotoxin MVIIA ziconotide
  • N-type calcium channel blocker see Heading, C., 1999; U.S. Pat. No. 5,859,186.
  • ⁇ -Conotoxin MVIIA isolated from Conus magus , is approximately 1000 times more potent than morphine, yet does not produce the tolerance or addictive properties of opiates.
  • ⁇ -Conotoxin MVIIA has completed Phase III (final stages) of human clinical trials and has been approved as a therapeutic agent.
  • ⁇ -Conotoxin MVIIA is introduced into human patients by means of an implantable, programmable pump with a catheter threaded into the intrathecal space.
  • Preclinical testing for use in post-surgical pain is being carried out on another Conus peptide, Contulakin-G, isolated from Conus geographus (Craig et al. 1999).
  • Contulakin-G is a 16 amino acid O-linked glycopeptide whose C-terminus resembles neurotensin. It is an agonist of neurotensin receptors, but appears significantly more potent than neurotensin in inhibiting pain in in vivo assays.
  • the present invention is directed to conotoxin peptides, derivatives or pharmaceutically acceptable salts thereof.
  • the present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated ion channels, ligand-gated ion channels and/or G-protein coupled receptors (GPCRs).
  • GPCRs G-protein coupled receptors
  • the invention is further directed to nucleic acid sequences encoding the conotoxin peptides and encoding propeptides, as well as the propeptides.
  • the present invention is directed to conotoxin peptides, having the amino acid sequences set forth in Tables 1-3 below.
  • the peptide may be bridged [1,4/2,3] or [1,3/2,4].
  • the present invention is also directed to derivatives or pharmaceutically acceptable salts of the conotoxin peptides or the derivatives.
  • derivatives include peptides in which the Arg residues may be substituted by Lys, ornithine, homoarginine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any synthetic basic amino acid.
  • the Lys residues may be substituted by Arg, omithine, homoarginine, nor-Lys, or any synthetic basic amino acid.
  • the Tyr residues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, 125 I-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 D or L, may be substituted at the ortho, meta, and/or para positions with a halogen or may be substituted with any synthetic aromatic amino acid.
  • Trp residues may be substituted with Trp (D), neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, 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-hydroxylisomers (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 Leu may be substituted with Leu (D).
  • the Glu residues may be substituted with Gla or Asp.
  • the Gla residues may be substituted with Glu or Asp.
  • the acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g. tetrazolyl derivatives of Gly and Ala.
  • the N-terminal Gln may be substituted with pyro-glutamate (Z).
  • the Met residues may be substituted with nor-leucine (Nle).
  • the Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L).
  • Basic residues in the backbone may be D or L configuration.
  • the central Trp residue within the beta-turn is preferably epimerized to the D-form.
  • Examples of synthetic aromatic amino acid include, but are not limited to, nitro-Phe, 4-substituted-Phe wherein the substituent is C 1 -C 3 alkyl, carboxyl, hyrdroxymethyl, sulphomethyl, halo, phenyl, —CHO, —CN, —SO 3 H and —NHAc.
  • Examples of synthetic hydroxy containing amino acid include, but are not limited to, such as 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr.
  • Examples of synthetic basic amino acids include, but are not limited to, N-1-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4-piperinyl)-Ala, 2-[3-(2S)pyrrolininyl)-Gly and 2-[3-(2S)pyrrolininyl)-Ala.
  • These and other synthetic basic amino acids, synthetic hydroxy containing amino acids or synthetic aromatic amino acids are described in Building Block Index, Version 3.0 (1999 Catalog, pages 4-47 for hydroxy containing amino acids and aromatic amino acids and pages 66-87 for basic amino acids; see also web address amino-acids.
  • Additional derivatives are peptides in which the Asn residues may be modified to contain an N-glycan and the Ser, Thr and Hyp residues may be modified to contain an O-glycan (e.g., g-N, g-S, g-T and g-Hyp).
  • a glycan shall mean any N-, S- or O-linked mono-, di-, tri-, poly- or oligosaccharide that can be attached to any hydroxy, amino or thiol group of natural or modified amino acids by synthetic or enzymatic methodologies known in the art.
  • the monosaccharides making up the glycan can include D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose, D-galactosamine, D-glucosamine, D-N-acetyl-glucosamine (GlcNAc), D-N-acetyl-galactosamine (GalNAc), D-fucose or D-arabinose.
  • These saccharides may be structurally modified, e.g., with one or more O-sulfate, O-phosphate, O-acetyl or acidic groups, such as sialic acid, including combinations thereof.
  • the gylcan may also include similar polyhydroxy groups, such as D-penicillamine 2,5 and halogenated derivatives thereof or polypropylene glycol derivatives.
  • the glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3.
  • the linkage between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-.
  • Core O-glycans have been described by Van de Steen et al. (1998), incorporated herein by reference. Mucin type O-linked oligosaccharides are attached to Ser or Thr (or other hydroxylated residues of the present peptides) by a GalNAc residue. The monosaccharide building blocks and the linkage attached to this first GalNAc residue define the “core glycans,” of which eight have been identified. The type of glycosidic linkage (orientation and connectivities) are defined for each core glycan. Suitable glycans and glycan analogs are described further in U.S. Ser. No. 09/420,797 filed 19 Oct. 1999 (now U.S. Pat. No.
  • a preferred glycan is Gal( ⁇ 1 ⁇ 3)GalNAc( ⁇ 1 ⁇ ).
  • Derivatives also include peptides in which pairs of Cys residues may be replaced pairwise with isosteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/Ala combinations. Sequential coupling by known methods (Barnay et al., 2000; Hruby et al., 1994; Bitan et al., 1997) allows replacement of native Cys bridges with lactam bridges. Thioether analogs may be readily synthesized using halo-Ala residues commercially available from RSP Amino Acid Analogues.
  • Cys residues may be replaced with homoCys, seleno-Cys or penicillamine, so that disulfide bridges may be formed between Cys-homoCys or Cys-penicillamine, or homoCys-penicllamine and the like.
  • Derivatives and analogs also include truncations of the peptides disclosed herein.
  • truncations are used to refer to peptides in which the sequence has been shortened from the mature conotoxin sequence that is predicted by the prepropeptide cleavage site with significant retention of activity of the native conotoxin. These truncations can be shortened from the N-terminus, the C-terminus, or both.
  • significant retention of activity is used to refer to an activity of the truncated conotoxin which is less that 100-fold loss of activity and specificity.
  • Derivatives also include radiometal and chelated anti-tumor peptides.
  • the incorporation of the radiometal eg 99m Tc, 111 In, 90 Y, 188 Re, 105RhS 4 , 188 Re-tisuccin, 89 Sr, 153 Sm, 186 Re, 67 Ga, 211 At, 212 Bi, 213 Bi, 177 Lu, 67 Cu, 64 Cu, 105 Rh, 47 Sc, 109 Pd] in to the conotoxin generally involves use of a chelate, specific to the particular metal, and a linker group to covalently attach the chelate to the conotoxin [the bifunctional chelate approach].
  • DTPA, DOTA, P 2 S 2 —COOH BFCA requirement for kinetic TETA, NOTA are common egs.
  • the requirement for kinetic stability of the metal complex is often achieved through the use of multidentate chelate ligands with a functionalised arm for covalent bonding to some part of the conotoxin ie the amino lysine group.
  • the conotoxins of the present invention may be tagged to produce radiopharmaceuticals.
  • synthesis of such screening tools is not restricted to radioiodinated tyrosine derivatives. Incorporation of standard commercially available tritiated amino acid residues can also be utilized.
  • the present invention is further directed to a method of treating disorders associated with voltage-gated ion channels, ligand-gated ion channels and/or receptor disorders in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a conotoxin peptide 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 conotoxin peptide described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
  • the present invention is also directed to nucleic acids which encode conotoxin peptides of the present invention or which encodes precursor peptides for these conotoxin peptides, as well as the precursor peptide.
  • the nucleic acid sequences encoding the precursor peptides of other conotoxin peptides of the present invention are set forth in Table 1. Table 1 also sets forth the amino acid sequences of these precursor peptides.
  • Another embodiment of the invention contemplates a method of identifying compounds that mimic the therapeutic activity of the instant peptide, comprising the steps of: (a) conducting a biological assay on a test compound to determine the therapeutic activity; and (b) comparing the results obtained from the biological assay of the test compound to the results obtained from the biological assay of the peptide.
  • the present invention is directed to ⁇ -superfamily conotoxin peptides (also referred to as ⁇ -conotoxins), derivatives or pharmaceutically acceptable salts thereof.
  • the present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated ion channels, ligand-gated ion channels and/or receptors, such as G-protein coupled receptors (GPCRs).
  • GPCRs G-protein coupled receptors
  • the invention is further directed to nucleic acid sequences encoding the ⁇ -superfamily conotoxin peptides 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 a ⁇ -superfamily conotoxin peptide, a mutein thereof, an analog thereof, a derivative 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, ligand-gated ion channels and/or receptors (such as G-protein coupled receptors (GPCRs)), 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 such channels or receptors 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.
  • GPCRs G-protein coupled receptors
  • GPCRs G-protein-coupled receptors
  • TM transmembrane
  • GPCRs are considered to be one of the most important groups of drug targets because they are involved in a broad range of body functions and processes and are related to major diseases.
  • GPCR G Protein-Coupled Receptor
  • This beta turn toxin template may also be used to characterize new functional allosteric sites on known GPCRs. Radiolabelled dervatives serve as screening tools for such sites and will allow for identification of new small molecule modulators.
  • the reverse beta turn motif serves as a template for beta turn peptidomimetic design in which the turn template contains the cone snail WK recognition “fingerprint”, examples of such templates can be found in Golebiowski et al. (2001), Horwell (1996) and Beeley (2000).
  • Somatostatin Receptors Somatostatin (SRIF)
  • Somatostatin was first identified as a peptide that inhibits growth hormone release. Later it was shown to have other physiological activities, including the inhibition of the release of many endocrine secretions such as prolactin, TSH and insulin. The peptide also exhibits neuromodulatory functions and may act as a neurotransmitter. Somatostatin has two major actions; inhibition of hormone and cytokine (IFN- ⁇ , IL-6, IL-8, IL-1) release and inhibition of cellular proliferation. SRIF can inhibit the release of hormones in the brain and almost all hormone release in the gut, together with many cytokines and growth factors eg PDGF.
  • SRIF can be produced in cells from neuroendocrine and immune systems. It is produced in two forms SRIF-28 and SRIF-14. Additionally a novel SST-like peptide called cortistatin (CST) has been isolated from human. CST-14 shares 11 of the 14 amino acids with SRIF.
  • CST cortistatin
  • sst receptors Five sst receptors have been identified sst1, 2, 3, 4, 5. All are GPCRs and are encoded on a different chromosome. Both SRIF-14 and SRIF-28 bind to all receptors but SRIF-28 has higher affinity for sst 5 . It must be noted that 2 isoforms of sst 2 exist namely, SSt2A and SSt2B. SRIF receptors are widely expressed. Cells from the CNS, gut, pancreas, kidney, thyroid, lung and the immune system express the receptors in varying proportions.
  • SRIF analogs suppress the release of GH and thus can benefit patients.
  • a majority of tumours originating from tissues naturally targeted by SRIF express sst receptors at high levels.
  • Synthetic peptides such as, lanreotide, octreotide and vapreotide bind sst 2 and 5 with high affinity and sst 3 to a lesser extent.
  • peptide analogs of SRIF been used to reduce tumour growth directly through somatostatin receptor signalling but also medicine finds considerable use for somatostatin receptors in tumour detection and imaging and now in tumour targeting (Slooter et al., 2001).
  • SSTR somatostatin receptors
  • 111 In-DTPA-DPhe1-octreotide which binds to h-SSTR 2 and 5 with high affinity (Kd 0.1-5 nM), to h-SSTR 3 with moderate affinity (Kd 10-100 nM) and does not bind to h-SSTR 1 and h-SSTR 4
  • 111 In/ 90 Y-DOTA-lanreotide was found to bind to h-SSTR 2, 3, 4 , and 5 with high affinity, and to h-SSTR 1 with lower affinity (K d 200 nM).
  • 111 In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and 90 Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy.
  • 111 In-DTPA-DPhe1-octreotide and 111 In-DOTA-DPhe1-Tyr3-octreotide discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions.
  • melanocortin receptors During the last decade five different subtypes of melanocortin receptors have been identified and cloned, all of them are possible as new targets for drugs in the treatment of a number of clinical important conditions such as inflammatory diseases (MC 1 -receptor agonists), MC 3 /MC 4 -receptors in the treatment of feeding disorder, agonists for treatment of obesity and antagonists for anorectic conditions. MC 3 /MC 4 -agonists or also assumed to be useful for treating sexual dysfunction. In the treatment of seborrheic dermatitis the MC 5 receptor is considered as a target. A number of peptide or peptide like ligands, agonists and/or antagonist has been discovered, however, most of them have a large similarity with the endogenous ligand A-MSH.
  • Melanocortins The major source of melanocortins is the pituitary, where ACTH and ⁇ -lipotropin are the main products from the anterior pituitary, and ⁇ -MSH and ⁇ -lipotropin are major products from the intermediate lobe. All melanocortins, i.e. ⁇ -Melanocyte stimulating hormone ( ⁇ -MSH), ⁇ -MSH, ⁇ -MSH and the endogenous opioid ⁇ -endorphin, are cleaved from POMC, but ⁇ -MSH and ⁇ -endorphin emanate from the C-terminal part of POMC, i.e. the ⁇ -lipotropin.
  • ⁇ -MSH ⁇ -Melanocyte stimulating hormone
  • ⁇ -MSH ⁇ -MSH
  • ⁇ -MSH endogenous opioid ⁇ -endorphin
  • ⁇ -MSH is cleaved from the N-terminal part of POMC. While ⁇ -MSH is a tri-decapeptide proteolytically cleaved from proopiomelanocortin (POMC) comprising of the N-terminal part of ACTH and is considered as the endogenous ligand to the melanocortin receptors.
  • POMC proopiomelanocortin
  • ⁇ -MSH is found in the hypothalamus, whereas ⁇ -MSH is found in different areas of the CNS, adrenal medulla and neurons of the intestine. ⁇ -MSH has been demonstrated in the pituitary, but also in other parts of the CNS, as well as in peripheral parts of the body. Only low circulating concentrations of ⁇ -MSH have been detected in humans in normal situations, whereas the concentration is increased in several diseases.
  • Melanocortin Receptors MCRs Melanocortin receptors belong to the family of G-protein coupled, 7-TM receptors, and have been identified in several tissues of the body. Today, 5 different subtypes of receptors, MC1-5, have been described. The MC 2 receptor binds only ACTH, and is present in the adrenal cortex and also in white adipose tissue of rodents, but not in man or primates. The MC 1 , MC 2 , MC 3 , MC 4 and MC 5 receptors are distributed in different areas/organs of the body. The MC 2 receptor is not further discussed since it is considered as the ACTH receptor.
  • the MC 3 receptor is expressed in low abundance during fetal life and expression increases to adult levels after birth, as demonstrated in rats.
  • both receptors seem to be important for different physiological functions postnatally.
  • the MC receptors and ⁇ -MSH are involved in several physiological functions besides affecting skin pigmentation. They have effects on learning, memory, behaviour, including sexual behaviour, regeneration in the neuromuscular system and protection from central nerve injury, cardiovascular functions, feeding and weight homeostasis, fever and immunomodulation/inflammation, exocrine functions and interact with opioids and dopamine. They are also ascribed effects such as regulation of the release of pituitary and peripheral hormone.
  • Examples of voltage-gated ion channels include the voltage-gated calcium channel, the voltage-gated sodium channel, the voltage-gated potassium channel and the proton-gated ion channel.
  • Examples of ligand-gated channels include the nicotinic ligand-gated ion channel, ligand-gated glutamate (NMDA) channel and the ligand-gated 5HT 3 (serotonin) channel.
  • Examples of receptors include the G-protein receptors.
  • Activity of ⁇ -conotoxins is described in U.S. Pat. No. 5,969,096 and in Shon et al. (1997).
  • Activity of bromosleeper conotoxins is described in U.S. Pat. No.
  • ⁇ -conotoxins are antagonists of the 5HT 3 receptor, they are also useful in treating irritable bowel syndrome (IBS) and visceral pain. Visceral pain is a common experience in health and disease. Chronic visceral hyperalgesia in the absence of detectable organic disease has been implicated in many common functional bowel disorders (FDB), such as IBS, non-ulcer dyspepsia (NUD) and non-cardiac chest pain (NCCP).
  • FDB common functional bowel disorders
  • NUD non-ulcer dyspepsia
  • NCCP non-cardiac chest pain
  • FDBs are a result of increased excitability of spinal neurones. According to their model, many inputs can result in transient, short term, or life long sensitization of afferent pathways involved in visceral reflexes and sensations from the gut.
  • the increased sensory input to interneurons and/or dorsal horn neurons in the spinal cord will result in secondary hyperalgesia, in which adjacent, undamaged viscera develop sensitivity to normal innocuous stimuli (allodynia), and central hyperexcitability as a consequence of changes in the circuitary of the dorsal horn. This central sensitization may subsequently extend to supraspinal centers also.
  • Altered spinal processing of visceral sensory information can explain altered sensory thresholds and altered referral patterns, the perception of visceral sensations without stimulation of visceral mechnoreceptors (sensation of incomplete evacuation), and the symptomatic involvement of multiple sites in the GI tract, including extra intestinal sites.
  • Increased excitability of dorsal horn neurones, resulting in the recruitment of previously sub-threshold inputs, may explain cutaneous allodynia in some patients with IBS, burning sensations referred to different parts of the body, cold hypersensitivity and pain referral to upper and lower extremities.
  • a number of compounds have been shown to modulate visceral sensitivity in IBS patients. These include octreotide (sst2; Novartis), the 5-HT 3 antgonists odansetron (Glaxo) and granisetron (SKB) and the peripheral kappa opioid agonist, fedotozine (Jouveinal SA).
  • the 5-HT 3 antagonist alosteron (Glaxo) cuurrently in development for IBS, is active in modifying the perception of colonic distension and gut compliance in IBS patients.
  • New drugs in development for the treatment of IBS that are targeted at pain control as well as dysmotility include 5-HT 3 and 5-HT 4 receptor antagonists.
  • 5-HT 3 receptors are located throughout the central and peripheral nervous system—their role in modulating the activity of visceral afferent and enteric neurones has led to the proposal that 5-HT acts as a sensitizing agent via these receptors on visceral afferent neurones.
  • 5-HT 3 receptor antagonists have been widely reported to attenuate blood pressure responses to intestinal distension.
  • 5-HT 3 antagonists in development for IBS include Alosteron (phase III), which is reported to reduce abdominal pain, slow colonic transit and increase colon compliance in IBS patients.
  • Other compounds with positive effects include the antiemetic Ramosteron (Yamanouchi), Cilansteron (Solvay) and YM-114 (Yamanouchi).
  • An animal model for dysmotility of the GI tract has been described by Maric et al. (1989).
  • the peptides of the present invention are also useful (i) for treating or diagnosis of cancer, neoplasm, solid tumor, diabetic nephropathy, fibrosis, hypophysis tumor, GI disease, IBS, restinosis, angiogenesis disorder, diabetes mellitus, endocrine tumor, diarrhea, pancreatic disease, prostate tumor, bleeding, apoptosis, inflammation, pain, diabetes, obesity, sexual dysfunction, acromegaly, glaucoma, cardiovascular, diabetic, retinopathy, depression, myocardial infarction, stroke, epilepsy, anorexia, wasting diseases, seborrheic dermatitis, schizophrenia, mood disorders, chemotherapeutic induced emesis, disorders associated with changes in blood pressure, immune disorders, nerve damage, acne, GI infections, myocardial infarction, angina, thromboembolism, cardiovascular disease, (ii) as templates for small molecule design and (iii) as screening
  • GPCRs seven-transmembrane-domain G-protein-coupled receptors
  • Each of the approximately 1000 family members found in vertebrates responds to stimuli as diverse as hormones, neurotransmitters, odorants and light, which selectively activate intracellular signaling events mediated by heterotrimeric G proteins.
  • GPCRs are centrally positioned in the plasma membrane to initiate a cascade of cellular responses by diverse extracellular mediators, it is not surprising that modulation of GPCR function has been successful in the development of many marketed therapeutic agents.
  • the reverse molecular pharmacological methodology includes cloning and expression of orphan GPCRs in mammalian cells and screening these cells for a functional response to cognate or surrogate agonists present in biological extract preparations, peptide libraries, and complex compound collections.
  • the functional genomics approach involves the use of “humanized” yeast cells, where the yeast GPCR transduction system is engineered to permit functional expression and coupling of human GPCRs to the endogenous signalling machinery. Both systems provide an excellent platform for identifying novel receptor ligands. Once activating ligands are identified they can be used as pharmacological tools to explore receptor function and relationship to disease.
  • the ⁇ -superfamily conotoxins can also be used to design a ⁇ -turn mimetic of the ⁇ -superfamily conotoxins containing a ⁇ -turn motif, e.g., the —CX1X2KX1C— (SEQ ID NO:338) motif where X1 is any amino acid and X2 is Trp in the D or L orientation (or halogenated at position 6 of the indole) or the —CPX3RVC— (SEQ ID NO:339) motif where X3 is Phe in the D or L configuration.
  • Other ⁇ -turn motifs are also present in the ⁇ -superfamily conotoxins as evident from the peptide sequences disclosed in Tables 2 and 3.
  • This hairpin turn would be replaced by a non-peptide turn mimetic, preferably an orally available mimetic.
  • the unique receptor binding domains contained within the N and C-terminal regions of the ⁇ -superfamily conotoxin would then be attached to the ⁇ -turn scaffold, in such a way as to mimic the 3D spatial array within the native toxin.
  • ⁇ -turn motif and a ⁇ -turn mimetic see Scheme 4.
  • the ⁇ -superfamily conotoxins of the present invention are also useful for characterizing sites on GPCRs and for identifying novel receptor ligands for GPCRS, especially orphan GCPRs.
  • the ⁇ -beta turn toxin template may also be used to characterize new functional allosteric sites on known GPCRs. Radiolabelled derivatives serve as screening tools for such sites and will allow for identification of new small molecule modulators.
  • the reverse beta turn motif serves as a template for beta turn peptidomimetic design in which the turn template contains the cone snail WK recognition “fingerprint”, examples of such templates can be found in Golebiowski et al. (2001) and Horwell (2000).
  • a ligand which binds to an orphan G-protein coupled receptor can be identified by contacting a ⁇ -superfamily conotoxin with an orphan GPCR and measuring the amount of binding of the conotoxin to the orphan GPCR by methods that are well known in the art (Murphy et al., 1998).
  • a homology search to identify other candidate ligands for testing can then be done on the basis of any peptide which binds to the orphan GPCR.
  • the candidate ligands may be peptides or peptide mimetics.
  • conotoxin peptides described herein are sufficiently small to be chemically synthesized.
  • General chemical syntheses for preparing the foregoing conotoxin peptides are described hereinafter.
  • Various ones of the conotoxin peptides can also be obtained by isolation and purification from specific Conus species using the technique described in U.S. Pat. No. 4,447,356 (Olivera et al., 1984); U.S. Pat. Nos. 5,514,774; 5,719,264; and 5,591,821, as well as in PCT published application WO 98/03189, the disclosures of which are incorporated herein by reference.
  • the conotoxin peptides of the present invention can be obtained by purification from cone snails, because the amounts of conotoxin peptides obtainable from individual snails are very small, the desired substantially pure conotoxin peptides 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 conotoxin peptides 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 conotoxin peptides peptides depends of course upon correct determination of the amino acid sequence.
  • the conotoxin peptides 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 conotoxin peptides
  • 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 conotoxin peptides of the present invention is the air oxidation of the linear peptides for prolonged periods under cold room temperatures or at room temperature. This procedure results in the creation of a substantial amount of the bioactive, disulfide-linked peptides.
  • the oxidized peptides are fractionated using reverse-phase high performance liquid chromatography (HPLC) or the like, to separate peptides having different linked configurations. Thereafter, either by comparing these fractions with the elution of the native material or by using a simple assay, the particular fraction having the correct linkage for maximum biological potency is easily determined. However, because of the dilution resulting from the presence of other fractions of less biopotency, a somewhat higher dosage may be required.
  • the peptides are synthesized by a suitable method, such as by exclusively solid-phase techniques, by partial solid-phase techniques, by fragment condensation or by classical solution couplings.
  • the peptide chain can be prepared by a series of coupling reactions in which constituent amino acids are added to the growing peptide chain in the desired sequence.
  • various coupling reagents e.g., dicyclohexylcarbodiimide or diisopropylcarbonyldimidazole
  • various active esters e.g., esters of N-hydroxyphthalimide or N-hydroxy-succinimide
  • the various cleavage reagents to carry out reaction in solution, with subsequent isolation and purification of intermediates, is well known classical peptide methodology.
  • the protecting group preferably retains its protecting properties and is not split off under coupling conditions
  • the protecting group should be stable under the reaction conditions selected for removing the ⁇ -amino protecting group at each step of the synthesis
  • the side chain protecting group must be removable, upon the completion of the synthesis containing the desired amino acid sequence, under reaction conditions that will not undesirably alter the peptide chain.
  • peptides are not so prepared, they are preferably prepared using the Merrifield solid-phase synthesis, although other equivalent chemical syntheses known in the art can also be used as previously mentioned. Solid-phase synthesis is commenced from the C-terminus of the peptide by coupling a protected ⁇ -amino acid to a suitable resin.
  • Such a starting material can be prepared by attaching an ⁇ -amino-protected amino acid by an ester linkage to a chloromethylated resin or a hydroxymethyl resin, or by an amide bond to a benzhydrylamine (BHA) resin or paramethylbenzhydrylamine (MBHA) resin.
  • BHA benzhydrylamine
  • MBHA paramethylbenzhydrylamine
  • Preparation of the hydroxymethyl resin is described by Bodansky et al. (1966). Chloromethylated resins are commercially available from Bio Rad Laboratories (Richmond, Calif.) and from Lab. Systems, Inc. The preparation of such a resin is described by Stewart and Young (1969).
  • BHA and MBHA resin supports are commercially available, and are generally used when the desired polypeptide being synthesized has an unsubstituted amide at the C-terminus.
  • solid resin supports may be any of those known in the art, such as one having the formulae —O—CH 2 -resin support, —NH BHA resin support, or —NH-MBHA resin support.
  • unsubstituted amide use of a BHA or MBHA resin is preferred, because cleavage directly gives the amide.
  • N-methyl amide is desired, it can be generated from an N-methyl BHA resin. Should other substituted amides be desired, the teaching of U.S. Pat. No.
  • the C-terminal amino acid, protected by Boc or Fmoc and by a side-chain protecting group, if appropriate, can be first coupled to a chloromethylated resin according to the procedure set forth in K. Horiki et al. (1978), using KF in DMF at about 60° C. for 24 hours with stirring, when a peptide having free acid at the C-terminus is to be synthesized.
  • the ⁇ -amino protecting group is removed, as by using trifluoroacetic acid (TFA) in methylene chloride or TFA alone.
  • TFA trifluoroacetic acid
  • the deprotection is carried out at a temperature between about 0° C. and room temperature.
  • Other standard cleaving reagents, such as HCl in dioxane, and conditions for removal of specific ⁇ -amino protecting groups may be used as described in Schroder & Lubke (1965).
  • the remaining ⁇ -amino- and side chain-protected amino acids are coupled step-wise in the desired order to obtain the intermediate compound defined hereinbefore, or as an alternative to adding each amino acid separately in the synthesis, some of them may be coupled to one another prior to addition to the solid phase reactor.
  • Selection of an appropriate coupling reagent is within the skill of the art. Particularly suitable as a coupling reagent is N,N′-dicyclohexylcarbodiimide (DCC, DIC, HBTU, HATU, TBTU in the presence of HoBt or HoAt).
  • activating reagents used in the solid phase synthesis of the peptides are well known in the peptide art.
  • suitable activating reagents are carbodiimides, such as N,N′-diisopropylcarbodiimide and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide.
  • Other activating reagents and their use in peptide coupling are described by Schroder & Lubke (1965) and Kapoor (1970).
  • Each protected amino acid or amino acid sequence is introduced into the solid-phase reactor in about a twofold or more excess, and the coupling may be carried out in a medium of dimethylformamide (DMF):CH 2 Cl 2 (1:1) or in DMF or CH 2 Cl 2 alone.
  • DMF dimethylformamide
  • the coupling procedure is repeated before removal of the ⁇ -amino protecting group prior to the coupling of the next amino acid.
  • the success of the coupling reaction at each stage of the synthesis if performed manually, is preferably monitored by the ninhydrin reaction, as described by Kaiser et al. (1970).
  • Coupling reactions can be performed automatically, as on a Beckman 990 automatic synthesizer, using a program such as that reported in Rivier et al. (1978).
  • the intermediate peptide can be removed from the resin support by treatment with a reagent, such as liquid hydrogen fluoride or TFA (if using Fmoc chemistry), which not only cleaves the peptide from the resin but also cleaves all remaining side chain protecting groups and also the amino protecting group at the N-terminus if it was not previously removed to obtain the peptide in the form of the free acid.
  • a reagent such as liquid hydrogen fluoride or TFA (if using Fmoc chemistry)
  • TFA trifluoroacetic acid
  • scavengers such as anisole, cresol, dimethyl sulfide and methylethyl sulfide are included in the reaction vessel.
  • Cyclization of the linear peptide is preferably affected, as opposed to cyclizing the peptide while a part of the peptido-resin, to create bonds between Cys residues.
  • fully protected peptide can be cleaved from a hydroxymethylated resin or a chloromethylated resin support by ammonolysis, as is well known in the art, to yield the fully protected amide intermediate, which is thereafter suitably cyclized and deprotected.
  • deprotection, as well as cleavage of the peptide from the above resins or a benzhydrylamine (BHA) resin or a methylbenzhydrylamine (MBHA), can take place at 0° C. with hydrofluoric acid (HF) or TFA, followed by oxidation as described above.
  • HF hydrofluoric acid
  • TFA methylbenzhydrylamine
  • the peptides are also synthesized using an automatic synthesizer.
  • Amino acids are sequentially coupled to an MBHA Rink resin (typically 100 mg of resin) beginning at the C-terminus using an Advanced Chemtech 357 Automatic Peptide Synthesizer. Couplings are carried out using 1,3-diisopropylcarbodimide in N-methylpyrrolidinone (NMP) or by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and diethylisopropylethylamine (DIEA).
  • NMP N-methylpyrrolidinone
  • HBTU 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • DIEA diethylisopropylethylamine
  • the FMOC protecting group is removed by treatment with a 20% solution of
  • Radiolabeled peptides have been used to show that perhaps only the amino acid sequence actually involved in binding to the receptor is essential for achieving tumor uptake.
  • 111 In-radiolabelled octreotide which is used to image somatostatin positive tumors, is a prime example of this.
  • advances in tumor biology have demonstrated metabolic pathways to deliver the nuclide within the cell cytoplasm through internalization mechanisms.
  • Some classes of tumors have been shown to overexpress certain receptors, e.g., glutamate, AMPA, NMDA, somatostatin, melanocortin and the like, and whenever these substances can be radiolabeled and introduced to the system, they can become the lethal magic bullet by working inside the cell.
  • Radionuclide therapy is the paramount goal in radionuclide therapy because with specificity comes safety and efficacy.
  • the strategy in biologically targeted therapy is to chemically package the radionuclide to take advantage of metabolic pathways or tumor characteristics so that the radionuclide is localized in the target organ or tissue while the nuclear energy is discharged with minimal exposure to healthy tissue.
  • the concentration differential of the therapeutic radio-pharmaceutical must be orders of magnitude between target and non-target tissues. Radiation doses of 4000-6000 rads are desirable in the target tissue, while only a few tens of radiation units can be functionally tolerated by some radiosensitive tissues. The short range of the emitted particles in the tissues makes them very damaging over the range in which their decay energy is deposited.
  • the specificity of certain of the ⁇ -superfamily conotoxins for the somatostatin receptor provide the necessary specificity for the treatment and diagnosis of tumors.
  • a diagnostic agent that is detectable upon imaging, such as a paramagnetic, radioactive or fluorogenic agent.
  • a diagnostic agent that is detectable upon imaging, such as a paramagnetic, radioactive or fluorogenic agent.
  • Many diagnostic agents are known in the art to be useful for imaging purposes, as are methods for their attachment to peptides (see, e.g., U.S. Pat. Nos. 5,021,236 and 4,472,509, both incorporated herein by reference).
  • paramagnetic ions such as chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) and erbium (III), with gadolinium being particularly preferred.
  • Ions useful in other contexts, such as X-ray imaging include but are not limited to lanthanum (III), gold (III), lead (II), and especially bismuth (III).
  • radioactive isotopes for therapeutic and/or diagnostic application, one might mention 131 iodine, 123 iodine, 99m technicium, 111 indium, 188 rhenium, 186 rhenium, 67 gallium, 67 copper, 90 yttrium, 125 iodine, or 211 astatine.
  • Short-lived positron emission tomography (PET) isotopes such as 18 flourine, can also be used for labeling peptides for use in tumor diagnosis (Okarvi, 2001).
  • radionuclides include 131 iodine, 123 iodine, 99m technicium, 111 indium, 188 rhenium, 186 rhenium, 67 gallium, 90 yttrium, 105 rhodium, 89 strontium, 153 samarium, 211 astatine, 212 bismuth, 213 bismuth, 177 lutetium, 67 copper, 47 scandium, 109 palladium.
  • radionuclides are chosen for the specific application on the basis of physical and chemical properties such that (a) their decay mode and emitted energy are matched to the delivery site, (b) their half life and chemical properties are complementary to the biological processing and (c) production methods can yield the radionuclide at the necessary level of specific activity and radionuclide purity.
  • the incorporation of the radiometal into the P-superfamily conotoxins generally involves use of a chelate, specific to the particular metal, and a linker group to covalently attach the chelate to the conotoxin, i.e., a the bifunctional chelate approach.
  • the design of useful chelates is dependent on the coordination requirements of the specific radiometal. DTPA, DOTA, P 2 S 2 —COOH BFCA requirement for kinetic TETA, NOTA are common examples.
  • the requirement for kinetic stability of the metal complex is often achieved through the use of multidentate chelate ligands with a functionalized arm for covalent bonding to some part of the conantokin or ⁇ -carboxyglutamate containing conopeptide, i.e., the lysine amino group.
  • multidentate chelate ligands with a functionalized arm for covalent bonding to some part of the conantokin or ⁇ -carboxyglutamate containing conopeptide, i.e., the lysine amino group.
  • the ⁇ -superfamily conotoxins are used in combination with one or more potentiators and/or chemotherapeutic agents for the treatment of cancer or tumors.
  • An exemplary potentiator is triprolidine (U.S. Pat. No. 5,114,951) or its cis-isomer which are used in combination with chemotherapeutic agents.
  • Another potentiator is procodazole, which is a non-specific immunoprotective agent active against viral and bacterial infections.
  • the chemotherapeutic agents which can be used with conantokins or ⁇ -carboxyglutamate containing peptides and an optional potentiator are generally grouped as DNA-interactive agents, antimetabolites, tubulin-interactive agents, hormonal agents and others such as asparaginase or hydroxyurea. Each of the groups of chemotherapeutic agents can be further divided by type of activity or compound.
  • the chemotherapeutic agents used in combination with y-carboxy-glutamate containing peptides include members of all of these groups.
  • DNA-interactive agents include the alkylating agents, e.g. cisplatin, cyclophosphamide, altretamine; the DNA strand-breakage agents, such as bleomycin; the intercalating topoisomerase II inhibitors, e.g., dactinomycin and doxorubicin; the nonintercalating topoisomerase II inhibitors such as, etoposide and teniposde; and the DNA minor groove binder plicamydin.
  • the alkylating agents form covalent chemical adducts with cellular DNA, RNA, and protein molecules and with smaller amino acids, glutathione and similar chemicals.
  • these alkylating agents react with a nucleophilic atom in a cellular constituent, such as an amino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins, amino acids, or glutathione.
  • a nucleophilic atom such as an amino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins, amino acids, or glutathione.
  • the antimetabolites interfere with the production of nucleic acids by one or the other of two major mechanisms. Some of the drugs inhibit production of the deoxyribonucleoside triphosphates that are the immediate precursors for DNA synthesis, thus inhibiting DNA replication. Some of the compounds are sufficiently like purines or pyrimidines to be able to substitute for them in the anabolic nucleotide pathways. These analogs can then be substituted into the DNA and RNA instead of their normal counterparts.
  • Tubulin interactive agents act by binding to specific sites on tubulin, a protein that polymerizes to form cellular microtubules. Microtubules are critical cell structure units. When the interactive agents bind on the protein, the cell cannot form microtubules.
  • Tubulin interactive agents include colchicine, vincristine and vinblastine, both alkaloids and paclitaxel and cytoxan.
  • Hormonal agents are also useful in the treatment of cancers and tumors. They are used in hormonally susceptible tumors and are usually derived from natural sources. These include: estrogens, conjugated estrogens and ethinyl estradiol and diethylstilbesterol, chlortrianisen and idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate; fluoxymesterone, methyltestosterone.
  • Adrenal corticosteroids are derived from natural adrenal cortisol or hydrocortisone.
  • Leutinizing hormone releasing hormone agents or gonadotropin-releasing hormone antagonists are used primarily the treatment of prostate cancer. These include leuprolide acetate and goserelin acetate. They prevent the biosynthesis of steroids in the testes.
  • Antihormonal antigens include: antiestrogenic agents such as tamoxifen, antiandrogen agents such as flutamide; and antiadrenal agents such as mitotane and aminoglutethimide.
  • compositions containing a compound of the present invention as the active ingredient can be prepared according to conventional pharmaceutical compounding techniques. See, for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa.). Typically, an antagonistic amount of active ingredient will be admixed with a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral, parenteral or intrathecally. For examples of delivery methods see U.S. Pat. No. 5,844,077, incorporated herein by reference.
  • “Pharmaceutical composition” means physically discrete coherent portions suitable for medical administration.
  • “Pharmaceutical composition in dosage unit form” means physically discrete coherent units suitable for medical administration, each containing a daily dose or a multiple (up to four times) or a sub-multiple (down to a fortieth) of a daily dose of the active compound in association with a carrier and/or enclosed within an envelope. Whether the composition contains a daily dose, or for example, a half, a third or a quarter of a daily dose, will depend on whether the pharmaceutical composition is to be administered once or, for example, twice, three times or four times a day, respectively.
  • salt denotes acidic and/or basic salts, formed with inorganic or organic acids and/or bases, preferably basic salts. While pharmaceutically acceptable salts are preferred, particularly when employing the compounds of the invention as medicaments, other salts find utility, for example, in processing these compounds, or where non-medicament-type uses are contemplated. Salts of these compounds may be prepared by art-recognized techniques.
  • Examples of such pharmaceutically acceptable salts include, but are not limited to, inorganic and organic addition salts, such as hydrochloride, sulphates, nitrates or phosphates and acetates, trifluoroacetates, propionates, succinates, benzoates, citrates, tartrates, fumarates, maleates, methane-sulfonates, isothionates, theophylline acetates, salicylates, respectively, or the like. Lower alkyl quaternary ammonium salts and the like are suitable, as well.
  • 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, salicy
  • 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 such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • antioxidants examples include, but are not limited to, water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, aloha-tocopherol and the like; and the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like
  • oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (B
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions or emulsions.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, suspending agents, and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions); or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets).
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques.
  • the active agent can be encapsulated to make it stable to passage through the gastrointestinal tract while at the same time allowing for passage across the blood brain barrier. See for example, WO 96/11698.
  • the compound may be dissolved in a pharmaceutical carrier and administered as either a solution or a suspension.
  • suitable carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative or synthetic origin.
  • the carrier may also contain other ingredients, for example, preservatives, suspending agents, solubilizing agents, buffers and the like.
  • the compounds When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid.
  • a variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selected, the severity of the disease state being treated and the dosage required for therapeutic efficacy.
  • the methods of this invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
  • modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes.
  • parenteral includes subcutaneous, intravenous, epidural, irrigation, intramuscular, release pumps, or infusion.
  • administration of the active agent according to this invention may be achieved using any suitable delivery means, including:
  • microencapsulation see, e.g., U.S. Pat. Nos. 4,352,883; 4,353,888; and 5,084,350);
  • an active agent is delivered directly into the CNS, preferably to the brain ventricles, brain parenchyma, the intrathecal space or other suitable CNS location, most preferably intrathecally.
  • targeting therapies may be used to deliver the active agent more specifically to certain types of cell, by the use of targeting systems such as antibodies or cell specific ligands. Targeting may be desirable for a variety of reasons, e.g. if the agent is unacceptably toxic, or if it would otherwise require too high a dosage, or if it would not otherwise be able to enter the target cells.
  • the active agents which are peptides, can also be administered in a cell based delivery system in which a DNA sequence encoding an active agent is introduced into cells designed for implantation in the body of the patient, especially in the spinal cord region.
  • a cell based delivery system in which a DNA sequence encoding an active agent is introduced into cells designed for implantation in the body of the patient, especially in the spinal cord region.
  • Suitable delivery systems are described in U.S. Pat. No. 5,550,050 and published PCT Application Nos. WO 92/19195, WO 94/25503, WO 95/01203, WO 95/05452, WO 96/02286, WO 96/02646, WO 96/40871, WO 96/40959 and WO 97/12635.
  • Suitable DNA sequences can be prepared synthetically for each active agent on the basis of the developed sequences and the known genetic code.
  • Exemplary methods for administering compounds will be apparent to the skilled artisan.
  • Certain methods suitable for administering compounds useful according to the present invention are set forth in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 7th Ed. (1985).
  • the administration to the patient can be intermittent; or at a gradual, continuous, constant or controlled rate.
  • Administration can be to a warm-blooded animal (e.g. a mammal, such as a mouse, rat, cat, rabbit, dog, pig, cow or monkey); but advantageously is administered to a human being.
  • Administration occurs after general anesthesia is administered.
  • the frequency of administration normally is determined by an anesthesiologist, and typically varies from patient to patient.
  • the active agent is preferably administered in an therapeutically effective amount.
  • a “therapeutically effective amount” or simply “effective amount” of an active compound is meant a sufficient amount of the compound to treat the desired condition at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the actual amount administered, and the rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage, timing, etc., is within the responsibility of general practitioners or spealists, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in Remington 's Pharmaceutical Sciences.
  • Dosage may be adjusted appropriately to achieve desired levels, locally or systemically, and depending on use as a diagnostic agent or a therapeutic agent.
  • the active agents of the present invention typically 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. 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.
  • an appropriate dosage will depend on the peptide and the detectable label.
  • a suitable dose to be injected is in the range to enable imaging by scanning procedures known in the art.
  • a radiolabeled conantokin When used, it may be administered in a dose having a radioactivity of form 0.1 to 50 mCi, preferably, 0.1 to 30 mCi and more preferably, 0.1 to 20 mCi.
  • an appropriate dosage will depend on the peptide, the radionuculide, the size and location of the tumor and the half life of the active agent in the tumor. In general, the dose is calculated on the basis of of the radioactivity distribution to each organ and on observed target uptake.
  • the active agent may be administered at a daily dosage range having a radioactivity of from 0.1 to 3 mCi/kg, preferably 1 to 3 mCi/kg, more preferably 1 to 1.5 mCi/kg.
  • compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients.
  • Tablets, coated tablets, capsules, ampoules and suppositories are examples of dosage forms according to the invention.
  • the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be consistent with the dosage form employed in single or multiple unit doses.
  • a suitable effective dosage will be consistent with the dosage form employed in single or multiple unit doses.
  • the exact individual dosages, as well as daily dosages, are determined according to standard medical principles under the direction of a physician or veterinarian for use humans or animals.
  • the pharmaceutical compositions will generally contain from about 0.0001 to 99 wt. %, preferably about 0.001 to 50 wt. %, more preferably about 0.01 to 10 wt. % of the active ingredient by weight of the total composition.
  • the pharmaceutical compositions and medicaments can also contain other pharmaceutically active compounds.
  • other pharmaceutically active compounds include, but are not limited to, analgesic agents, cytokines and therapeutic agents in all of the major areas of clinical medicine.
  • the conopeptides of the present invention may be delivered in the form of drug cocktails.
  • a cocktail is a mixture of any one of the compounds useful with this invention with another drug or agent.
  • a common administration vehicle e.g., pill, tablet, implant, pump, injectable solution, etc.
  • a common administration vehicle e.g., pill, tablet, implant, pump, injectable solution, etc.
  • the individual drugs of the cocktail are each administered in therapeutically effective amounts.
  • a therapeutically effective amount will be determined by the parameters described above; but, in any event, is that amount which establishes a level of the drugs in the area of body where the drugs are required for a period of time which is effective in attaining the desired effects.
  • the present invention also relates to rational drug design for the indentification of additional drugs which can be used for the pursposes described herein.
  • the goal of rational drug design is to produce structural analogs of biologically active polypeptides of interest or of small molecules with which they interact (e.g., agonists, antagonists, inhibitors) in order to fashion drugs which are, for example, more active or stable forms of the polypeptide, or which, e.g., enhance or interfere with the function of a polypeptide in vivo.
  • Several approaches for use in rational drug design include analysis of three-dimensional structure, alanine scans, molecular modeling and use of anti-id antibodies. These techniques are well known to those skilled in the art.
  • Such techniques may include providing atomic coordinates defining a three-dimensional structure of a protein complex formed by said first polypeptide and said second polypeptide, and designing or selecting compounds capable of interfering with the interaction between a first polypeptide and a second polypeptide based on said atomic coordinates.
  • the substance may be further investigated. Furthermore, it may be manufactured and/or used in preparation, i.e., manufacture or formulation, or a composition such as a medicament, pharmaceutical composition or drug. These may be administered to individuals.
  • a substance identified as a modulator of polypeptide function may be peptide or non-peptide in nature.
  • Non-peptide “small molecules” are often preferred for many in vivo pharmaceutical uses. Accordingly, a mimetic or mimic of the substance (particularly if a peptide) may be designed for pharmaceutical use.
  • the designing of mimetics to a known pharmaceutically active compound is a known approach to the development of pharmaceuticals based on a “lead” compound. This approach might be desirable where the active compound is difficult or expensive to synthesize or where it is unsuitable for a particular method of administration, e.g., pure peptides are unsuitable active agents for oral compositions as they tend to be quickly degraded by proteases in the alimentary canal.
  • Mimetic design, synthesis and testing is generally used to avoid randomly screening large numbers of molecules for a target property.
  • the pharmacophore Once the pharmacophore has been found, its structure is modeled according to its physical properties, e.g., stereochemistry, bonding, size and/or charge, using data from a range of sources, e.g., spectroscopic techniques, x-ray diffraction data and NMR. Computational analysis, similarity mapping (which models the charge and/or volume of a pharmacophore, rather than the bonding between atoms) and other techniques can be used in this modeling process.
  • a range of sources e.g., spectroscopic techniques, x-ray diffraction data and NMR.
  • Computational analysis, similarity mapping which models the charge and/or volume of a pharmacophore, rather than the bonding between atoms
  • other techniques can be used in this modeling process.
  • a template molecule is then selected, onto which chemical groups that mimic the pharmacophore can be grafted.
  • the template molecule and the chemical groups grafted thereon can be conveniently selected so that the mimetic is easy to synthesize, is likely to be pharmacologically acceptable, and does not degrade in vivo, while retaining the biological activity of the lead compound.
  • the mimetic is peptide-based
  • further stability can be achieved by cyclizing the peptide, increasing its rigidity.
  • the mimetic or mimetics found by this approach can then be screened to see whether they have the target property, or to what extent it is exhibited. Further optimization or modification can then be carried out to arrive at one or more final mimetics for in vivo or clinical testing.
  • the present invention further relates to the use of a labeled (e.g., radiolabel, fluorophore, chromophore or the like) of the ⁇ -conotoxins described herein as a molecular tool both in vitro and in vivo, for discovery of small molecules that exert their action at or partially at the same functional site as the native toxin and capable of elucidation similar functional responses as the native toxin.
  • a labeled e.g., radiolabel, fluorophore, chromophore or the like
  • the displacement of a labeled ⁇ -conotoxin from its receptor or other complex by a candidate drug agent is used to identify suitable candidate drugs.
  • a biological assay on a test compound to determine the therapeutic activity is conducted and compared to the results obtained from the biological assay of a ⁇ -conotoxin.
  • the binding affinity of a small molecule to the receptor of a ⁇ -conotoxin is measured and compared to the binding affinity of a ⁇ -conotoxin to its receptor.
  • cancer neoplasm, solid tumor, diabetic nephropathy, fibrosis, hypophysis tumor, GI disease, IBS, restinosis, angiogenesis disorder, diabetes mellitus, endocrine tumor, diarrhea, pancreatic disease, prostate tumor, bleeding, apoptosis), inflammation, pain, diabetes, obesity, sexual dysfunction, acromegaly, glaucoma, cardiovascular, diabetic, retinopathy, depression, myocardial infarction, stroke, epilepsy, anorexia, wasting diseases, seborrheic dermatitis, schizophrenia, mood disorders, chemotherapeutic induced emesis, disorders associated with changes in blood pressure, immune disorders, nerve damage, acne, GI infections, myocardial infarction, angina, thromboembolism and cardiovascular disease.
  • cancer neoplasm, solid tumor, diabetic nephropathy, fibrosis, hypophysis tumor, GI disease, IBS, restinosis, angiogenesis disorder, diabetes me
  • DNA coding for ⁇ -superfamily conotoxin peptides 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), including using primers based on the DNA sequence of known conotoxin peptides.
  • cDNA libraries was prepared from Conus venom duct using conventional techniques.
  • DNA from single clones was amplified by conventional techniques using primers which correspond approximately to the M13 universal priming site and the M13 reverse universal priming site. Clones having a size of approximately 300-500 nucleotides were sequenced and screened for similarity in sequence to known conotoxins.
  • the DNA sequences and encoded propeptide sequences are set forth in Table 1.
  • DNA sequences coding for the mature toxin can also be prepared on the basis of the DNA sequences set forth in Table1.
  • An alignment of the conopeptides of the present invention is set forth in Table 2.
  • Sequences of truncated and analog peptides are set forth in Table 3.
  • Test Substance and Concentration A ⁇ -M14.1 derivative, ⁇ -M14.1-D1 (LFCFXKSCWPRPYPWR (SEQ ID NO:309, where X is dW) was used for in vitro anti-tumor studies.
  • the test compound was dissolved and diluted with sterile distilled water to obtain initial working solutions of 10000, 1000, 100, 10, and 1 ⁇ M. In testing, 100-fold dilution was made in culture media to get final assay concentrations of 100, 10, 1, 0.1, and 0.01 ⁇ M.
  • the culture medium used for the MCF-7 cell line was Minimum Essential Medium, 90%; Fetal Bovine Serum, 10%.
  • the culture medium used for the MIA PaCa-2 cell line was Dulbecco's Modified Eagle's Medium, 90%; Fetal Bovine Serum, 10%. All media were supplemented with 1% Antibiotic-Antimycotic.
  • the cell line MCF-7 which is a breast adenocarcinoma, pleural effusion, human, was obtained from the American Type Culture Collection (ATCC HTB-22).
  • the cell line MIA PaCa-2 which is a pancreatic carcinoma, human, was obtained form the American Type culture Collection (ATCC CRL-1420).
  • the tumor cells were incubated in an air atmosphere of 5% CO 2 at 3° C.
  • Chemicals The sources of the chemicals were as follows: AlamarBlue (Biosource, USA), Antibiotic-Antimycotic (GIBCO BRL, USA), Dulbecco's Modified Eagle's Medium (GIBCO BRL, USA), Fetal Bovine Serum (HyClone, USA), Minimum Essential medium (GIBCO BRL, USA) and Mitomycin (Kyowa, Japan).
  • Equipment Centrifuge 5810R (Eppendorf, Germany), CO 2 Incubator (Forma Scientific Inc., USA), Hemacytometer(Hausser Scientific Horsham, USA), Inverted Microscope CK-40 (Olympus, Japan), Spectrafluor Plus (Tecan, Austria), System Microscope E-400 (Nikon, Japan) and Vertical Laminar Flow (Tsao-Hsin, Taiwan).
  • the media in microplate were all removed, and then 200 ⁇ l of fresh media and 20 ⁇ l of 90% alamarBlue reagent were added to each well for another 6-hour incubation before detection of cell viability by fluorescent intensity. Fluorescent intensity was measured using a Spectraflour Plus plate reader with excitation at 530 nm and emission at 590 nm.
  • Mean F time0 The average of 2 measured fluorescent intensities of reduced alamarBlue at the time just before exposure of cells to the test substance.
  • Mean F test The average of 2 measured fluorescent intensities of alamarBlue after 72-hour exposure of cells to the test substance.
  • Mean F ctrl The average of 2 measured fluorescent intensities of alamarBlue after 72-hour incubation without the test substance.
  • Mean F blank The average of 2 measured fluorescent intensities of alamarBlue in medium without cells after 72-hour incubation.
  • the assays were used to detect changes in cell proliferation based on the ability of viable cells to cause alamarBlue to change from its oxidized (non-fluorescent, blue) to a reduced (fluorescent, red) form. With the results obtained from the alamarBlue reaction, cell proliferation can be quantified and metabolic activity of viable cells can be examined.
  • the ⁇ -M14.1-D1 was tested for its effect upon the proliferation of 2 different human tumor cell lines, MCF-7 (breast) and MIA PaCa-2 (pancreas), at five final assay concentrations from 0.01 to 100 ⁇ M through serial 10-fold dilutions.
  • the ⁇ -M14.1-D1 exhibited significant growth inhibition ( ⁇ 50%) relative to the respective vehicle treated control group at concentrations between 10 ⁇ M to 100 ⁇ M in the 2 human tumor cells lines (Table 4). Significant activity was observed for the concurrently tested standard reference agent Mitomycin at ⁇ 10 ⁇ M (Table 1). Consequently, semi-quantitative determinations of estimated IC 50 (50% inhibition concentration), TGI (total growth inhibition) and LC 50 (50% lethal concentration) by nonlinear regression analysis were calculated (Table 5).
  • Biochemical assay results are presented as the percent inhibition of specific binding or activity. All other results are expressed in terms of that assay's quantitation method. For primary assays, only the lowest concentration with a significant response judged by the assays' criteria, is shown. Primary screening in duplicate with quantitative data are shown where applicable for individual assays. Significant responses were noted in the primary assays shown in Table 6. TABLE 6 Primary Tests a Primary Tissue Assay Tissue, gp Conc.
  • Biochemical assay results are presented as the percent inhibition of specific binding or activity. All other results are expressed in terms of that assay's quantitation method. For primary assays, only the lowest concentration with a significant response judged by the assays' criteria, is shown. Primary screening in duplicate with quantitative data (e.g., IC 50 ⁇ SEM, K i ⁇ SEM and nH) are shown where applicable for individual assays. In screening packages, primary screening in duplicate with semi-quantitative data (e.g., estimated IC 50 , K i and nH) are shown where applicable (concentration range of 4 log units). Significant responses were noted in the primary assays shown in Table 7. TABLE 7 Primary Test Primary Biochemical % Assay Species Conc.
  • NonSpecific Ligand 1 ⁇ M NDP- ⁇ MSH K d : 0.05 nM (historical value) Quantitation Method: Radioligand Binding Significance Criteria: ⁇ 50% of max stimulation or inhibition Melanocortin MC 1 (Siegrist et al., 1988) Source: Human recombinant CHO cells Ligand: 0.05 nM 125 I NDP- ⁇ MSH Incubation Time/Temp: 90 min @ 22° C. NonSpecific Ligand: 0.1 ⁇ M MCH K d : 0.62 nM (historical value) Quantitation Method: Radioligand Binding Significance Criteria: ⁇ 50% of max stimulation or inhibition
  • Biochemical assay results are presented as the percent inhibition of specific binding or activity. All other results are expressed in terms of that assay's quantitation method. For primary assays, only the lowest concentration with a significant response judged by the assays' criteria, is shown. Primary screening in duplicate with quantitative data (e.g., IC 50 ⁇ SEM, K i ⁇ SEM and nH) are shown where applicable for individual assays. In screening packages, primary screening in duplicate with semi-quantitative data (e.g., estimated IC 50 , K i and nH) are shown where applicable (concentration range of 4 log units). Significant responses were noted in the primary assays shown in Tables 10 and 11.

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Abstract

The present invention is directed to β-superfamily conotoxin peptides, derivatives or pharmaceutically acceptable salts thereof. The present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated ion channels, ligand gated channels and other receptors. The invention is further directed to nucleic acid sequences encoding the β-superfamily conotoxin peptides and encoding β-superfamily conotoxin propeptides, as well as the β-superfamily conotoxin propeptides.

Description

    CROSS-REFERENCE TO RELATED APPLICATION
  • The present application is a continuation of U.S. patent application Ser. No. 10/058,053 filed on 29 Jan. 2002. The present application is also related to and claims priority under 35 USC § 119(e) to U.S. provisional patent application Serial No. 60/264,323 filed on 29 Jan. 2001. Each application is incorporated herein by reference.[0001]
  • [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, Md. The United States Government has certain rights in the invention.
    • BACKGROUND OF THE INVENTION
  • The present invention is directed to β-superfamily conotoxin peptides (also referred to as β-conotoxins), derivatives or pharmaceutically acceptable salts thereof. The present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated ion channels, ligand-gated ion channels and/or receptors. The invention is further directed to nucleic acid sequences encoding the conotoxin peptides and encoding propeptides, as well as the propeptides. [0003]
  • The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography. [0004]
  • Conus is a genus of predatory marine gastropods (snails) which envenomate their prey. Venomous cone snails use a highly developed projectile apparatus to deliver their cocktail of toxic conotoxins into their prey. In fish-eating species such as Conus magus the cone detects the presence of the fish using chemosensors in its siphon. When close enough it extends its proboscis and impales the fish hollow harpoon-like tooth containing venom. This immobilizes the fish and enables the cone snail to wind it into its mouth via the tooth at the end of the proboscis. For general information on Conus and their venom see the website address grimwade.biochem.unimelb. edu.au/cone/referenc.html. Prey capture is accomplished through a sophisticated arsenal of peptides which target specific ion channel and receptor subtypes. Each Conus species venom appears to contain a unique set of 50-200 peptides. The composition of the venom differs greatly between species and between individual snails within each species, each optimally evolved to paralyse it's prey. The active components of the venom are small peptides toxins, typically 10-30 amino acid residues in length and are typically highly constrained peptides due to their high density of disulphide bonds. [0005]
  • The venoms consist of a large number of different peptide components that when separated exhibit a range of biological activities: when injected into mice they elicit a range of physiological responses from shaking to depression. The paralytic components of the venom that have been the focus of recent investigation are the α-, ω- and μ-conotoxins. All of these conotoxins act by preventing neuronal communication, but each targets a different aspect of the process to achieve this. The α-conotoxins target nicotinic ligand gated channels, the μ-conotoxins target the voltage-gated sodium channels and the ω-conotoxins target the voltage-gated calcium channels (Olivera et al., 1985; Olivera et al., 1990). For example a linkage has been established between α-, αA- & ψ-conotoxins and the nicotinic ligand-gated ion channel; co-conotoxins and the voltage-gated calcium channel; κ-conotoxins and the voltage-gated sodium channel; δ-conotoxins and the voltage-gated sodium channel; κ-conotoxins and the voltage-gated potassium channel; conantokins and the ligand-gated glutamate (NMDA) channel. [0006]
  • However, the structure and function of only a small minority of these peptides have been determined to date. For peptides where function has been determined, three classes of targets have been elucidated: voltage-gated ion channels; ligand-gated ion channels, and G-protein-linked receptors. [0007]
  • Conus peptides which target voltage-gated ion channels include those that delay the inactivation of sodium channels, as well as blockers specific for sodium channels, calcium channels and potassium channels. Peptides that target ligand-gated ion channels include antagonists of NMDA and serotonin receptors, as well as competitive and noncompetitive nicotinic receptor antagonists. Peptides which act on G-protein receptors include neurotensin and vasopressin receptor agonists. The unprecedented pharmaceutical selectivity of conotoxins is at least in part defined by a specific disulfide bond frameworks combined with hypervariable amino acids within disulfide loops (for a review see McIntosh et al., 1998). [0008]
  • There are drugs used in the treatment of pain, which are known in the literature and to the skilled artisan. See, for example, Merck Manual, 16th Ed. (1992). However, there is a demand for more active analgesic agents with diminished side effects and toxicity and which are non-addictive. The ideal analgesic would reduce the awareness of pain, produce analgesia over a wide range of pain types, act satisfactorily whether given orally or parenterally, produce minimal or no side effects, be free from tendency to produce tolerance and drug dependence. [0009]
  • Due to the high potency and exquisite selectivity of the conopeptides, several are in various stages of clinical development for treatment of human disorders. For example, two Conus peptides are being developed for the treatment of pain. The most advanced is co-conotoxin MVIIA (ziconotide), an N-type calcium channel blocker (see Heading, C., 1999; U.S. Pat. No. 5,859,186). ω-Conotoxin MVIIA, isolated from [0010] Conus magus, is approximately 1000 times more potent than morphine, yet does not produce the tolerance or addictive properties of opiates. ω-Conotoxin MVIIA has completed Phase III (final stages) of human clinical trials and has been approved as a therapeutic agent. ω-Conotoxin MVIIA is introduced into human patients by means of an implantable, programmable pump with a catheter threaded into the intrathecal space. Preclinical testing for use in post-surgical pain is being carried out on another Conus peptide, contulakin-G, isolated from Conus geographus (Craig et al. 1999). Contulakin-G is a 16 amino acid O-linked glycopeptide whose C-terminus resembles neurotensin. It is an agonist of neurotensin receptors, but appears significantly more potent than neurotensin in inhibiting pain in in vivo assays.
  • In view of a large number of biologically active substances in Conus species it is desirable to further characterize them and to identify peptides capable of treating disorders voltage-gated ion channels, ligand-gated ion channels and/or receptors. 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, ligand-gated ion channels and/or receptors and could address a long felt need for a safe and effective treatment. [0011]
    • SUMMARY OF THE INVENTION
  • The present invention is directed to conotoxin peptides, derivatives or pharmaceutically acceptable salts thereof. The present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated ion channels, ligand-gated ion channels and/or G-protein coupled receptors (GPCRs). The invention is further directed to nucleic acid sequences encoding the conotoxin peptides and encoding propeptides, as well as the propeptides. [0012]
  • More specifically, the present invention is directed to conotoxin peptides, having the amino acid sequences set forth in Tables 1-3 below. In the β-superfamily conotoxins containing 4-Cys residues (e.g., Ge14.1), the peptide may be bridged [1,4/2,3] or [1,3/2,4]. [0013]
  • The present invention is also directed to derivatives or pharmaceutically acceptable salts of the conotoxin peptides or the derivatives. Examples of derivatives include peptides in which the Arg residues may be substituted by Lys, ornithine, homoarginine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any synthetic basic amino acid. The Lys residues may be substituted by Arg, omithine, homoarginine, nor-Lys, or any synthetic basic amino acid. The Tyr residues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, [0014] 125I-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 D or L, may be substituted at the ortho, meta, and/or para positions with a halogen or may be substituted with any synthetic aromatic amino acid. The Trp residues may be substituted with Trp (D), neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, 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-hydroxylisomers (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 Leu may be substituted with Leu (D). The Glu residues may be substituted with Gla or Asp. The Gla residues may be substituted with Glu or Asp. The acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g. tetrazolyl derivatives of Gly and Ala. The N-terminal Gln may be substituted with pyro-glutamate (Z). The aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains CnH2n+2 up to and including n=8. The Met residues may be substituted with nor-leucine (Nle). The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L). Basic residues in the backbone may be D or L configuration. The central Trp residue within the beta-turn is preferably epimerized to the D-form.
  • Examples of synthetic aromatic amino acid include, but are not limited to, nitro-Phe, 4-substituted-Phe wherein the substituent is C[0015] 1-C3 alkyl, carboxyl, hyrdroxymethyl, sulphomethyl, halo, phenyl, —CHO, —CN, —SO3H and —NHAc. Examples of synthetic hydroxy containing amino acid, include, but are not limited to, such as 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr. Examples of synthetic basic amino acids include, but are not limited to, N-1-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4-piperinyl)-Ala, 2-[3-(2S)pyrrolininyl)-Gly and 2-[3-(2S)pyrrolininyl)-Ala. These and other synthetic basic amino acids, synthetic hydroxy containing amino acids or synthetic aromatic amino acids are described in Building Block Index, Version 3.0 (1999 Catalog, pages 4-47 for hydroxy containing amino acids and aromatic amino acids and pages 66-87 for basic amino acids; see also web address amino-acids. com), incorporated herein by reference, by and available from RSP Amino Acid Analogues, Inc., Worcester, Mass. Examples of synthetic acid amino acids include those derivatives bearing acidic functionality, including carboxyl, phosphate, sulfonate and synthetic tetrazolyl derivatives such as described by Ornstein et al. (1993) and in U.S. Pat. No. 5,331,001, each incorporated herein by reference, and such as shown in the following schemes 1-3.
    Figure US20040176278A1-20040909-C00001
    Figure US20040176278A1-20040909-C00002
    Figure US20040176278A1-20040909-C00003
  • Additional derivatives are peptides in which the Asn residues may be modified to contain an N-glycan and the Ser, Thr and Hyp residues may be modified to contain an O-glycan (e.g., g-N, g-S, g-T and g-Hyp). In accordance with the present invention, a glycan shall mean any N-, S- or O-linked mono-, di-, tri-, poly- or oligosaccharide that can be attached to any hydroxy, amino or thiol group of natural or modified amino acids by synthetic or enzymatic methodologies known in the art. The monosaccharides making up the glycan can include D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose, D-galactosamine, D-glucosamine, D-N-acetyl-glucosamine (GlcNAc), D-N-acetyl-galactosamine (GalNAc), D-fucose or D-arabinose. These saccharides may be structurally modified, e.g., with one or more O-sulfate, O-phosphate, O-acetyl or acidic groups, such as sialic acid, including combinations thereof. The gylcan may also include similar polyhydroxy groups, such as D-penicillamine 2,5 and halogenated derivatives thereof or polypropylene glycol derivatives. The glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3. The linkage between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-. [0016]
  • Core O-glycans have been described by Van de Steen et al. (1998), incorporated herein by reference. Mucin type O-linked oligosaccharides are attached to Ser or Thr (or other hydroxylated residues of the present peptides) by a GalNAc residue. The monosaccharide building blocks and the linkage attached to this first GalNAc residue define the “core glycans,” of which eight have been identified. The type of glycosidic linkage (orientation and connectivities) are defined for each core glycan. Suitable glycans and glycan analogs are described further in U.S. Ser. No. 09/420,797 filed 19 Oct. 1999 (now U.S. Pat. No. 6,369,193) and in PCT Application No. PCT/US99/24380 filed 19 Oct. 1999 (PCT Published Application No. WO 00/23092), each incorporated herein by reference. A preferred glycan is Gal(β1→3)GalNAc(α[0017] 1→).
  • Derivatives also include peptides in which pairs of Cys residues may be replaced pairwise with isosteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/Ala combinations. Sequential coupling by known methods (Barnay et al., 2000; Hruby et al., 1994; Bitan et al., 1997) allows replacement of native Cys bridges with lactam bridges. Thioether analogs may be readily synthesized using halo-Ala residues commercially available from RSP Amino Acid Analogues. In addition, individual Cys residues may be replaced with homoCys, seleno-Cys or penicillamine, so that disulfide bridges may be formed between Cys-homoCys or Cys-penicillamine, or homoCys-penicllamine and the like. [0018]
  • Derivatives and analogs also include truncations of the peptides disclosed herein. As used herein “truncations” are used to refer to peptides in which the sequence has been shortened from the mature conotoxin sequence that is predicted by the prepropeptide cleavage site with significant retention of activity of the native conotoxin. These truncations can be shortened from the N-terminus, the C-terminus, or both. As used herein significant retention of activity is used to refer to an activity of the truncated conotoxin which is less that 100-fold loss of activity and specificity. [0019]
  • Derivatives also include radiometal and chelated anti-tumor peptides. The incorporation of the radiometal eg [0020] 99mTc, 111In, 90Y, 188Re, 105RhS4, 188Re-tisuccin, 89Sr, 153Sm, 186Re, 67Ga, 211At, 212Bi, 213Bi, 177Lu, 67Cu, 64Cu, 105Rh, 47Sc, 109Pd] in to the conotoxin generally involves use of a chelate, specific to the particular metal, and a linker group to covalently attach the chelate to the conotoxin [the bifunctional chelate approach]. The design of useful chelates is dependent on the coordination requirements of the specific radiometal. DTPA, DOTA, P2S2—COOH BFCA requirement for kinetic TETA, NOTA are common egs. The requirement for kinetic stability of the metal complex is often achieved through the use of multidentate chelate ligands with a functionalised arm for covalent bonding to some part of the conotoxin ie the amino lysine group. Hence, the conotoxins of the present invention may be tagged to produce radiopharmaceuticals. In relation to radioligand probes of β-conotoxins for screening of small molecules, acting at unique allosteric sites, synthesis of such screening tools is not restricted to radioiodinated tyrosine derivatives. Incorporation of standard commercially available tritiated amino acid residues can also be utilized.
  • The present invention is further directed to a method of treating disorders associated with voltage-gated ion channels, ligand-gated ion channels and/or receptor disorders in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a conotoxin peptide 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 conotoxin peptide described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. [0021]
  • More specifically, the present invention is also directed to nucleic acids which encode conotoxin peptides of the present invention or which encodes precursor peptides for these conotoxin peptides, as well as the precursor peptide. The nucleic acid sequences encoding the precursor peptides of other conotoxin peptides of the present invention are set forth in Table 1. Table 1 also sets forth the amino acid sequences of these precursor peptides. [0022]
  • Another embodiment of the invention contemplates a method of identifying compounds that mimic the therapeutic activity of the instant peptide, comprising the steps of: (a) conducting a biological assay on a test compound to determine the therapeutic activity; and (b) comparing the results obtained from the biological assay of the test compound to the results obtained from the biological assay of the peptide. [0023]
    • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
  • The present invention is directed to β-superfamily conotoxin peptides (also referred to as β-conotoxins), derivatives or pharmaceutically acceptable salts thereof. The present invention is further directed to the use of this peptide, derivatives thereof and pharmaceutically acceptable salts thereof for the treatment of disorders associated with voltage-gated ion channels, ligand-gated ion channels and/or receptors, such as G-protein coupled receptors (GPCRs). The invention is further directed to nucleic acid sequences encoding the β-superfamily conotoxin peptides and encoding propeptides, as well as the propeptides. [0024]
  • The present invention, in another aspect, relates to a pharmaceutical composition comprising an effective amount of a β-superfamily conotoxin peptide, a mutein thereof, an analog thereof, a derivative 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, ligand-gated ion channels and/or receptors (such as G-protein coupled receptors (GPCRs)), 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 such channels or receptors 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. [0025]
  • G-protein-coupled receptors (GPCRs) are a large, upwards of 1000, and functionally diverse protein superfamily, which form a seven transmembrane (TM) helices bundle with alternating extra-cellular and intracellular loops. GPCRs are considered to be one of the most important groups of drug targets because they are involved in a broad range of body functions and processes and are related to major diseases. Over the last decades distinct members of the G Protein-Coupled Receptor (GPCR) family emerged as prominent drug targets within pharmaceutical research, since approximately 60% of marketed prescription drugs act by selectively addressing representatives of that class of transmembrane signal transduction systems. It is noteworthy that the majority of GPCR-targeted drugs elicit their biological activity by selective agonism or antagonism of biogenic monoamine receptors, while the development status of peptide-binding GPCR-addressing compounds is still in its infancy. [0026]
  • The β-conotoxins may function as allosteric modulators (i.e., agonists, partial agonists, neutral antagonists, inverse agonists) of GPCRs including, but not limited to, sst (sst[0027] 1, sst2, sst3, sst2a, sst2b, sst4, sst5), cortistatin (CST), melanocortin (MCxR, wherein x=1, 2, 3, 4, 5), opioid (μ, δ, κ), neurokinin (NK1, NK2, NK3), bradykinin (B1, B2), galanin (Gal1, Gal2, Gal3), CCKA, CCKB, endothelin, serotonin, adrenergic receptors, angiotensin (AT1, AT2), neuropeptide-Y, sigma1, sigrna2, oxytocin, CGRP, GRPR, histamine, imidazoline, neurotensin (NT1, NT2, NT3), VIP, vasopressin (V1a, V1b, V2), substance K, chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CCR1, CCR2b, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CX3CR1), CRF1, CRF2a, CRF2b, CRF2g, CRF-BP orexin (Ox1, Ox2), urotensin (UT-II), glycoprotein IIb/IIIa, thrombin receptors, orphan GPCRs (eg. MCH2R/SLT, SP1999/P2Y12, CRTH2, NPFF1, NPFF2, HH4R, h-GPR54, CysLT2, neuromedin receptors, BLTR2, G2A, TA1, LTB4, ghrelin, motilin MTL-R, purinergic receptors, muscarinic receptors, ORL-1, apelin, CB1, CB2 and the like). For an extensive list of GPCRs see web address gpcr. org/7tm/htmls/entries.html. For additional orphan GPCR references see Shaaban (2001) and Civelli et. al. (2001). This beta turn toxin template may also be used to characterize new functional allosteric sites on known GPCRs. Radiolabelled dervatives serve as screening tools for such sites and will allow for identification of new small molecule modulators. The reverse beta turn motif serves as a template for beta turn peptidomimetic design in which the turn template contains the cone snail WK recognition “fingerprint”, examples of such templates can be found in Golebiowski et al. (2001), Horwell (1996) and Beeley (2000).
  • Somatostatin Receptors (SSTRs): Somatostatin (SRIF), was first identified as a peptide that inhibits growth hormone release. Later it was shown to have other physiological activities, including the inhibition of the release of many endocrine secretions such as prolactin, TSH and insulin. The peptide also exhibits neuromodulatory functions and may act as a neurotransmitter. Somatostatin has two major actions; inhibition of hormone and cytokine (IFN-γ, IL-6, IL-8, IL-1) release and inhibition of cellular proliferation. SRIF can inhibit the release of hormones in the brain and almost all hormone release in the gut, together with many cytokines and growth factors eg PDGF. SRIF can be produced in cells from neuroendocrine and immune systems. It is produced in two forms SRIF-28 and SRIF-14. Additionally a novel SST-like peptide called cortistatin (CST) has been isolated from human. CST-14 shares 11 of the 14 amino acids with SRIF. One measurable difference between SRIF and CST is that SRIF increases the duration of REM sleep in rats whereas CST decreases it. It is thus possible to postulate that specific CST receptors exist. [0028]
  • Five sst receptors have been identified sst1, 2, 3, 4, 5. All are GPCRs and are encoded on a different chromosome. Both SRIF-14 and SRIF-28 bind to all receptors but SRIF-28 has higher affinity for sst[0029] 5. It must be noted that 2 isoforms of sst2 exist namely, SSt2A and SSt2B. SRIF receptors are widely expressed. Cells from the CNS, gut, pancreas, kidney, thyroid, lung and the immune system express the receptors in varying proportions.
  • Overproduction of growth factors from tumours can result in systemic effects, as seen in acromegaly, a chronic debilitating disease caused by excessive production of GH. SRIF analogs suppress the release of GH and thus can benefit patients. A majority of tumours originating from tissues naturally targeted by SRIF express sst receptors at high levels. [0030]
  • Synthetic peptides such as, lanreotide, octreotide and vapreotide bind sst[0031] 2 and 5 with high affinity and sst3 to a lesser extent. Not only have peptide analogs of SRIF been used to reduce tumour growth directly through somatostatin receptor signalling but also medicine finds considerable use for somatostatin receptors in tumour detection and imaging and now in tumour targeting (Slooter et al., 2001).
  • The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide/lanreotide analogs as tumor tracers in nuclear medicine, similar chemical; modifications of conotoxins bT2, bM1, bG1 may be achieved. The vast majority of human tumors seem to overexpress the one or the other of five distinct h-SSTR sub-type receptors. Whereas neuroendocrine tumors frequently overexpress h-SSTR[0032] 2, intestinal adenocarcinomas seem to over-express more often h-SSTR3 or h-SSTR4, or both of these h-SSTR. In contrast to 111In-DTPA-DPhe1-octreotide (OCTREOSCAN) which binds to h-SSTR2 and 5 with high affinity (Kd 0.1-5 nM), to h-SSTR3 with moderate affinity (Kd 10-100 nM) and does not bind to h-SSTR1 and h-SSTR4, 111In/90Y-DOTA-lanreotide was found to bind to h-SSTR2, 3, 4, and 5 with high affinity, and to h-SSTR1 with lower affinity (Kd 200 nM). Based on its unique h-SSTR binding profile, 111In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and 90Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to 111In-DTPA-DPhe1-octreotide and 111In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a “higher” high-affinity binding of 111In-DOTA-DPhe1-Tyr3-octreotide to h-SSTR2. Other somatostatin analogs with divergent affinity to the five known h-SSTR subtype receptors have also found their way into the clinics, including 99 mTc-HYNIC-octreotide or 99 mTc-depreotide (NEOSPECT; NEOTECT).
  • Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or non-small cell lung cancer ([0033] 99 mTc-depreotide), indicating high diagnostic capability of this type of receptor tracers. Consequently to their use as receptor imaging agents, h-SSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. The study “MAURITIUS” (MulticenterAnalysis of a Universal Receptor Imaging and Treatment Initiative, a European Study), a Phase IIa study, showed in patients with a calculated tumor dose>10 Gy/GBq 90Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with receptor imaging agents. Overall treatment results in>60 patients indicated stable tumor disease in roughly 35% of patients and regressive disease in 15% of tumor patients with different tumor entities. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to 90Y-DOTA-lanreotide, was reported. 90In-DOTA-DPhe1-Tyr3-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore provide even better treatment results in tumor patients, but there is only limited excess to long-term and survival data at present. Besides newer approaches and recent developments of 188Re-labeled radioligands no clinical results on the treatment response is available yet. In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plentitude of preclinical data and clinical studies confirm “proof-of-principle” for their use in diagnosis as well as therapy of cancer patients. However, an optimal radiopeptide formulation does not yet exist for receptor-targeted radionuclide therapy (Virgolini, 2001).
  • During the last decade five different subtypes of melanocortin receptors have been identified and cloned, all of them are possible as new targets for drugs in the treatment of a number of clinical important conditions such as inflammatory diseases (MC[0034] 1-receptor agonists), MC3/MC4-receptors in the treatment of feeding disorder, agonists for treatment of obesity and antagonists for anorectic conditions. MC3/MC4-agonists or also assumed to be useful for treating sexual dysfunction. In the treatment of seborrheic dermatitis the MC5 receptor is considered as a target. A number of peptide or peptide like ligands, agonists and/or antagonist has been discovered, however, most of them have a large similarity with the endogenous ligand A-MSH.
  • Melanocortins: The major source of melanocortins is the pituitary, where ACTH and β-lipotropin are the main products from the anterior pituitary, and α-MSH and β-lipotropin are major products from the intermediate lobe. All melanocortins, i.e. α-Melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH and the endogenous opioid β-endorphin, are cleaved from POMC, but β-MSH and β-endorphin emanate from the C-terminal part of POMC, i.e. the β-lipotropin. γ-MSH is cleaved from the N-terminal part of POMC. While α-MSH is a tri-decapeptide proteolytically cleaved from proopiomelanocortin (POMC) comprising of the N-terminal part of ACTH and is considered as the endogenous ligand to the melanocortin receptors. [0035]
  • β-MSH is found in the hypothalamus, whereas γ-MSH is found in different areas of the CNS, adrenal medulla and neurons of the intestine. α-MSH has been demonstrated in the pituitary, but also in other parts of the CNS, as well as in peripheral parts of the body. Only low circulating concentrations of α-MSH have been detected in humans in normal situations, whereas the concentration is increased in several diseases. [0036]
  • Melanocortin Receptors MCRs: Melanocortin receptors belong to the family of G-protein coupled, 7-TM receptors, and have been identified in several tissues of the body. Today, 5 different subtypes of receptors, MC1-5, have been described. The MC[0037] 2 receptor binds only ACTH, and is present in the adrenal cortex and also in white adipose tissue of rodents, but not in man or primates. The MC1, MC2, MC3, MC4 and MC5 receptors are distributed in different areas/organs of the body. The MC2 receptor is not further discussed since it is considered as the ACTH receptor. Interestingly, the MC3 receptor is expressed in low abundance during fetal life and expression increases to adult levels after birth, as demonstrated in rats. The opposite is true for the MC4 receptor, which is predominant during fetal life. However, both receptors seem to be important for different physiological functions postnatally.
  • The MC receptors and α-MSH are involved in several physiological functions besides affecting skin pigmentation. They have effects on learning, memory, behaviour, including sexual behaviour, regeneration in the neuromuscular system and protection from central nerve injury, cardiovascular functions, feeding and weight homeostasis, fever and immunomodulation/inflammation, exocrine functions and interact with opioids and dopamine. They are also ascribed effects such as regulation of the release of pituitary and peripheral hormone. [0038]
  • Examples of voltage-gated ion channels include the voltage-gated calcium channel, the voltage-gated sodium channel, the voltage-gated potassium channel and the proton-gated ion channel. Examples of ligand-gated channels include the nicotinic ligand-gated ion channel, ligand-gated glutamate (NMDA) channel and the ligand-gated 5HT[0039] 3 (serotonin) channel. Examples of receptors include the G-protein receptors. Activity of ψ-conotoxins is described in U.S. Pat. No. 5,969,096 and in Shon et al. (1997). Activity of bromosleeper conotoxins is described in U.S. Pat. No. 5,889,147 and in Craig et al. (1997). Activity of σ-conotoxins is described in U.S. Pat. No. 5,889,147. Activity of contryphan conotoxins is described in U.S. Pat. No. 6,077,934 and in Jimenez et al. (1996). Activity of conopressins is described in Cruz et al. (1987) and in Kruszynski et al. (1990). Activity of y-conotoxins is described in Fainzilber et al. (1998). Activity of γ-conotoxins is described in Jacobsen et al. (1997) and in Hopkins et al. (1995). Activity of γ-conotoxins is described in U.S. Ser. No. 09/497,491 (PCT/US00/03021, PCT published application WO 00/46371) as an antagonist for acetylcholine receptors and as analgesic agents for the treatment of pain (whether acute or chronic), including migraine, chronic pain, and neuropathic pain, without undesirable side effects. Activity of contulakins is described in U.S. Ser. No. 09/420,797 (now U.S. Pat. No. 6,369,193) (PCT/US99/24380, PCT published application WO 00/23092). Each of these references is incorporated herein by reference.
  • Since α-conotoxins are antagonists of the 5HT[0040] 3 receptor, they are also useful in treating irritable bowel syndrome (IBS) and visceral pain. Visceral pain is a common experience in health and disease. Chronic visceral hyperalgesia in the absence of detectable organic disease has been implicated in many common functional bowel disorders (FDB), such as IBS, non-ulcer dyspepsia (NUD) and non-cardiac chest pain (NCCP).
  • Pain in IBS cannot be explained by normal perception of abnormal motility. In the majority of patients, sensory perception itself is abnormal. Most visceral afferent information is part of the reflex activity of digestion and does not reach concious perception. Increasing evidence suggests that long term changes in the thresholds and gain of the visceral afferent pathways are present in patients with FDBs. This has been referred to as visceral hyperalgesia (Mayer et al., 1994). [0041]
  • It has been proposed that FDBs are a result of increased excitability of spinal neurones. According to their model, many inputs can result in transient, short term, or life long sensitization of afferent pathways involved in visceral reflexes and sensations from the gut. The increased sensory input to interneurons and/or dorsal horn neurons in the spinal cord will result in secondary hyperalgesia, in which adjacent, undamaged viscera develop sensitivity to normal innocuous stimuli (allodynia), and central hyperexcitability as a consequence of changes in the circuitary of the dorsal horn. This central sensitization may subsequently extend to supraspinal centers also. [0042]
  • Altered spinal processing of visceral sensory information can explain altered sensory thresholds and altered referral patterns, the perception of visceral sensations without stimulation of visceral mechnoreceptors (sensation of incomplete evacuation), and the symptomatic involvement of multiple sites in the GI tract, including extra intestinal sites. Increased excitability of dorsal horn neurones, resulting in the recruitment of previously sub-threshold inputs, may explain cutaneous allodynia in some patients with IBS, burning sensations referred to different parts of the body, cold hypersensitivity and pain referral to upper and lower extremities. [0043]
  • A number of compounds have been shown to modulate visceral sensitivity in IBS patients. These include octreotide (sst2; Novartis), the 5-HT[0044] 3 antgonists odansetron (Glaxo) and granisetron (SKB) and the peripheral kappa opioid agonist, fedotozine (Jouveinal SA). The 5-HT3 antagonist alosteron (Glaxo), cuurrently in development for IBS, is active in modifying the perception of colonic distension and gut compliance in IBS patients. New drugs in development for the treatment of IBS that are targeted at pain control as well as dysmotility include 5-HT3 and 5-HT4 receptor antagonists. 5-HT3 receptors are located throughout the central and peripheral nervous system—their role in modulating the activity of visceral afferent and enteric neurones has led to the proposal that 5-HT acts as a sensitizing agent via these receptors on visceral afferent neurones. 5-HT3 receptor antagonists have been widely reported to attenuate blood pressure responses to intestinal distension. 5-HT3 antagonists in development for IBS include Alosteron (phase III), which is reported to reduce abdominal pain, slow colonic transit and increase colon compliance in IBS patients. Other compounds with positive effects include the antiemetic Ramosteron (Yamanouchi), Cilansteron (Solvay) and YM-114 (Yamanouchi). An animal model for dysmotility of the GI tract has been described by Maric et al. (1989).
  • In addition to the above uses, the peptides of the present invention are also useful (i) for treating or diagnosis of cancer, neoplasm, solid tumor, diabetic nephropathy, fibrosis, hypophysis tumor, GI disease, IBS, restinosis, angiogenesis disorder, diabetes mellitus, endocrine tumor, diarrhea, pancreatic disease, prostate tumor, bleeding, apoptosis, inflammation, pain, diabetes, obesity, sexual dysfunction, acromegaly, glaucoma, cardiovascular, diabetic, retinopathy, depression, myocardial infarction, stroke, epilepsy, anorexia, wasting diseases, seborrheic dermatitis, schizophrenia, mood disorders, chemotherapeutic induced emesis, disorders associated with changes in blood pressure, immune disorders, nerve damage, acne, GI infections, myocardial infarction, angina, thromboembolism, cardiovascular disease, (ii) as templates for small molecule design and (iii) as screening tools. [0045]
  • The superfamily of seven-transmembrane-domain G-protein-coupled receptors (GPCRs) is the largest and most diverse group of transmembrane proteins involved in signal transduction. Each of the approximately 1000 family members found in vertebrates responds to stimuli as diverse as hormones, neurotransmitters, odorants and light, which selectively activate intracellular signaling events mediated by heterotrimeric G proteins. Because GPCRs are centrally positioned in the plasma membrane to initiate a cascade of cellular responses by diverse extracellular mediators, it is not surprising that modulation of GPCR function has been successful in the development of many marketed therapeutic agents. It has become clear that GPCRs for which a natural activating ligand has not yet been identified (orphan GPCRs) might provide a path to discovering new cellular substances that are important in human physiology. The process of ‘de-orphanizing’ these novel proteins has accelerated significantly and opened up new avenues for research in human physiology and pharmacology. [0046]
  • In most cases the extent of sequence homology is insufficient to assign these ‘orphan’ receptors to a particular receptor subfamily. Consequently, reverse molecular pharmacological and functional genomic strategies are being employed to identify the activating ligands of the cloned receptors. Briefly, the reverse molecular pharmacological methodology includes cloning and expression of orphan GPCRs in mammalian cells and screening these cells for a functional response to cognate or surrogate agonists present in biological extract preparations, peptide libraries, and complex compound collections. The functional genomics approach involves the use of “humanized” yeast cells, where the yeast GPCR transduction system is engineered to permit functional expression and coupling of human GPCRs to the endogenous signalling machinery. Both systems provide an excellent platform for identifying novel receptor ligands. Once activating ligands are identified they can be used as pharmacological tools to explore receptor function and relationship to disease. [0047]
  • The β-superfamily conotoxins can also be used to design a β-turn mimetic of the β-superfamily conotoxins containing a β-turn motif, e.g., the —CX1X2KX1C— (SEQ ID NO:338) motif where X1 is any amino acid and X2 is Trp in the D or L orientation (or halogenated at position 6 of the indole) or the —CPX3RVC— (SEQ ID NO:339) motif where X3 is Phe in the D or L configuration. Other β-turn motifs are also present in the β-superfamily conotoxins as evident from the peptide sequences disclosed in Tables 2 and 3. This hairpin turn would be replaced by a non-peptide turn mimetic, preferably an orally available mimetic. The unique receptor binding domains contained within the N and C-terminal regions of the β-superfamily conotoxin would then be attached to the β-turn scaffold, in such a way as to mimic the 3D spatial array within the native toxin. As an example of the β-turn motif and a β-turn mimetic, see Scheme 4. [0048]
    Figure US20040176278A1-20040909-C00004
  • The β-superfamily conotoxins of the present invention are also useful for characterizing sites on GPCRs and for identifying novel receptor ligands for GPCRS, especially orphan GCPRs. For example, the β-beta turn toxin template may also be used to characterize new functional allosteric sites on known GPCRs. Radiolabelled derivatives serve as screening tools for such sites and will allow for identification of new small molecule modulators. The reverse beta turn motif serves as a template for beta turn peptidomimetic design in which the turn template contains the cone snail WK recognition “fingerprint”, examples of such templates can be found in Golebiowski et al. (2001) and Horwell (2000). In addition, a ligand which binds to an orphan G-protein coupled receptor (orphan GPCR) can be identified by contacting a β-superfamily conotoxin with an orphan GPCR and measuring the amount of binding of the conotoxin to the orphan GPCR by methods that are well known in the art (Murphy et al., 1998). A homology search to identify other candidate ligands for testing can then be done on the basis of any peptide which binds to the orphan GPCR. The candidate ligands may be peptides or peptide mimetics. [0049]
  • The conotoxin peptides described herein are sufficiently small to be chemically synthesized. General chemical syntheses for preparing the foregoing conotoxin peptides are described hereinafter. Various ones of the conotoxin peptides can also be obtained by isolation and purification from specific Conus species using the technique described in U.S. Pat. No. 4,447,356 (Olivera et al., 1984); U.S. Pat. Nos. 5,514,774; 5,719,264; and 5,591,821, as well as in PCT published application WO 98/03189, the disclosures of which are incorporated herein by reference. [0050]
  • Although the conotoxin peptides of the present invention can be obtained by purification from cone snails, because the amounts of conotoxin peptides obtainable from individual snails are very small, the desired substantially pure conotoxin peptides 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 conotoxin peptides 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 conotoxin peptides peptides depends of course upon correct determination of the amino acid sequence. [0051]
  • The conotoxin peptides 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 conotoxin peptides) 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. [0052]
  • One method of forming disulfide bonds in the conotoxin peptides 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. [0053]
  • 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. [0054]
  • In conventional solution phase peptide synthesis, the peptide chain can be prepared by a series of coupling reactions in which constituent amino acids are added to the growing peptide chain in the desired sequence. Use of various coupling reagents, e.g., dicyclohexylcarbodiimide or diisopropylcarbonyldimidazole, various active esters, e.g., esters of N-hydroxyphthalimide or N-hydroxy-succinimide, and the various cleavage reagents, to carry out reaction in solution, with subsequent isolation and purification of intermediates, is well known classical peptide methodology. Classical solution synthesis is described in detail in the treatise, “Methoden der Organischen Chemie (Houben-Weyl): Synthese von Peptiden,” (1974). Techniques of exclusively solid-phase synthesis are set forth in the textbook, “Solid-Phase Peptide Synthesis,” (Stewart and Young, 1969), and are exemplified by the disclosure of U.S. Pat. No. 4,105,603 (Vale et al., 1978). The fragment condensation method of synthesis is exemplified in U.S. Pat. No. 3,972,859 (1976). Other available syntheses are exemplified by U.S. Pat. No. 3,842,067 (1974) and U.S. Pat. No. 3,862,925 (1975). The synthesis of peptides containing γ-carboxyglutamic acid residues is exemplified by Rivier et al. (1987), Nishiuchi et al. (1993) and Zhou et al. (1996). [0055]
  • 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. [0056]
  • 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. [0057]
  • It should be possible to prepare many, or even all, of these peptides using recombinant DNA technology. However, when peptides are not so prepared, they are preferably prepared using the Merrifield solid-phase synthesis, although other equivalent chemical syntheses known in the art can also be used as previously mentioned. Solid-phase synthesis is commenced from the C-terminus of the peptide by coupling a protected α-amino acid to a suitable resin. Such a starting material can be prepared by attaching an α-amino-protected amino acid by an ester linkage to a chloromethylated resin or a hydroxymethyl resin, or by an amide bond to a benzhydrylamine (BHA) resin or paramethylbenzhydrylamine (MBHA) resin. Preparation of the hydroxymethyl resin is described by Bodansky et al. (1966). Chloromethylated resins are commercially available from Bio Rad Laboratories (Richmond, Calif.) and from Lab. Systems, Inc. The preparation of such a resin is described by Stewart and Young (1969). BHA and MBHA resin supports are commercially available, and are generally used when the desired polypeptide being synthesized has an unsubstituted amide at the C-terminus. Thus, solid resin supports may be any of those known in the art, such as one having the formulae —O—CH[0058] 2-resin support, —NH BHA resin support, or —NH-MBHA resin support. When the unsubstituted amide is desired, use of a BHA or MBHA resin is preferred, because cleavage directly gives the amide. In case the N-methyl amide is desired, it can be generated from an N-methyl BHA resin. Should other substituted amides be desired, the teaching of U.S. Pat. No. 4,569,967 (Kornreich et al., 1986) can be used, or should still other groups than the free acid be desired at the C-terminus, it may be preferable to synthesize the peptide using classical methods as set forth in the Houben-Weyl text (1974).
  • The C-terminal amino acid, protected by Boc or Fmoc and by a side-chain protecting group, if appropriate, can be first coupled to a chloromethylated resin according to the procedure set forth in K. Horiki et al. (1978), using KF in DMF at about 60° C. for 24 hours with stirring, when a peptide having free acid at the C-terminus is to be synthesized. Following the coupling of the BOC-protected amino acid to the resin support, the α-amino protecting group is removed, as by using trifluoroacetic acid (TFA) in methylene chloride or TFA alone. The deprotection is carried out at a temperature between about 0° C. and room temperature. Other standard cleaving reagents, such as HCl in dioxane, and conditions for removal of specific α-amino protecting groups may be used as described in Schroder & Lubke (1965). [0059]
  • After removal of the α-amino-protecting group, the remaining α-amino- and side chain-protected amino acids are coupled step-wise in the desired order to obtain the intermediate compound defined hereinbefore, or as an alternative to adding each amino acid separately in the synthesis, some of them may be coupled to one another prior to addition to the solid phase reactor. Selection of an appropriate coupling reagent is within the skill of the art. Particularly suitable as a coupling reagent is N,N′-dicyclohexylcarbodiimide (DCC, DIC, HBTU, HATU, TBTU in the presence of HoBt or HoAt). [0060]
  • 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). [0061]
  • 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[0062] 2Cl2 (1:1) or in DMF or CH2Cl2 alone. In cases where intermediate coupling occurs, the coupling procedure is repeated before removal of the α-amino protecting group prior to the coupling of the next amino acid. The success of the coupling reaction at each stage of the synthesis, if performed manually, is preferably monitored by the ninhydrin reaction, as described by Kaiser et al. (1970). Coupling reactions can be performed automatically, as on a Beckman 990 automatic synthesizer, using a program such as that reported in Rivier et al. (1978).
  • After the desired amino acid sequence has been completed, the intermediate peptide can be removed from the resin support by treatment with a reagent, such as liquid hydrogen fluoride or TFA (if using Fmoc chemistry), which not only cleaves the peptide from the resin but also cleaves all remaining side chain protecting groups and also the amino protecting group at the N-terminus if it was not previously removed to obtain the peptide in the form of the free acid. If Met is present in the sequence, the Boc protecting group is preferably first removed using trifluoroacetic acid (TFA)/ethanedithiol prior to cleaving the peptide from the resin with HF to eliminate potential S-alkylation. When using hydrogen fluoride or TFA for cleaving, one or more scavengers such as anisole, cresol, dimethyl sulfide and methylethyl sulfide are included in the reaction vessel. [0063]
  • Cyclization of the linear peptide is preferably affected, as opposed to cyclizing the peptide while a part of the peptido-resin, to create bonds between Cys residues. To effect such a disulfide cyclizing linkage, fully protected peptide can be cleaved from a hydroxymethylated resin or a chloromethylated resin support by ammonolysis, as is well known in the art, to yield the fully protected amide intermediate, which is thereafter suitably cyclized and deprotected. Alternatively, deprotection, as well as cleavage of the peptide from the above resins or a benzhydrylamine (BHA) resin or a methylbenzhydrylamine (MBHA), can take place at 0° C. with hydrofluoric acid (HF) or TFA, followed by oxidation as described above. [0064]
  • The peptides are also synthesized using an automatic synthesizer. Amino acids are sequentially coupled to an MBHA Rink resin (typically 100 mg of resin) beginning at the C-terminus using an Advanced Chemtech 357 Automatic Peptide Synthesizer. Couplings are carried out using 1,3-diisopropylcarbodimide in N-methylpyrrolidinone (NMP) or by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and diethylisopropylethylamine (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. [0065]
  • Muteins, analogs or active fragments, of the foregoing conotoxin peptides are also contemplated here. See, e.g., Hammerland et al. (1992). Derivative muteins, analogs or active fragments of the conotoxin peptides may be synthesized according to known techniques, including conservative amino acid substitutions, such as outlined in U.S. Pat. No. 5,545,723 (see particularly col. 2, line 50—col. 3, line 8); U.S. Pat. No. 5,534,615 (see particularly col. 19, line 45—col. 22, line 33); and U.S. Pat. No. 5,364,769 (see particularly col. 4, line 55—col. 7, line 26), each herein incorporated by reference. [0066]
  • Radiolabeled peptides have been used to show that perhaps only the amino acid sequence actually involved in binding to the receptor is essential for achieving tumor uptake. [0067] 111In-radiolabelled octreotide, which is used to image somatostatin positive tumors, is a prime example of this. In addition, advances in tumor biology have demonstrated metabolic pathways to deliver the nuclide within the cell cytoplasm through internalization mechanisms. Some classes of tumors have been shown to overexpress certain receptors, e.g., glutamate, AMPA, NMDA, somatostatin, melanocortin and the like, and whenever these substances can be radiolabeled and introduced to the system, they can become the lethal magic bullet by working inside the cell.
  • Specificity is the paramount goal in radionuclide therapy because with specificity comes safety and efficacy. The strategy in biologically targeted therapy is to chemically package the radionuclide to take advantage of metabolic pathways or tumor characteristics so that the radionuclide is localized in the target organ or tissue while the nuclear energy is discharged with minimal exposure to healthy tissue. The concentration differential of the therapeutic radio-pharmaceutical must be orders of magnitude between target and non-target tissues. Radiation doses of 4000-6000 rads are desirable in the target tissue, while only a few tens of radiation units can be functionally tolerated by some radiosensitive tissues. The short range of the emitted particles in the tissues makes them very damaging over the range in which their decay energy is deposited. The specificity of certain of the β-superfamily conotoxins for the somatostatin receptor provide the necessary specificity for the treatment and diagnosis of tumors. [0068]
  • Where the aim is to provide an image of the tumor, one will desire to use a diagnostic agent that is detectable upon imaging, such as a paramagnetic, radioactive or fluorogenic agent. Many diagnostic agents are known in the art to be useful for imaging purposes, as are methods for their attachment to peptides (see, e.g., U.S. Pat. Nos. 5,021,236 and 4,472,509, both incorporated herein by reference). In the case of paramagnetic ions, one might mention by way of example ions such as chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) and erbium (III), with gadolinium being particularly preferred. Ions useful in other contexts, such as X-ray imaging, include but are not limited to lanthanum (III), gold (III), lead (II), and especially bismuth (III). Moreover, in the case of radioactive isotopes for therapeutic and/or diagnostic application, one might mention [0069] 131 iodine, 123iodine, 99mtechnicium, 111indium, 188rhenium, 186rhenium, 67gallium, 67copper, 90yttrium, 125iodine, or 211astatine. Short-lived positron emission tomography (PET) isotopes, such as 18flourine, can also be used for labeling peptides for use in tumor diagnosis (Okarvi, 2001).
  • Where the aim is to treat the tumor, one will desire to use a radionuclide that will irradiate the tumor. Suitable radionuclides include [0070] 131iodine, 123iodine, 99mtechnicium, 111indium, 188rhenium, 186rhenium, 67gallium, 90yttrium, 105rhodium, 89strontium, 153samarium, 211astatine, 212bismuth, 213bismuth, 177lutetium, 67copper, 47scandium, 109palladium. Optimally, radionuclides are chosen for the specific application on the basis of physical and chemical properties such that (a) their decay mode and emitted energy are matched to the delivery site, (b) their half life and chemical properties are complementary to the biological processing and (c) production methods can yield the radionuclide at the necessary level of specific activity and radionuclide purity.
  • The incorporation of the radiometal into the P-superfamily conotoxins generally involves use of a chelate, specific to the particular metal, and a linker group to covalently attach the chelate to the conotoxin, i.e., a the bifunctional chelate approach. The design of useful chelates is dependent on the coordination requirements of the specific radiometal. DTPA, DOTA, P[0071] 2S2—COOH BFCA requirement for kinetic TETA, NOTA are common examples. The requirement for kinetic stability of the metal complex is often achieved through the use of multidentate chelate ligands with a functionalized arm for covalent bonding to some part of the conantokin or γ-carboxyglutamate containing conopeptide, i.e., the lysine amino group. Techniques for chelating radioonuclides with proteins are well known in the art, such as demonstrated by interantional patent application publication No. WO 91/01144, incorporated herein by reference.
  • In some embodiments, the β-superfamily conotoxins are used in combination with one or more potentiators and/or chemotherapeutic agents for the treatment of cancer or tumors. An exemplary potentiator is triprolidine (U.S. Pat. No. 5,114,951) or its cis-isomer which are used in combination with chemotherapeutic agents. Another potentiator is procodazole, which is a non-specific immunoprotective agent active against viral and bacterial infections. Other potentiators which can be used with conantokins or γ-carboxyglutamate containing peptides and optionally another chemotherapeutic agent to treat or inhibit the growth of cancer include monensin, an anti-sense inhibitor of the RAD51 gene, bromodeoxyuridine, dipyridamole, indomethacin, a monoclonal antibody, an anti-transferrin receptor immunotoxin, metoclopramide, 7-thia-8-oxoguanosine, N-solanesyl-N,N′-bis(3,4-dimethoxybenzyl)ethylene-diamine, leucovorin, heparin, N-[4-[(4-fluorphenyl)sulfonly]phenyl] acetamide, heparin sulfate, cimetidine, a radiosensitizer, a chemosensitizer, a hypoxic cell cytotoxic agent, muramyl dipeptide, vitamin A, 2′-deoxycoformycin, a bis-diketopiperazine derivative, and dimethyl sulfoxide. [0072]
  • The chemotherapeutic agents which can be used with conantokins or γ-carboxyglutamate containing peptides and an optional potentiator are generally grouped as DNA-interactive agents, antimetabolites, tubulin-interactive agents, hormonal agents and others such as asparaginase or hydroxyurea. Each of the groups of chemotherapeutic agents can be further divided by type of activity or compound. The chemotherapeutic agents used in combination with y-carboxy-glutamate containing peptides include members of all of these groups. For a detailed discussion of chemotherapeutic agents and their method of administration, see Dorr et al. (1994) and U.S. Pat. No. 6,290,929. [0073]
  • DNA-interactive agents include the alkylating agents, e.g. cisplatin, cyclophosphamide, altretamine; the DNA strand-breakage agents, such as bleomycin; the intercalating topoisomerase II inhibitors, e.g., dactinomycin and doxorubicin; the nonintercalating topoisomerase II inhibitors such as, etoposide and teniposde; and the DNA minor groove binder plicamydin. The alkylating agents form covalent chemical adducts with cellular DNA, RNA, and protein molecules and with smaller amino acids, glutathione and similar chemicals. Generally, these alkylating agents react with a nucleophilic atom in a cellular constituent, such as an amino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins, amino acids, or glutathione. [0074]
  • The antimetabolites interfere with the production of nucleic acids by one or the other of two major mechanisms. Some of the drugs inhibit production of the deoxyribonucleoside triphosphates that are the immediate precursors for DNA synthesis, thus inhibiting DNA replication. Some of the compounds are sufficiently like purines or pyrimidines to be able to substitute for them in the anabolic nucleotide pathways. These analogs can then be substituted into the DNA and RNA instead of their normal counterparts. [0075]
  • Tubulin interactive agents act by binding to specific sites on tubulin, a protein that polymerizes to form cellular microtubules. Microtubules are critical cell structure units. When the interactive agents bind on the protein, the cell cannot form microtubules. Tubulin interactive agents include colchicine, vincristine and vinblastine, both alkaloids and paclitaxel and cytoxan. [0076]
  • Hormonal agents are also useful in the treatment of cancers and tumors. They are used in hormonally susceptible tumors and are usually derived from natural sources. These include: estrogens, conjugated estrogens and ethinyl estradiol and diethylstilbesterol, chlortrianisen and idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate; fluoxymesterone, methyltestosterone. Adrenal corticosteroids are derived from natural adrenal cortisol or hydrocortisone. They are used because of their anti inflammatory benefits as well as the ability of some to inhibit mitotic divisions and to halt DNA synthesis. These compounds include, prednisone, dexamethasone, methylprednisolone, and prednisolone. Leutinizing hormone releasing hormone agents or gonadotropin-releasing hormone antagonists are used primarily the treatment of prostate cancer. These include leuprolide acetate and goserelin acetate. They prevent the biosynthesis of steroids in the testes. Antihormonal antigens include: antiestrogenic agents such as tamoxifen, antiandrogen agents such as flutamide; and antiadrenal agents such as mitotane and aminoglutethimide. [0077]
  • 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, [0078] Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa.). Typically, an antagonistic amount of active ingredient will be admixed with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral, parenteral or intrathecally. For examples of delivery methods see U.S. Pat. No. 5,844,077, incorporated herein by reference.
  • “Pharmaceutical composition” means physically discrete coherent portions suitable for medical administration. “Pharmaceutical composition in dosage unit form” means physically discrete coherent units suitable for medical administration, each containing a daily dose or a multiple (up to four times) or a sub-multiple (down to a fortieth) of a daily dose of the active compound in association with a carrier and/or enclosed within an envelope. Whether the composition contains a daily dose, or for example, a half, a third or a quarter of a daily dose, will depend on whether the pharmaceutical composition is to be administered once or, for example, twice, three times or four times a day, respectively. [0079]
  • 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. [0080]
  • Examples of such pharmaceutically acceptable salts include, but are not limited to, inorganic and organic addition salts, such as hydrochloride, sulphates, nitrates or phosphates and acetates, trifluoroacetates, propionates, succinates, benzoates, citrates, tartrates, fumarates, maleates, methane-sulfonates, isothionates, theophylline acetates, salicylates, respectively, or the like. Lower alkyl quaternary ammonium salts and the like are suitable, as well. [0081]
  • 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. [0082]
  • 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. [0083]
  • 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. [0084]
  • 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. [0085]
  • 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. [0086]
  • For example, administration of the active agent according to this invention may be achieved using any suitable delivery means, including: [0087]
  • (a) pump (see, e.g., Luer & Hatton (1993), Zimm et al. (1984) and Ettinger et al. (1978)); [0088]
  • (b), microencapsulation (see, e.g., U.S. Pat. Nos. 4,352,883; 4,353,888; and 5,084,350); [0089]
  • (c) continuous release polymer implants (see, e.g., U.S. Pat. No. 4,883,666); [0090]
  • (d) macroencapsulation (see, e.g., U.S. Pat. Nos. 5,284,761, 5,158,881, 4,976,859 and 4,968,733 and published PCT patent applications WO92/19195, WO 95/05452); [0091]
  • (e) naked or unencapsulated cell grafts to the CNS (see, e.g., U.S. Pat. Nos. 5,082,670 and 5,618,531); [0092]
  • (f) injection, either subcutaneously, intravenously, intra-arterially, intramuscularly, or to other suitable site; or [0093]
  • (g) oral administration, in capsule, liquid, tablet, pill, or prolonged release formulation. [0094]
  • 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. [0095]
  • 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. [0096]
  • The active agents, which are peptides, can also be administered in a cell based delivery system in which a DNA sequence encoding an active agent is introduced into cells designed for implantation in the body of the patient, especially in the spinal cord region. Suitable delivery systems are described in U.S. Pat. No. 5,550,050 and published PCT Application Nos. WO 92/19195, WO 94/25503, WO 95/01203, WO 95/05452, WO 96/02286, WO 96/02646, WO 96/40871, WO 96/40959 and WO 97/12635. Suitable DNA sequences can be prepared synthetically for each active agent on the basis of the developed sequences and the known genetic code. [0097]
  • Exemplary methods for administering compounds (e.g., so as to achieve sterile or aseptic conditions) will be apparent to the skilled artisan. Certain methods suitable for administering compounds useful according to the present invention are set forth in Goodman and Gilman's [0098] The Pharmacological Basis of Therapeutics, 7th Ed. (1985). The administration to the patient can be intermittent; or at a gradual, continuous, constant or controlled rate. Administration can be to a warm-blooded animal (e.g. a mammal, such as a mouse, rat, cat, rabbit, dog, pig, cow or monkey); but advantageously is administered to a human being. Administration occurs after general anesthesia is administered. The frequency of administration normally is determined by an anesthesiologist, and typically varies from patient to patient.
  • The active agent is preferably administered in an therapeutically effective amount. By a “therapeutically effective amount” or simply “effective amount” of an active compound is meant a sufficient amount of the compound to treat the desired condition at a reasonable benefit/risk ratio applicable to any medical treatment. The actual amount administered, and the rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage, timing, etc., is within the responsibility of general practitioners or spealists, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in [0099] Remington 's Pharmaceutical Sciences.
  • Dosage may be adjusted appropriately to achieve desired levels, locally or systemically, and depending on use as a diagnostic agent or a therapeutic agent. For therapeutic uses, the active agents of the present invention typically 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. [0100]
  • For diagnostic uses, an appropriate dosage will depend on the peptide and the detectable label. A suitable dose to be injected is in the range to enable imaging by scanning procedures known in the art. When a radiolabeled conantokin is used, it may be administered in a dose having a radioactivity of form 0.1 to 50 mCi, preferably, 0.1 to 30 mCi and more preferably, 0.1 to 20 mCi. For therpeutic uses, an appropriate dosage will depend on the peptide, the radionuculide, the size and location of the tumor and the half life of the active agent in the tumor. In general, the dose is calculated on the basis of of the radioactivity distribution to each organ and on observed target uptake. For example, the active agent may be administered at a daily dosage range having a radioactivity of from 0.1 to 3 mCi/kg, preferably 1 to 3 mCi/kg, more preferably 1 to 1.5 mCi/kg. [0101]
  • 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. [0102]
  • 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. [0103]
  • The pharmaceutical compositions will generally contain from about 0.0001 to 99 wt. %, preferably about 0.001 to 50 wt. %, more preferably about 0.01 to 10 wt. % of the active ingredient by weight of the total composition. In addition to the active agent, the pharmaceutical compositions and medicaments can also contain other pharmaceutically active compounds. Examples of other pharmaceutically active compounds include, but are not limited to, analgesic agents, cytokines and therapeutic agents in all of the major areas of clinical medicine. When used with other pharmaceutically active compounds, the conopeptides of the present invention may be delivered in the form of drug cocktails. A cocktail is a mixture of any one of the compounds useful with this invention with another drug or agent. In this embodiment, a common administration vehicle (e.g., pill, tablet, implant, pump, injectable solution, etc.) would contain both the instant composition in combination supplementary potentiating agent. The individual drugs of the cocktail are each administered in therapeutically effective amounts. A therapeutically effective amount will be determined by the parameters described above; but, in any event, is that amount which establishes a level of the drugs in the area of body where the drugs are required for a period of time which is effective in attaining the desired effects. [0104]
  • The present invention also relates to rational drug design for the indentification of additional drugs which can be used for the pursposes described herein. The goal of rational drug design is to produce structural analogs of biologically active polypeptides of interest or of small molecules with which they interact (e.g., agonists, antagonists, inhibitors) in order to fashion drugs which are, for example, more active or stable forms of the polypeptide, or which, e.g., enhance or interfere with the function of a polypeptide in vivo. Several approaches for use in rational drug design include analysis of three-dimensional structure, alanine scans, molecular modeling and use of anti-id antibodies. These techniques are well known to those skilled in the art. Such techniques may include providing atomic coordinates defining a three-dimensional structure of a protein complex formed by said first polypeptide and said second polypeptide, and designing or selecting compounds capable of interfering with the interaction between a first polypeptide and a second polypeptide based on said atomic coordinates. [0105]
  • Following identification of a substance which modulates or affects polypeptide activity, the substance may be further investigated. Furthermore, it may be manufactured and/or used in preparation, i.e., manufacture or formulation, or a composition such as a medicament, pharmaceutical composition or drug. These may be administered to individuals. [0106]
  • A substance identified as a modulator of polypeptide function may be peptide or non-peptide in nature. Non-peptide “small molecules” are often preferred for many in vivo pharmaceutical uses. Accordingly, a mimetic or mimic of the substance (particularly if a peptide) may be designed for pharmaceutical use. [0107]
  • The designing of mimetics to a known pharmaceutically active compound is a known approach to the development of pharmaceuticals based on a “lead” compound. This approach might be desirable where the active compound is difficult or expensive to synthesize or where it is unsuitable for a particular method of administration, e.g., pure peptides are unsuitable active agents for oral compositions as they tend to be quickly degraded by proteases in the alimentary canal. Mimetic design, synthesis and testing is generally used to avoid randomly screening large numbers of molecules for a target property. [0108]
  • Once the pharmacophore has been found, its structure is modeled according to its physical properties, e.g., stereochemistry, bonding, size and/or charge, using data from a range of sources, e.g., spectroscopic techniques, x-ray diffraction data and NMR. Computational analysis, similarity mapping (which models the charge and/or volume of a pharmacophore, rather than the bonding between atoms) and other techniques can be used in this modeling process. [0109]
  • A template molecule is then selected, onto which chemical groups that mimic the pharmacophore can be grafted. The template molecule and the chemical groups grafted thereon can be conveniently selected so that the mimetic is easy to synthesize, is likely to be pharmacologically acceptable, and does not degrade in vivo, while retaining the biological activity of the lead compound. Alternatively, where the mimetic is peptide-based, further stability can be achieved by cyclizing the peptide, increasing its rigidity. The mimetic or mimetics found by this approach can then be screened to see whether they have the target property, or to what extent it is exhibited. Further optimization or modification can then be carried out to arrive at one or more final mimetics for in vivo or clinical testing. [0110]
  • The present invention further relates to the use of a labeled (e.g., radiolabel, fluorophore, chromophore or the like) of the β-conotoxins described herein as a molecular tool both in vitro and in vivo, for discovery of small molecules that exert their action at or partially at the same functional site as the native toxin and capable of elucidation similar functional responses as the native toxin. In one embodiment, the displacement of a labeled β-conotoxin from its receptor or other complex by a candidate drug agent is used to identify suitable candidate drugs. In a second embodiment, a biological assay on a test compound to determine the therapeutic activity is conducted and compared to the results obtained from the biological assay of a β-conotoxin. In a third embodiment, the binding affinity of a small molecule to the receptor of a β-conotoxin is measured and compared to the binding affinity of a β-conotoxin to its receptor. [0111]
  • In view of the targets of the β-conotoxins, they may be used for treating the following conditions: cancer (neoplasm, solid tumor, diabetic nephropathy, fibrosis, hypophysis tumor, GI disease, IBS, restinosis, angiogenesis disorder, diabetes mellitus, endocrine tumor, diarrhea, pancreatic disease, prostate tumor, bleeding, apoptosis), inflammation, pain, diabetes, obesity, sexual dysfunction, acromegaly, glaucoma, cardiovascular, diabetic, retinopathy, depression, myocardial infarction, stroke, epilepsy, anorexia, wasting diseases, seborrheic dermatitis, schizophrenia, mood disorders, chemotherapeutic induced emesis, disorders associated with changes in blood pressure, immune disorders, nerve damage, acne, GI infections, myocardial infarction, angina, thromboembolism and cardiovascular disease. [0112]
  • 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[0113] ; Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds. 1984); Transcription And Translation (B. D. Hames & S. J. Higgins eds. 1984); Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds., 1986); Riott, Essential Immunology, 6th Edition, Blackwell Scientific Publications, Oxford, 1988; Hogan et al., Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).
    • EXAMPLES
  • The present invention is described by reference to the following Examples, which are offered by way of illustration and are not intended to limit the invention in any manner. Standard techniques well known in the art or the techniques specifically described below were utilized. [0114]
    • Example 1 Isolation of DNA Encoding β-Superfamily Conopeptides
  • DNA coding for β-superfamily conotoxin peptides 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), including using primers based on the DNA sequence of known conotoxin peptides. Alternatively, cDNA libraries was prepared from Conus venom duct using conventional techniques. DNA from single clones was amplified by conventional techniques using primers which correspond approximately to the M13 universal priming site and the M13 reverse universal priming site. Clones having a size of approximately 300-500 nucleotides were sequenced and screened for similarity in sequence to known 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 Table1. An alignment of the conopeptides of the present invention is set forth in Table 2. Sequences of truncated and analog peptides are set forth in Table 3. [0115]
    TABLE 1
    Sequences of β-Superfamily Conotoxins
    Name: Fd14.1
    Species: flavidus
    Cloned: Yes
    DNA Sequence:
    GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGC (SEQ ID NO:1)
    CCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATG
    ACTTAACCCCACAGCTTATTTTGCAAAGTCTGGATTCCCGTCGTCATGATCACGGC
    ATTCGTCCGAAGAGAGTCGACATATGTAACTGGAGGATATGTGCACCAAACCCATT
    GAGACGACATGATCTTAAGAAAGGAAACAATTGACGTCAGACAACCGCCACAACTT
    GAGTACGACATCGTTAATACGACTTCAGCAAATATGAAATTTTCAGCATCACTGTG
    GTTGTGAAGAAATCAGTTGCTTTAAAAGGTTGGATTTGTCCTTGTTTAAGCCGTTG
    TACTGATGACATCTCTGCACTATGAAATAAAGCTGATGTGACAAACTAAAAAAAAA
    AAAAAAAA
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPDDLTPQLILQSLDSRRHDHGIR (SEQ ID NO:2)
    PKRVDICNWRICAPNPLRRHDLKKGNN
    Toxin Sequence:
    His-Asp-His-Gly-Ile-Arg-Xaa3-Lys-Arg-Val-Asp-Ile-Cys- (SEQ ID NO:3)
    Asn-Xaa4-Arg-Ile-Cys-Ala-Xaa3-Asn-Xaa3-Leu-Arg-Arg-His-
    Asp-Leu-Lys-Lys-Gly-Asn-Asn-{circumflex over ( )}
    Name: Mi14.1
    Species: miles
    Cloned: Yes
    DNA Sequence:
    GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGGTGGGGCTCAC (SEQ ID NO:4)
    CGTCGGGAGTCACGTCCATCGGTCTCACAGTCCTACATCGCGCAGCCATGGTGATG
    ACTCCATTCATGACAAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCTGGAG
    AACAACGACGACCATCGTTCTGTGGATCTTCCTGCAGGGAATGGTGCAGGCAACAC
    CAAGCAACAAGACCAAAGTCCTCATCATGTGTGTTGTGCTATTGGTCCGGTTCTTC
    CATTCTGTTGTGTCAGTTGGCTGCACAAACTCCATTGAACTGGCCAATGAAAATAA
    CTCAGGAATAGACAGAAAGGCAAAAAAAAAAAAAAAAA
    Translation:
    MQTAYWVMVMMMVVGLTVGSHVHRSHSPTSRSHGDDSIHDKTIHQHLFARLPLENN (SEQ ID NO:5)
    DDHRSVDLPAGNGAGNTKQQDQSPHHVCCAIGPVLPFCCVSWLHKLH
    Toxin Sequence:
    Xaa2-Gln-Asp-Gln-Ser-Xaa3-His-His-Val-Cys-Cys-Ala-Ile- (SEQ ID NO:6)
    Gly-Xaa3-Val-Leu-Xaa3-Phe-Cys-Cys-Val-Ser-Xaa4-Leu-His-
    Lys-Leu-His-{circumflex over ( )}
    Name: Mi14.2
    Species: miles
    Isolated: No
    Cloned: Yes
    DNA Sequence:
    GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGGTGGGGTTCAC (SEQ ID NO:7)
    CGTCGGGGGTCACGTCCATCGGTCTCACAGTCCTACATCGCGCAGCCATGGTGATG
    ACTCCATTCATGACAAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCAGGAG
    AACAACGACGACCATCGTTCTGTGGATCTTCCTGCAGGGACTAGCGCAGGCGACAT
    GAAACCACAACGCCAAAGACGTCTCTGCTGCATCTTTGCCCCGATTCTTTGGTTCT
    GTTGTCACGGTTAACAGCTCAAATTACACTGCACTGGCCGATTGAAAGAACTGCAA
    TAAACGGAAAAAAAAAAAAAAAA
    Translation:
    MQTAYWVMVMMMVVGFTVGGHVHRSHSPTSRSHGDDSIHDKTIHQHLFARLPQENN (SEQ ID NO:8)
    DDHRSVDLPAGTSAGDMKPQRQRRLCCIFAPILWFCCHG
    Toxin Sequence:
    Leu-Cys-Cys-Ile-Phe-Ala-Xaa3-Ile-Leu-Xaa4-Phe-Cys-Cys- (SEQ ID NO:9)
    His-#
    Name: Cp14.1
    Species: capitaneus
    Cloned: Yes
    DNA Sequence:
    GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGGTGGGGTTCAC (SEQ ID NO:10)
    CGTCGGGGGTCACGTCCATCGGTCTCACAGTCCTACATCGCGCAGCCATGGTGATG
    ACTCCATTCATGACGAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCAGGAG
    AACAACGACGACCATCGTTCTGTGGATCTTCCTGCAGGGACTAGCGCAGGCGACAT
    GAAACCACAACGCCAAAGAGGTTTCTGCTGCGACTTTCCCCCGATTTTTTGGTTCT
    GTTGTATCGGTTAACAGCACAAATTACACTGCACTGGCCGATTGAAAGAACTGCAA
    TAAACGGAAAAAAAA
    Translation:
    MQTAYWVMVMMMVVGFTVGGHVHRSHSPTSRSHGDDSIHDETIHQHLFARLPQENN (SEQ ID NO:11)
    DDHRSVDLPAGTSAGDMKPQRQRGFCCDFPPIFWFCCIG
    Toxin Sequence:
    Gly-Phe-Cys-Cys-Asp-Phe-Xaa3-Xaa3-Ile-Phe-Xaa4-Phe-Cys- (SEQ ID NO:12)
    Cys-Ile-#
    Name: Ge14.1
    Species: generalis
    Cloned: Yes
    DNA Sequence:
    GGATCCATGCAGACGGCCTACTGGGTAATGGTGATGATGATGGTGTGGATTAAAGG (SEQ ID NO:13)
    CCCTGTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGACG
    ACTTGACCCCAGTGTTTGCCTTGCATCATCCGGTTTCCCATCGTCGGTCTCACAGC
    AGTAGTTTGTGGTGTGTATGTCCATTCAGGGTGTGTCCACCATGCCATGGAAGATG
    ACCTGGTCCCAAACCAACAAAATAACGTCAGACAACCGCCACAACTTTAGTACGAC
    ATCCCTTAATACGACTTCAGCAAGTATTTTAACATCACTATGGTGTGATGAAATCA
    GTTGCTTTAAAA
    Translation:
    MQTAYWVMVMMMVWIKGPVSEGGKLNDVIRGLVPDDLTPVFALHHPVSHRRSHSSS (SEQ ID NO:14)
    LWCVCPFRVCPPCHGR
    Toxin Sequence:
    Ser-His-Ser-Ser-Ser-Leu-Xaa4-Cys-Val-Cys-Xaa3-Phe-Arg- (SEQ ID NO:15)
    Val-Cys-Xaa3-Xaa3-Cys-His-#
    Name: Wi14.1
    Species: wittigi
    Cloned: Yes
    DNA Sequence:
    ATGATGTTGGTGTGGATTACAGCCCCTCTGCCTGAAGGTGGTAAACTGAAGCACGT (SEQ ID NO:16)
    AATTCGGGGTTTGGTGCCAGACGACTTAACCCCACAGCTTATCTTGCGAAGTCTGA
    TTTCCCGTCGTAGTTCTGACGGCAGTGATCCGAAGGCAAAAAAACAGTGTATGTGG
    AAGAGATGTATACCAGACCAATCGAGACTAGAAGAAGATGAATGATGTCAGACAAC
    CGCCATCACTGTAGTATGACATCGTTAATACGACTTAAGCAAATATTTTAACATCA
    CTGTGGTTCTGAAGACATCAGTTGCTTTAAAAGATTGGATTCTTCCTTGTTTAAGA
    GTTGTACTGANATCATTCCTGCCCTGTGAAATAAAGCTGATGTTGACNNCAAACAA
    AAAAAAAAAAAA
    Translation:
    MMLVWITAPLPEGGKLKHVIRGLVPDDLTPQLILRSLISRRSSDGSDPKAKKQCMW (SEQ ID NO:17)
    KRCIPDQSRLEEDE
    Toxin Sequence:
    Ser-Ser-Asp-Gly-Ser-Asp-Xaa3-Lys-Ala-Lys-Lys-Gln-Cys- (SEQ ID NO:18)
    Met-Xaa4-Lys-Arg-Cys-Ile-Xaa3-Asp-Gln-Ser-Arg-Leu-Xaa1-
    Xaa1-Asp-Xaa1-{circumflex over ( )}
    Name: Cn14.1
    Species: consors
    Cloned: Yes
    DNA Sequence:
    GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGC (SEQ ID NO:19)
    CCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGTCACACA
    TCTTAATCCCACAGCATACCTTGCGAAGTCTGACTTCCCGTGATCGTTCTGACAAC
    GGTGGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATA
    GAGACGACCACGAGGAAAAAGATGAACGGCGTCAGACAACCGCCACAACTGTAGTA
    CGACATCGTTGATACGACTTCAGCAACTATTTTAACATCACTGTGGTTGTGAAGAA
    ATCAGTCGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAG
    CTCTGCACTATGAAATAAAGCTGATGTGACATAAAAAAAAAAAAAAAAAGTACTCT
    GCGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVSHILIPQHTLRSLTSRDRSDNGG (SEQ ID NO:20)
    SSGAQICIWKVCPPSP
    Toxin Sequence:
    Asp-Arg-Ser-Asp-Asn-Gly-Gly-Ser-Ser-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:21)
    Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-{circumflex over ( )}
    Name: Cn14.2
    Species: consors
    Cloned: Yes
    DNA Sequence:
    GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGC (SEQ ID NO:22)
    CCCTCTGTCTGAAGGTGGTAAATTGAACGACGCAATTCGGGGTTTGGTGTCACACA
    TCTTAATCCCACAGCATACCTTGCGAAGTCTGACTTCCCGTGCTCGTTCTGACAAC
    GGTGGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATG
    GAGACGACCACAAGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTA
    CGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAA
    ATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAG
    CTCTGCACTATGAAATAAAGCTGATGTGACAAACAATAAAAAAGAAAAAAAAAAAA
    GTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDAIRGLVSHILIPQHTLRSLTSRARSDNGG (SEQ ID NO:23)
    SSGAQICIWKVCPPSPWRRPQGKR
    Toxin Sequence:
    Ala-Arg-Ser-Asp-Asn-Gly-Gly-Ser-Ser-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:24)
    Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-
    Xaa3-Gln-#
    Name: Cn14.3
    Species: consors
    Cloned: Yes
    DNA Sequence:
    GGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGC (SEQ ID NO:25)
    CCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACT
    TCTTAACCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTAATGGTTCTGGCAGC
    AGTAATCAGAAAGAAGCACAACTATGCATCTGGAAGGTATGTCCACCATCCCCATG
    GAGATGACCACAAGGAAAAAGATGAACGGCGTCAGACAACCGCCACAACTGTAGTG
    GGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAA
    ATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAATTGTACTGATATCAG
    CTCTGCACTATGAAATAAAGCTGATGTGACAACCCAAAAAAAAAAAAAAAAAAAAG
    TACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHFLTPQHILQSLTSRNGSGSSN (SEQ ID NO:26)
    QKEAQLCIWKVCPPSPWR
    Toxin Sequence:
    Asn-Gly-Ser-Gly-Ser-Ser-Asn-Gln-Lys-Xaa1-Ala-Gln-Leu- (SEQ ID NO:27)
    Cys-Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-{circumflex over ( )}
    Name: T14.1
    Species: tulipa
    Cloned: Yes
    DNA Sequence:
    GGATCCATGCAGACGGCCTACTGGGTGATGCTGATGATGATGGTGTGGATTACAGC (SEQ ID NO:28)
    CCCTCTGTCTGAAGGTGGTAAACTGAACGACGTAATTCGGGGTTTGGTGCCACACG
    TCTTAACCCCACAGCATATCTTGCAAAGTCTGGTTTCCCGTCGTCATTTTAACAGC
    GTTGTTCCGACGGTATACATATGCATGTGGAAGGTATGTCCACCATCGCCATAGAG
    ACGACCATAAGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGA
    CATCGTTAATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATC
    AGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTCAGAGTTGTACTGATATCAGCTC
    TGCACTATCAAATAAAGCTGAAGTGACAAACCNNAAAAAAAAAAAAAAAAAAAAAA
    AAGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMLMMMVWITAPLSEGGKLNDVIRGLVPHVLTPQHILQSLVSRRHFNSVV (SEQ ID NO:29)
    PTVYICMWKVCPPSP
    Toxin Sequence:
    His-Phe-Asn-Ser-Val-Val-Xaa3-Thr-Val-Xaa5-Ile-Cys-Met- (SEQ ID NO:30)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-{circumflex over ( )}
    Name: T14.2
    Species: tulipa
    Isolated: No
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGCTGTTGATGATGGTGGGCATTACAGCCCCTCT (SEQ ID NO:31)
    GCCTGAAGGTGGTAAACCGAACAGCGTAATTCGGGGTTTGGTGCCAAACGACTTAA
    CTCCACAGCATACCTTGCGAAGTCTGATTTCCCGTCGTCAAACTGACGTTCTTCTG
    GAGGCTACCCTTTTGACAACACCAGCCCCCGAGCAGAGATTGTTCTGCTTCTGGAA
    GTCATGTTGGCCAAGGCCCTACCCTTGGAGACGACGTGATCTTAATGGAAAACGAT
    GAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCATTAATACGACTTCAG
    CAAATATTTTAACATTACTGTGGTTGTGAAGAAATCACTTGCTTTAAAAGATTGGT
    TTTTTCCTTGTTTCAGAGTTGTACTGATATCAGCTCTGCCCTATGAAATAAAGCTG
    ATG
    Translation:
    MQTAYWVMLLMMVGITAPLPEGGKPNSVIRGLVPNDLTPQHTLRSLISRRQTDVLL (SEQ ID NO:32)
    EATLLTTPAPEQRLFCFWKSCWPRPYPWRRRDLNGKR
    Toxin Sequence:
    Xaa2-Thr-Asp-Val-Leu-Leu-Xaa1-Ala-Thr-Leu-Leu-Thr-Thr- (SEQ ID NO:33)
    Xaa3-Ala-Xaa3-Xaa1-Gln-Arg-Leu-Phe-Cys-Phe-Xaa4-Lys-Ser-
    Cys-Xaa4-Xaa3-Arg-Xaa3-Xaa5-Xaa3-Xaa4-Arg-Arg-Arg-Asp-
    Leu-Asn-#
    Name: Sl14.2
    Species: sulcatus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:34)
    GTCTGAAGGTGGTAAACCGAACGACGTAATTCGGGGTTTGGTGCCAGACGACTTAA
    CCCCACAGCGTGTCTTGCGAAGTCTGATTTCCCGTCGTCAATCTGGCTGCAGAGTC
    CCGTTTGAATTGAAATGCATCTGGAAGTTCTGTACAATATACCCATCGAGACCATT
    TGCTTCTCTGGAAGAAAAAGACGAATGTCAGACAGTCACCATAACTGTAACATGGG
    ATTTTTAATACGTCTCCAGCAAGTATTTTAACATCACTGTGGTTGTGAAGAAATCA
    GTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCT
    GCCCTGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKPNDVIRGLVPDDLTPQRVLRSLISRRQSGCRV (SEQ ID NO:35)
    PFELKCIWKFCTIYPSRPFASLEEKDECQTVTITVTWDF
    Toxin Sequence:
    Xaa2-Ser-Gly-Cys-Arg-Val-Xaa3-Phe-Xaa1-Leu-Lys-Cys-Ile- (SEQ ID NO:36)
    Xaa4-Lys-Phe-Cys-Thr-Ile-Xaa5-Xaa3-Ser-Arg-Xaa3-Phe-Ala-
    Ser-Leu-Xaa1-Xaa1-Lys-Asp-Xaa1-Cys-Gln-Thr-Val-Thr-Ile-
    Thr-Val-Thr-Xaa4-Asp-Phe-{circumflex over ( )}
    Name: Sl14.1
    Species: sulcatus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCTCTCT (SEQ ID NO:37)
    GTCTGAAGGTGGTAAACCGAACGACGTCATTCGGGGTTTTGTGCCAGACGACTTAA
    CCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTCGTTCTGACAAGGATGTT
    GGGAAGAGAATGGAATGTTACTGGAAGGCATGTAGACCCACGCTATCGAGACGACA
    TGATCTTGGGTAAAAGATGAATGACGTCAGACAACAGCCACAACTATAGTATGACA
    TCGTTAATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAG
    TTGCTTTAAAAGATTGGATTTTTCCGTGTTTAAGAGTTGTACTGATATCAGCTCTG
    CCCTGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITASLSEGGKPNDVIRGFVPDDLTPQLILRSLISRRRSDKDV (SEQ ID NO:38)
    GKRMECYWKACRPTLSRRHDLG
    Toxin Sequence:
    Arg-Ser-Asp-Lys-Asp-Val-Gly-Lys-Arg-Met-Xaa1-Cys-Xaa5- (SEQ ID NO:39)
    Xaa4-Lys-Ala-Cys-Arg-Xaa3-Thr-Leu-Ser-Arg-Arg-His-Asp-
    Leu-#
    Name: M14.1
    Species: magus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGCTGATGATGATGGTGTGCATCACAGCCCCTCT (SEQ ID NO:40)
    GCCTGAAGGTGGTAAACCGAACAGCGGAATTCGGGGTTTGGTGCCAAACGACTTAA
    CTCCACAGCATACCTTGCGAAGTCTGATTTCCCGTCGTCAAACTGACGTTCTTCTG
    GATGCTACCCTTTTGACAACACCAGCCCCCGAGCAGAGATTGTTCTGCTTCTGGAA
    GTCATGTTGGCCAAGGCCCTACCCTTGGAGACGACGTAATCTTAATGGAAAACGAT
    GAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCGTTAATACGACTTCAG
    CAAATATTTTAACATAACTGTGGTTGTGAAGAAATCGGTTGCTTTAAAAGATTGGA
    TTTTTCCTTGTTTCAGAGTTGTACTGATATGAGCTCTGCCCTGTGAAATAAAGCTG
    ATG
    Translation:
    MQTAYWVMLMMMVCITAPLPEGGKPNSGIRGLVPNDLTPQHTLRSLISRRQTDVLL (SEQ ID NO:41)
    DATLLTTPAPEQRLFCFWKSCWPRPYPWRRRNLNGKR
    Toxin Sequence:
    Xaa2-Thr-Asp-Val-Leu-Leu-Asp-Ala-Thr-Leu-Leu-Thr-Thr- (SEQ ID NO:42)
    Xaa3-Ala-Xaa3-Xaa1-Gln-Arg-Leu-Phe-Cys-Phe-Xaa4-Lys-Ser-
    Cys-Xaa4-Xaa3-Arg-Xaa3-Xaa5-Xaa3-Xaa4-Arg-Arg-Arg-Asn-
    Leu-Asn-#
    Name: Em14.1
    Species: emaciatus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGCGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:43)
    GTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATGACTTAA
    CCCCACAGCTTGTTTTGCAAAGTCTGGATTCCCGTCGTCATACTCACGGCATTCGT
    CCGAAGGGAGACGGCATATGTATCTGGAAGGTATGTCCACCAGACCCATGGAGACG
    ACATCGTCTTAAGAAAAGAAACAATTGACGTCAGACAACCGCCACAACTTGAGTAC
    GACATCGTTAATACGACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGTC
    AAGAAATCAGTTGCTTTAAAAGATTGGATTTGTCCTTGTTTAAGAGTTGTACTGAT
    GTCAGCTCTGCCCTGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMAMMMVWITAPLSEGGKLNDVIRGLVPDDLTPQLVLQSLDSRRHTHGIR (SEQ ID NO:44)
    PKGDGICIWKVCPPDPWRRHRLKKRNN
    Toxin Sequence:
    His-Thr-His-Gly-Ile-Arg-Xaa3-Lys-Gly-Asp-Gly-Ile-Cys- (SEQ ID NO:45)
    Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Asp-Xaa3-Xaa4-Arg-Arg-
    His-Arg-Leu-Lys-Lys-Arg-Asn-Asn-{circumflex over ( )}
    Name: Cr14.1
    Species: circumcisus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGGTGGTGTGGATTACAGCCCCTCT (SEQ ID NO:46)
    GTCTGAAGGTGGTAAATCGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAA
    CCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTCTTCGTTCTGACAGCAGTGGT
    CAGAAAGGAGCACAAATATGCATCTGGAAGGTATGTCCACTATCCCCATGGAGACG
    ACCACAAGGAAAAAGATGAATGACGTCAGACAACCGCTACAACTGTAGTACGACAT
    CGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGT
    TGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGC
    CCTGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMVVWITAPLSEGGKSNDVIRGLVPHILTPQHILQSLTSRLRSDSSG (SEQ ID NO:47)
    QKGAQICIWKVCPLSPWRRPQGKR
    Toxin Sequence:
    Leu-Arg-Ser-Asp-Ser-Ser-Gly-Gln-Lys-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:48)
    Ile-Xaa4-Lys-Val-Cys-Xaa3-Leu-Ser-Xaa3-Xaa4-Arg-Arg-
    Xaa3-Gln-#
    Name: Bt14.1
    Species: betulinus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:49)
    GTCCGAAGGTGGTAAACTGAACGATGTAATTCGGGCTTTGGCGCCAGACGACGTAA
    CCCCACAGTTTATCTTGCGAAGTCTGATTTCCCGTCGTCGTTCTGACAGCGATGTT
    CGGGAGGTACCCGTATGTTCCTGGAAGATATGTCCACCATAGCCATAGAGACGACA
    TGATCTTAAGGAAAAAGAGAAATGACGTCAGACAACCGCCACAACTGTAGTACGGC
    ATCGTTAATACGACTTCAGCAAATGTTTTAACATCACTGTGGTTGTGAAGAAATCA
    GCTGCTTTAAAAGATTGGATTTTTCCTTAAGAGTTGCACTGATGTCAGTTCTGCCC
    TGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRALAPDDVTPQFILRSLISRRRSDSDV (SEQ ID NO:50)
    REVPVCSWKICPP
    Toxin Sequence:
    Arg-Ser-Asp-Ser-Asp-Val-Arg-Xaa1-Val-Xaa3-Val-Cys-Ser- (SEQ ID NO:51)
    Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-{circumflex over ( )}
    Name: A14.1
    Species: aurisiacus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGCGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:52)
    GTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATGACTTAA
    CCCCACAGCTTGTTTTGCAAAGTCTGGATTCCCGTCGTCATACTCACGGCATTCGT
    CCGAAGGGAGACGGCATATGTATCTGGAAGGTATGTCCACCAGACCCATGGAGACG
    ACATCATCTTAAGAAAAGAAACAATTGACGTCAGACAACCGCCACAACTTGAGTAC
    GACATCGTTAATACGACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGTC
    AAGAAATCAGTTGCTTTAAAAGATTGGATTTGTCCTTGTTTAAGAGTTGTACTGAT
    GTCAGCTCTGCCCTATGAAATAAAGCTGATG
    Translation:
    MQTAYWVMAMMMVWITAPLSEGGKLNDVIRGLVPDDLTPQLVLQSLDSRRHTHGIR (SEQ ID NO:53)
    PKGDGICIWKVCPPDPWRRHHLKKRNN
    Toxin Sequence:
    His-Thr-His-Gly-Ile-Arg-Xaa3-Lys-Gly-Asp-Gly-Ile-Cys- (SEQ ID NO:54)
    Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Asp-Xaa3-Xaa4-Arg-Arg-
    His-His-Leu-Lys-Lys-Arg-Asn-Asn-{circumflex over ( )}
    Name: A14.2
    Species: aurisiacus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:55)
    GTCTGAAGGTGGTAAATTGAACGACGTAATTTGGGGTTTGGTGCCACACATCTTAA
    CCCCACAGCATATCTTGCAAAGCCTGACTTCCCGTCTTCATTCTGACAGCAGTGAT
    CAGAAAGGAGGCATGAACGCATGGACAGGAGCAGGAGCACAAATATGCATCTGGAA
    GGTATGTCCACCACCCCCATGGAGATGAACACAAGGAAAAAGATGAATGACGTCAG
    ACAACCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTAA
    CATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTT
    TAAGAGTTGTACTGATATCAGCTCTGCCCTGTGAAGTAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIWGLVPHILTPQHILQSLTSRLHSDSSD (SEQ ID NO:56)
    QKGGMNAWTGAGAQICIWKVCPPPPWR
    Toxin Sequence:
    Leu-His-Ser-Asp-Ser-Ser-Asp-Gln-Lys-Gly-Gly-Met-Asn-Ala- (SEQ ID NO:57)
    Xaa4-Thr-Gly-Ala-Gly-Ala-Gln-Ile-Cys-Ile-Xaa4-Lys-Val-
    Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-{circumflex over ( )}
    Name: A14.3
    Species: aurisiacus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:58)
    GTCTGAAGGTGGTAAATTGAACGACGTAATTTGGGGTTTGGTGCCACACATCTTAA
    CCCCACAGCATATCTTGCAAAGCCTGACTTCCCGTCTTCATTCTGACAGCAGTGAT
    CAGAAAGGAGCACAAATATGCATCTGGAAGGTATGTCCACCACCCCCATGGAGATG
    AACACAAGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACAT
    CGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGT
    TGCTTTAAAAGATTGGATTTTTCCTTGTTTAGGAGTTGTATTGATATCAGCTCTGC
    CCTGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIWGLVPHILTPQHILQSLTSRLHSDSSD (SEQ ID NO:59)
    QKGAQICIWKVCPPPPWR
    Toxin Sequence:
    Leu-His-Ser-Asp-Ser-Ser-Asp-Gln-Lys-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:60)
    Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-{circumflex over ( )}
    Name: A14.4
    Species: aurisiacus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:61)
    GTTTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAA
    CCCCACAGCATATCTTGCAAAGCCTGACTTCCCGTCTTCGTTCTGACAGCAGTGAT
    CAGAAAGGAGGCATGAACGCATCGACAGGAGCAGGAGCACAAATATGCATCTGGAA
    GGTATGTCCACCATCCCCATGGAGACGAACACAAGGAAAAAGATGAATGACGTCAG
    ACAACCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTAA
    CATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTT
    TAAGAGTTGTACTGATATCAGCTCTGCACTGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITAPLFEGGKLNDVIRGLVPHILTPQHILQSLTSRLRSDSSD (SEQ ID NO:62)
    QKGGMNASTGAGAQICIWKVCPPSPWRRTQGKR
    Toxin Sequence:
    Leu-Arg-Ser-Asp-Ser-Ser-Asp-Gln-Lys-Gly-Gly-Met-Asn-Ala- (SEQ ID NO:63)
    Ser-Thr-Gly-Ala-Gly-Ala-Gln-Ile-Cys-Ile-Xaa4-Lys-Val-
    Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Thr-Gln-#
    Name: Ac14.1
    Species: achatinus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:64)
    GTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAA
    CCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTCTTCGTTCTGACAACGGTGGT
    TCGAGTGGAGCACAAATATGCATCTGGAAGGTGTGTCCACCATCCCCATGGAGACG
    ACCACAAGGAAAAAGATGAACGGCGTCAGACAACCGCCACAACTGTAGTGGGACAT
    CGTTGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGT
    TGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGC
    CCTATGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHILTPQHILQSLTSRLRSDNGG (SEQ ID NO:65)
    SSGAQICIWKVCPPSPWRRPQGKR
    Toxin Sequence:
    Leu-Arg-Ser-Asp-Asn-Gly-Gly-Ser-Ser-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:66)
    Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-
    Xaa3-Gln-#
    Name: P14.2
    Species: purpurascens
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGACGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:67)
    GTCTGAAGGTGGAAAACTGAACGATGTAATTCGGGGTTTGGTGCCAGACGACTTAG
    CCCTACAGCTTATCTTGCAAAGTCCGGTTTTCCGTCGTCAATCTGAAGAGGAAAAA
    ATATGCCTCTGGAAGATATGTCCACCACCCCCATGGAGACGATCATAAGGAAAAAA
    AAATGAATGACGTCAGACAACCACCACAACTGTAATACGACATCGTTAATACGACT
    TCAGCAAACATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAGAAGCT
    TGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTATGAAATAAA
    GCTGATG
    Translation:
    MQTAYWVMVMTMVWITAPLSEGGKLNDVIRGLVPDDLALQLILQSPVFRRQSEEEK (SEQ ID NO:68)
    ICLWKICPPPPWRRS
    Toxin Sequence:
    Xaa2-Ser-Xaa1-Xaa1-Xaa1-Lys-Ile-Cys-Leu-Xaa4-Lys-Ile- (SEQ ID NO:69)
    Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Ser-{circumflex over ( )}
    Name: P14.1
    Species: purpurascens
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:70)
    GTCTGAGGGTAGAAAACCGAACGATGTAATTCGGGGTTTGGTGCCAGATGACTTAG
    CCCTACAGCTTATCTTGCAAAGTCAGGTTTCCCGTCGTGAATCTAATGGGGTGGAA
    ATATGCATGTGGAAGGTATGTCCACCATCCCCATGGAGACGATCATAAGGAAAAAA
    AATGAATGACGTCAGACAACCACCACAACTGTAATACGACATCGTTAATACGACTT
    CAGCAAACATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATT
    GGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCTATGAAATAAAG
    CTGATG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGRKPNDVIRGLVPDDLALQLILQSQVSRRESNGVE (SEQ ID NO:71)
    ICMWKVCPPSPWRRS
    Toxin Sequence:
    Xaa1-Ser-Asn-Gly-Val-Xaa1-Ile-Cys-Met-Xaa4-Lys-Val-Cys- (SEQ ID NO:72)
    Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Ser-{circumflex over ( )}
    Name: Sm14.1
    Species: stercusmuscarum
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:73)
    GTCTGAAGGTGGTAAATTGACCGACGTAATTCGGGGTTTGGTGCCACACATCTTAA
    CCCCACAGCATATCTTGCAAAGTATGACTTCCCGTCTTGGTATTGGCAGCAGTGAT
    CAAAATGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATAGAGACGACC
    ATAAGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACATCGT
    TGATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAGTTGC
    TTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGCCCT
    GTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLTDVIRGLVPHILTPQHILQSMTSRLGIGSSD (SEQ ID NO:74)
    QNAQICIWKVCPPSP
    Toxin Sequence:
    Leu-Gly-Ile-Gly-Ser-Ser-Asp-Gln-Asn-Ala-Gln-Ile-Cys-Ile- (SEQ ID NO:75)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-{circumflex over ( )}
    Name: Ba14.1
    Species: baileyi
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATAATGGTGTGGATTACAGTCCCTCT (SEQ ID NO:76)
    GTCTGAAGGTGGTAAATTGAACGACATAATTCGGGGTTTGTTGCCAGACAACTTCC
    CCCCACAGCTTACCTTGCATCGTCTGGTTTCCCGTCGTCATTCTGACAGCATTATT
    CTGAGGGGCTTATGTATCTGGAAGGTGTGTGAACCTCCGCCACAAAGATGATCTGG
    TCCAAAGCCAAAAAACGAATGATGTCAGACAACCGCCACAGCTTTAGTACGACATG
    GTTAATACGACTTCAGCAAATATTTCAACATCACTGTGGTTGTGAAGAAATCAGTT
    ACTTTAAAAGATTGGAATGATGTCAGCTGTGCACTATCAAATAAAGTTGATGTGAC
    AAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMIMVWITVPLSEGGKLNDIIRGLLPDNFPPQLTLHRLVSRRHSDSII (SEQ ID NO:77)
    LRGLCIWKVCEPPPQR
    Toxin Sequence:
    His-Ser-Asp-Ser-Ile-Ile-Leu-Arg-Gly-Leu-Cys-Ile-Xaa4- (SEQ ID NO:78)
    Lys-Val-Cys-Xaa1-Xaa3-Xaa3-Xaa3-Gln-Arg-{circumflex over ( )}
    Name: Bk14.1
    Species: bocki
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:79)
    GTCTGAAAGTGATAAACTGAACGACGTAATTCGGGGTTTGGTGCCAGACAACTTAA
    CCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTCGTTCTGACAAGGATGAT
    CCGGGAGGACAAGAATGTTACTGGAACGTATGTGCACCAAACCAGGGAGACCACAT
    GATCTTAAGAAAAAAGATGAATGACGACAGACAACCGCCACAACTGTAATACGACA
    TCGTTAATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAG
    TTGCTTTAAAAGATTGGATTTTTCCGTGTTTAAGAGCTGTACTGATATCTGCTCTG
    CCCTGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITAPLSESDKLNDVIRGLVPDNLTPQLILRSLISRRRSDKDD (SEQ ID NO:80)
    PGGQECYWNVCAPNQGDHMILRKKMNDDRQPPQL
    Toxin Sequence:
    Arg-Ser-Asp-Lys-Asp-Asp-Xaa3-Gly-Gly-Gln-Xaa1-Cys-Xaa5- (SEQ ID NO:81)
    Xaa4-Asn-Val-Cys-Ala-Xaa3-Asn-Gln-Gly-Asp-His-Met-Ile-
    Leu-Arg-Lys-Lys-Met-Asn-Asp-Asp-Arg-Gln-Xaa3-Xaa3-Gln-
    Leu-{circumflex over ( )}
    Name: Cd14.1
    Species: chaldaeus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGGGGATGATG (SEQ ID NO:82)
    ATGGTGTGGATTACAGCCCCTCTGTCTGGAGGTGGTAAACTGAACGACGTAATTCG
    GGGTTTGGTGCCAGACGACTTAACCCTACAGCGTATGTTCGAAACTCCGGTTTCCC
    ATCGTCTTTCTGAGGGCAGAAATTCGACGGTACACATATGTACGTGGAAGGTATGT
    CCACCTCCCCCATGGAGACGACCACATGGACAAAGATGAATGACGTCAGACAACCT
    CCACAACTGTAGTACGACATCGTTAACACGACGTCAGCTAATCTTTTAACATCACT
    GTGGCTGTGAAGAACTCGGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGT
    TGTGCTGATATGAACTCTGCACTACGAAATAAAGCTGATGTGACAAACAAAAAAAA
    GAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMMGMMMVWITAPLSGGGKLNDVIRGLVPDDLTLQRMFETPVSHRLSEGR (SEQ ID NO:83)
    NSTVHICTWKVCPPPPWRRPHGQR
    Toxin Sequence:
    Leu-Ser-Xaa1-Gly-Arg-Asn-Ser-Thr-Val-His-Ile-Cys-Thr- (SEQ ID NO:84)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Xaa3-
    His-Gly-Gln-Arg-{circumflex over ( )}
    Name: Cd14.2
    Species: chaldaeus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGGGGATGATG (SEQ ID NO:85)
    ATGGTGTGGATTACAGCCCCTCTGTCTGGAGGTGGTAAACTGAACGACGTAATTCG
    GGGTTTGGTGCCAGACGACTTAACCCTACAGCGTATGTTCGAAACTCCGGTTTCCC
    ATCGTCTTTCTGAGGGCAGAAATTCGACGGTACACATATGTATGTGGAAGGTATGT
    CCACCTCCCCCATGGAGACGACCACATGGACAAAGATGAATGACGTCAGACAACCT
    CCACAACTGTAGTACGACATCGTTAACACGACGTCAGCTAATCTTTTAACATCACT
    GTGGTTGTGAAGAAATCGGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGT
    TGTGCTGATATGAACTCTGCACTACGAAATAAAGCTGATGTGACAAACGGAAAAAA
    AAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMMGMMMVWITAPLSGGGKLNDVIRGLVPDDLTLQRMFETPVSHRLSEGR (SEQ ID NO:86)
    NSTVHICMWKVCPPPPWRRPHGQR
    Toxin Sequence:
    Leu-Ser-Xaa1-Gly-Arg-Asn-Ser-Thr-Val-His-Ile-Cys-Met- (SEQ ID NO:87)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Xaa3-
    His-Gly-Gln-Arg-{circumflex over ( )}
    Name: Ci14.1
    Species: cinereus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGTTG (SEQ ID NO:88)
    GTGTGGATTACAGCCCCTCTGCCTGAGGGTGGTAAACCGAAGCACGTAATTCGGGG
    TTTGGTACCAGACGACTTAACCCCACAGCATATCTTGCGAAGTTTGATTTCCCGTC
    GTTCATCTGGCTGCAGTGTTTCGTTGGGCTTCAAATGCTTCTGGAAGAGCTGTACA
    GTAATCCCAGTGAGACCATTTGTATCTCTGGAAGAAGAAAATGAATGCCAGAAAGT
    CCAAATAAGTGCAGTATGGGGTCCTTGATACGACTTCAGCAAGGATCACTGTGGTT
    GTGAAGAAATCAGTTGCTTTAAAAGATTTGATTTTTCCTTGTTTAAGAGTTGTACT
    GATATCAGCTCTGTACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAA
    AAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMLVWITAPLPEGGKPKHVILGLVPDDLTPQHILRSLISRRSSGCSV (SEQ ID NO:89)
    SLGFKCFWKSCTVIPVRPFVSLEEENECQKVQISAVWGP
    Toxin Sequence:
    Ser-Ser-Gly-Cys-Ser-Val-Ser-Leu-Gly-Phe-Lys-Cys-Phe- (SEQ ID NO:90)
    Xaa4-Lys-Ser-Cys-Thr-Val-Ile-Xaa3-Val-Arg-Xaa3-Phe-Val-
    Ser-Leu-Xaa1-Xaa1-Xaa1-Asn-Xaa1-Cys-Gln-Lys-Val-Gln-Ile-
    Ser-Ala-Val-Xaa4-Gly-Xaa3-{circumflex over ( )}
    Name: Ci14.2
    Species: cinereus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGGTG (SEQ ID NO:91)
    GTGGTGTGGATTACAGCCCCTCTGCCTGAAGGTGGTAAACCGGAGCACGTAATAAT
    CGGGGTTTGGTGCCAGACGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTC
    CCGTCGTAGTTCTGACGGCAAGGCAAAAAGAAATTGTTTCTGGAAGGCATGTGTAC
    CAGAACAATGGAGACAACGTGATCTTAAGGAAAAAGATGAATGATGTCAGACAACC
    GCCATCACTGTAGTATGACATCGTTAATACGACTTAAGCAAATATTTTAACATCAC
    TGTGGATCTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTCGTTTAAGAG
    TTGTACTGATGTCAGCTCTGCACTGTGAAATAAAGCTGATGTGACAAACGAAAAAA
    AAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMVVVWITAPLPEGGKPEHVIRGLVPDDLTPQLILRSLISRRSSDGK (SEQ ID NO:92)
    AKRNCFWKACVPEQWRQRDLKEKDE
    Toxin Sequence:
    Ser-Ser-Asp-Gly-Lys-Ala-Lys-Arg-Asn-Cys-Phe-Xaa4-Lys- (SEQ ID NO:93)
    Ala-Cys-Val-Xaa3-Xaa1-Gln-Xaa4-Arg-Gln-Arg-Asp-Leu-Lys-
    Xaa1-Lys-Asp-Xaa1-{circumflex over ( )}
    Name: Ci14.3
    Species: cinereus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:94)
    GTGGTGTGGATTACAGCCCCTCTGCCTGAAGGTGGTAAACCGAAGCACGTAATTCG
    GGGTTTGGTGCCAGACGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCC
    GTCGTAGTTCTGACGGCAAGGCAAAAAGAAATTGTTTCTGGAAGGCATGTGTACCA
    GAACAATGGAGACAACGTGATCCTAAGGAAAAAGATGAATGATGTCAGACAACCGC
    CATCACTGTAGTATGACATCGTTAATACGACTTAAGCAAATATTTTAACATCACTG
    TGGATCTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTCGTTTAAGAGTT
    GTACTGATGTCAGCTCTGCACTGTGAAATAAAGCTGACGTGACAAGCAAAAAAAAA
    AAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVVWITAPLPEGGKPKHVIRGLVPDDLTPQLILRSLISRRSSDGK (SEQ ID NO:95)
    AKRNCFWKACVPEQWRQRDPKEKDE
    Toxin Sequence:
    Ser-Ser-Asp-Gly-Lys-Ala-Lys-Arg-Asn-Cys-Phe-Xaa4-Lys- (SEQ ID NO:96)
    Ala-Cys-Val-Xaa3-Xaa1-Gln-Xaa4-Arg-Gln-Arg-Asp-Xaa3-Lys-
    Xaa1-Lys-Asp-Xaa1-{circumflex over ( )}
    Name: Ci14.4
    Species: cinereus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATAATGATG (SEQ ID NO:97)
    GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAACCGAAGCACGTAATTCGGGG
    TTTGGTGCCAGTCGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTC
    GTAGTTCTGACGGCAAGGCAAAAAAACAATGTGCCTGGAAGACATGTGTACCAACC
    CAATGGAGACGACGTGATCTTAAGGAAAAAGATGAATGATGTCAGACAACCGCCAT
    CACTGTAGTATGACATCGTTAATACGACTTAAGCAAATATTTTAACATCACTGTGG
    TTCTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTA
    CTGATATCAGCTCTGCACTGTGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAA
    AAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVIMMVWITAPLSEGGKPKHVIRGLVPVDLTPQLILRSLISRRSSDGKA (SEQ ID NO:98)
    KKQCAWKTCVPTQWRRRDLKEKDE
    Toxin Sequence:
    Ser-Ser-Asp-Gly-Lys-Ala-Lys-Lys-Gln-Cys-Ala-Xaa4-Lys- (SEQ ID NO:99)
    Thr-Cys-Val-Xaa3-Thr-Gln-Xaa4-Arg-Arg-Arg-Asp-Leu-Lys-
    Xaa1-Lys-Asp-Xaa1-{circumflex over ( )}
    Name: Cr14.2
    Species: circumcisus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:100)
    GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAGGTCTGACTTCCCGTC
    TTCGTTCTGACAGCAGTGGTCAGAAAGGAGCACAAATATGCATCTGGAAGGTATGT
    CCACTATCCCCATGGAGACGACCACAAGGAAAAGATGAATGACGTCAGACAACCGC
    TACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACTG
    TGGTTGTGAAGAAATCAGCTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTT
    GTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAA
    AAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHILTPQHILQGLTSRLRSDSSG (SEQ ID NO:101)
    QKGAQICIWKVCPLSPWRRPQGKDE
    Toxin Sequence:
    Leu-Arg-Ser-Asp-Ser-Ser-Gly-Gln-Lys-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:102)
    Ile-Xaa4-Lys-Val-Cys-Xaa3-Leu-Ser-Xaa3-Xaa4-Arg-Arg-
    Xaa3-Gln-Gly-Lys-Asp-Xaa1-{circumflex over ( )}
    Name: Cn14.4
    Species: consors
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:103)
    GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCACACTTCTTAACCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTA
    ATGGTTCTGGCAGCAGTAATCAGAAAGAAGCACAACTATGCATCTGGAAGGTATGT
    CCACCAACCCCATGGAGATGACCACAAGGAAAAAGATGAACGGCGTCAGACAACCG
    CCACAACTGTAGTGGGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACT
    GTGGTTGTGAAGAAATCAGTTGTTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGT
    TGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAGCAAAAAAAA
    AAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHFLTPQHILQSLTSRNGSGSSN (SEQ ID NO:104)
    QKEAQLCIWKVCPPTPWR
    Toxin Sequence:
    Asn-Gly-Ser-Gly-Ser-Ser-Asn-Gln-Lys-Xaa1-Ala-Gln-Leu- (SEQ ID NO:105)
    Cys-Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Thr-Xaa3-Xaa4-Arg-{circumflex over ( )}
    Name: Cn14.5
    Species: consors
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:106)
    GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAACTGAACGGCGTAATTCGGGG
    TTTGGTGTCACACATCTTAATCCCACAGCATACCTTGCGAAGTCTGACTTCCCGTG
    ATCGTTCTGACAACGGTGGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGT
    CCACCATCCCCATGGAAATGACCACAAGGAAAAAGATGAACGGCGTCAGACAACCA
    CCACAACTGTAGTGGGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACT
    GTGGTCGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGT
    TGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAA
    AAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNGVIRGLVSHILIPQHTLRSLTSRDRSDNGG (SEQ ID NO:107)
    SSGAQICIWKVCPPSPWK
    Toxin Sequence:
    Asp-Arg-Ser-Asp-Asn-Gly-Gly-Ser-Ser-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:108)
    Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Lys-{circumflex over ( )}
    Name: Ct14.1
    Species: coronatus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGATGATGATGATGATGGTGTGGATTACAGCCCC (SEQ ID NO:109)
    TCTGTCTGAAGGTGGTAAACTGAACGACGTAATTCGGGGTTTGGTGCCAGACGACT
    TAACCCTACAGCGTATGTTCAAAGCTCTGGTTTCCCATCGTCTTTCTGACGGCAGA
    GATTGGACGGGATACATATGTATCTGGAAGGCATGTCCACGTCCCCCATGGATCCC
    ACCAAAGGGAAAAAGATGAATGACGTCAGACAACCGCCACAACTGTAGTACGACAT
    CGTTAACACAACTTCAGCTAATATTTTAACATCACTGTGGTTGTGAAGAAATCGGT
    TGCTTTAAAAGATTGAATTTTTCGTTTAAGAGTTGTGCTGATACGAGCTCTGCACT
    ATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAAAAAAGTACTCTGCGT
    TGTTACTCGAG
    Translation:
    MQTAYWVMMMMMMVWITAPLSEGGKLNDVIRGLVPDDLTLQRMFKALVSHRLSDGR (SEQ ID NO:110)
    DWTGYICIWKACPRPPWIPPKGKR
    Toxin Sequence:
    Leu-Ser-Asp-Gly-Arg-Asp-Xaa4-Thr-Gly-Xaa5-Ile-Cys-Ile- (SEQ ID NO:111)
    Xaa4-Lys-Ala-Cys-Xaa3-Arg-Xaa3-Xaa3-Xaa4-Ile-Xaa3-Xaa3-
    Lys-#
    Name: Eb14.1
    Species: ebraeus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGATGATGATG (SEQ ID NO:112)
    ATGGTGTGGATTACAGCCCCTCTGTCTGAAGGCGGTAAACTGAACGACGTAATTCG
    GGGTTTGGTGCCAGACGACTTAACCCTACAGCGTATGTTCAAAAGTCTGTTTTCCC
    ATCGTCTTTCTGGCGGCACATATTCGAGGGTAGACACATGCATCTGGAAGGTATGT
    CCACAATCTCCATAGGGACGATCATATGGAAAAAGATGAGTGACATCAGACAACTG
    CCACAACTGTAGTACGACATCGTTAACACGACTTCAGCTAATATTTTAACATCACT
    GTGGTTGTGAAGAAATCGGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGT
    TGTGCTGATATGAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAA
    AAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMMMMMMVWITAPLSEGGKLNDVIRGLVPDDLTLQRMFKSLFSHRLSGGT (SEQ ID NO:113)
    YSRVDTCIWKVCPQSP
    Toxin Sequence:
    Leu-Ser-Gly-Gly-Thr-Xaa5-Ser-Arg-Val-Asp-Thr-Cys-Ile- (SEQ ID NO:114)
    Xaa4-Lys-Val-Cys-Xaa3-Gln-Ser-Xaa3-{circumflex over ( )}
    Name: G14.2
    Species: geographus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGCTGATGATGATG (SEQ ID NO:115)
    GTGTGCATCACAGCCCCTCTGCCTGAAGGTGGTAAACCGAACAGCGGAATTCGGGG
    TTTGGTGCCAAACGACTTAACTCCACAGCATACCTTGCGAAGTCTGATTTCCCGTC
    GTCAAACTGACGTTCTTCTGGAGGCTACCCTTTTGACAACACCAGCCCCCGAGCAG
    AGATTGTTCTGCTTCTGGAAGTCATGTACGTGGAGGCCCTACCCTTGGAGACGACG
    TGATCTTAATGGAAAACGATGAATGACGCCAGACAACCGCCACAACTGTAGTACGA
    CATCGTTAATACGACTTCAGCAAACATTTTAACATAACTGTGGTTGTGAAGAAATC
    AGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTCAGAGTTGTACTGATATGAGCTC
    TGCACCATGAAATAAAGCTGAAGTGACGAACAAAAAAAAAAAAAAAAAAAAAGTAC
    TCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMLMMMVCITAPLPEGGKPNSGIRGLVPNDLTPQHTLRSLISRRQTDVLL (SEQ ID NO:116)
    EATLLTTPAPEQRLFCFWKSCTWRPYPWRRRDLNGKR
    Toxin Sequence:
    Xaa2-Thr-Asp-Val-Leu-Leu-Xaa1-Ala-Thr-Leu-Leu-Thr-Thr- (SEQ ID NO:117)
    Xaa3-Ala-Xaa3-Xaa1-Gln-Arg-Leu-Phe-Cys-Phe-Xaa4-Lys-Ser-
    Cys-Thr-Xaa4-Arg-Xaa3-Xaa5-Xaa3-Xaa4-Arg-Arg-Arg-Asp-
    Leu-Asn-#
    Name: Gd14.1
    Species: gladiator
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGGTTACAGTCCCTCG (SEQ ID NO:118)
    ATCTGAAGGTGGCACGTGGAACTACTTAATTCGGGGTTTGGTGCCAGACGACCTAA
    CCCCACAGCTTACCTTGCATCGTCTGGTTACCCGTCGTCATCCTGCCAACGTTAGA
    CAGCAGGGGAAAATATGTGTATGGAAGGTGTGTCCACCATGGCCAGTAAGATCACC
    TGGTCCACAGCCAAAAAACAAATGACGTCAGACAACCGCCACAACTTTAGTACGAC
    ATCGTTGATACAACTTCAGCAAGTATTTTAACATCACTGTGGCTCTGAAGAAATCA
    GTTGCTTTAAAAGATTGGATTTTTCCTTGTTTTAGAGTTTTACTGATATCAGCTCT
    GCACTATGAAATAAAGATGTGACGAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTG
    TTACTCGAG
    Translation:
    MQTAYWVMVMMMVWVTVPRSEGGTWNYLIRGLVPDDLTPQLTLHRLVTRRHPANVR (SEQ ID NO:119)
    QQGKICVWKVCPPWPVRSPGPQPKNK
    Toxin Sequence:
    His-Xaa3-Ala-Asn-Val-Arg-Gln-Gln-Gly-Lys-Ile-Cys-Val- (SEQ ID NO:120)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Xaa4-Xaa3-Val-Arg-Ser-Xaa3-
    Gly-Xaa3-Gln-Xaa3-Lys-Asn-Lys-{circumflex over ( )}
    Name: Gd14.2
    Species: gladiator
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGGTTACAGTCCCTCG (SEQ ID NO:121)
    ATCTGAAGGTGGCACGTGGAACTACTTAATTCGGGGTTTGGTGCCAGACGACCTAA
    CCCCACAGCTTACCTTGCATCGTCTGGTTACCCGTCGTCATCCTGCCAACGTTAGA
    CAGCAGGGGAAAATATGTGTATGGAAGGTGTGTCCACCATCGCCAGTAAGATCACC
    TGGTCCACTGCCAAAAAACAAATGACGTCAGACAACCGCCACAACTTTAGTACGAC
    ATCGTTGATACAACTTCAGCAAGTATTTTAACATCACTGTGGCTCTGAAGAAATCA
    GTTGCTTTAAAAGATTGGATTTTTCCTTGTTTTAGAGTTTTACTGATATCAGCTCT
    GCACTATGAAATAAAGATGTGACGGACAAAAAAAAAAAAAAAAAAGTACTCTGCGT
    TGTTACTCGAG
    Translation:
    MQTAYWVMVMMMVWVTVPRSEGGTWNYLIRGLVPDDLTPQLTLHRLVTRRHPANVR (SEQ ID NO:122)
    QQGKICVWKVCPPSPVRSPGPLPKNK
    Toxin Sequence:
    His-Xaa3-Ala-Asn-Val-Arg-Gln-Gln-Gly-Lys-Ile-Cys-Val- (SEQ ID NO:123)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Val-Arg-Ser-Xaa3-
    Gly-Xaa3-Leu-Xaa3-Lys-Asn-Lys-{circumflex over ( )}
    Name: Ly14.1
    Species: litoglyphus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:124)
    GTGTGGATTACAGCCCCTCTGTCTGAAGGTGATAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCAGATAACTTAGCCCCACAGCTTGTTTTGCAAAGTCTGGATTCCCGTC
    GTCATCCTCACGGCATTCGTCAGGATGGAGCCCAAATATGTATCTGGAAGATATGT
    CCACCATCCCCATGGAGACGACTTGGATCTTAAGAAAAGAAACAATTGACGTCAGA
    CAACCGCCACATCTTGAGTACGACATCGTTAATACGACTTCAGCAAATATGAAATT
    TTCAGCATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTGTCC
    TTGTTTAAGAGTTGTACTGATGTCATCTCTGCACTATGAAATAAAGCTGATGTGAA
    AAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWITAPLSEGDKLNDVIRGLVPDNLAPQLVLQSLDSRRHPHGIR (SEQ ID NO:125)
    QDGAQICIWKICPPSPWRRLGS
    Toxin Sequence:
    His-Xaa3-His-Gly-Ile-Arg-Gln-Asp-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:126)
    Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-
    Leu-Gly-Ser-{circumflex over ( )}
    Name: Ly14.2
    Species: litoglyphus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:127)
    GTGTGGATTACAGCCCCTCTGTCTGAAGGTGATAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCAGATAACTTAGCCCCACAGCTTGTTTTGCAAAGTCTGGATTCCCGTC
    GTCATCCTCACGGCATTCGTCAGGATGGAGCCCAAATATGTATCTGGAAGATATGT
    CCACCATCCCCATGGAAACGACTTGGATCTTAAGAAAAGAAACAATTGACGTCAGA
    CAACCGCCACAACTTGAGTACGACATCGTTAATACAACTTCAGCAAATATGAAATT
    TTCAGCATCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAAGGATTGGATTTGTCC
    TTGTTTAAGAGTTGTACTGATGTCATCTCTGCACTATGAAATAAAGCTGATGTGAC
    AAGCAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAA
    TTC
    Translation:
    MQTAYWVMVMMMVWITAPLSEGDKLNDVIRGLVPDNLAPQLVLQSLDSRRHPHGIR (SEQ ID NO:128)
    QDGAQICIWKICPPSPWKRLGS
    Toxin Sequence:
    His-Xaa3-His-Gly-Ile-Arg-Gln-Asp-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:129)
    Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Lys-Arg-
    Leu-Gly-Ser-{circumflex over ( )}
    Name: Lt14.1
    Species: litteratus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:130)
    GTGGGGATTACAGCCCCTCTGTCTGAAGGTCGTAAATTGAACGACGCAATTCGGGG
    TTTGGTGCCAGATGACTTAACCCCACAGCTTTTGCGAAGTCCGGTTTCGACTCCTT
    ATCCTGAGTTTCATCTTGATGAACCTTATCTGAAGATACCCGTATGTATCTGGAAG
    ATATGTCCACCAAACCTATTGAGACGACGTGATCTTAAGAAAAGAAACAAAGTACG
    TCAGACAACCGCCACAACTTGAGTACGACATCGTTCATACAACTTGAGCAAATATT
    TCAGCATCACTATGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATCTTTCCT
    TGTTTAAGAGTTGTATTGATGTCAGCTCTGCACTCTGAAATAAAGCTGATGTGACA
    AACAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAA
    TTC
    Translation:
    MQTAYWVMVMMMVGITAPLSEGRKLNDAIRGLVPDDLTPQLLRSPVSTPYPEFHLD (SEQ ID NO:131)
    EPYLKIPVCIWKICPPNLLRRRDLKKRNKVRQTTATT
    Toxin Sequence:
    Ser-Xaa3-Val-Ser-Thr-Xaa3-Xaa5-Xaa3-Xaa1-Phe-His-Leu- (SEQ ID NO:132)
    Asp-Xaa1-Xaa3-Xaa5-Leu-Lys-Ile-Xaa3-Val-Cys-Ile-Xaa4-
    Lys-Ile-Cys-Xaa3-Xaa3-Asn-Leu-Leu-Arg-Arg-Arg-Asp-Leu-
    Lys-Lys-Arg-Asn-Lys-Val-Arg-Gln-Thr-Thr-Ala-Thr-Thr-{circumflex over ( )}
    Name: Lt14.2
    Species: litteratus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:133)
    GTGGGGATTACAGCCCCTCTGTCTGAAGGTCGTAAATTGAACGACGCAATTCGGGG
    TTTGGTGCCAAATGACTTAACCCCACAGCTTTTGCAAAGTCTGGTTTCCCGTCGTC
    ATCGTGTGTTTCATCTTGACAACACTTATCTCAAGATACCCATATGTGCCTGGAAG
    GTATGTCCACCAACCCCATGGAGACGACGTGATCTTAAGAAAAGAAACAAATGACG
    TCAGACAACCGCCACAACTTGAGTACGACATTGTTAATGCGACTTGAGCAAATTTT
    TCAGCATCACTATGGTTGTAAAGAAATCAGCTGCTTTAAACGATTGGATCTTTCCT
    TATTTAAGAGTTGTATTGATGTCAGCTCTGCACTCTGAAATAAAGCTGATGTGACA
    AACAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGA
    ATTC
    Translation:
    MQTAYWVMVMMMVGITAPLSEGRKLNDAIRGLVPNDLTPQLLQSLVSRRHRVFHLD (SEQ ID NO:134)
    NTYLKIPICAWKVCPPTPWRRRDLKKRNK
    Toxin Sequence:
    His-Arg-Val-Phe-His-Leu-Asp-Asn-Thr-Xaa5-Leu-Lys-Ile- (SEQ ID NO:135)
    Xaa3-Ile-Cys-Ala-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Thr-Xaa3-
    Xaa4-Arg-Arg-Arg-Asp-Leu-Lys-Lys-Arg-Asn-Lys-{circumflex over ( )}
    Name: Ls14.1
    Species: loroisii
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:136)
    GTGTGGATTAAAGGCCCTGTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCAGACGACTTAACCCCACAGCTTATCTTGCAAAGTCTGATGTCCCGTC
    GTCGTTCTGACAGCGATGTTCGGGAGGTGTACATATTATGCATCTGGAAGATATGT
    CCACCATTGCCATGAAGACGACATGATCTTAAGGAAAAGGATAAACGACGTCAGAC
    AACCGCTACAACTGTAGTACGACATCGTTAATACGACTTCAGCAAATATTTGAACA
    TCACTGTGGTTGTGAAGAAATCAGTTGCTTTAAACGATTGGATTTTTCCTTAAGAG
    TTGCACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACTACCAAAAAAA
    AAAAAAAAAAAAAGTACTNTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWIKGPVSEGGKLNDVIRGLVPDDLTPQLILQSLMSRRRSDSDV (SEQ ID NO:137)
    REVYILCIWKICPPLP
    Toxin Sequence:
    Arg-Ser-Asp-Ser-Asp-Val-Arg-Xaa1-Val-Xaa5-Ile-Leu-Cys- (SEQ ID NO:138)
    Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Leu-Xaa3-{circumflex over ( )}
    Name: M14.2
    Species: magus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:139)
    GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCACACTCCTTAACCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTA
    ATGGTTCTGGCAGCAGCAATCAGAAAGAAGCACAACTATGCATCTGGAAGGTATGT
    CCACCATCCCCATGGAGATGACCACAAGGAAAAAGATGAACGGCGTCAGACAACCG
    CCACAACTGTAGTGGGACATCGTTGATACGACTTCAACAAATATTTTAACATCACT
    GTGGTTGTAAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGT
    TGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAA
    AAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHSLTPQHILQSLTSRNGSGSSN (SEQ ID NO:140)
    QKEAQLCIWKVCPPSPWR
    Toxin Sequence:
    Asn-Gly-Ser-Gly-Ser-Ser-Asn-Gln-Lys-Xaa1-Ala-Gln-Leu- (SEQ ID NO:141)
    Cys-Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-{circumflex over ( )}
    Name: Mi14.3
    Species: miles
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGATGGTGGTG (SEQ ID NO:142)
    ATGATGGTGGGGGTTACTGTCGCTGGCTCCCTGCCTGTGTTTGATGACGACAACGA
    CTCTGACCCCGCTGTCAAGCGCGCTATCACGTGGTCCCGCATCCTGGGCGTGTCTC
    CAGCCTTCCTGGCACAGCAGCGAGCGCTGGTTCCCTTCGCCAACCGATTCATCAGT
    GAGCAGAAACGTTTCCGACCCGCCATGCAGAGCCGATCAGGAGGAATGTCGCTGTG
    CCTATGGAAAGTGTGTCCTGCAGCCCCCTGGCTGGTCGCCAAACGTAAACAGGAAA
    CCAGCGACTACTGACGTCATACCTCTAAAGACCCACTCATGACGTCAACGCTGAAC
    TGACGTCACCGACAGCTCCAACGTCACAGCAGGAGCGAGAGAGAGGCTGGAGCATT
    TCTCTTTCTTTTGGTTTTTCGAGTTGAAGTGTGATCAGCTGGGCTGGTGAAAAAAT
    TGTTGAGTAAAGTTGAATGAAAATCAAAAAAAAAAAAAAAAAAAGTACTCTGCGTT
    GGTACTCGAGGCTTAAAGGCGNAATTC
    Translation:
    MQTAYWVMMMVVMMVGVTVAGSLPVFDDDNPSDPAVKRAITWSRILGVSPAFLAQQ (SEQ ID NO:143)
    RALVPFANRFISEQKRFRPAMQSRSGGMSLCLWKVCPAAPWLVAKRKQETSDY
    Toxin Sequence:
    Phe-Arg-Xaa3-Ala-Met-Gln-Ser-Arg-Ser-Gly-Gly-Met-Ser- (SEQ ID NO:144)
    Leu-Cys-Leu-Xaa4-Lys-Val-Cys-Xaa3-Ala-Ala-Xaa3-Xaa4-Leu-
    Val-Ala-Lys-Arg-Lys-Gln-Xaa1-Thr-Ser-Asp-Xaa5-{circumflex over ( )}
    Name: Mi14.4
    Species: miles
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:145)
    GTGGTGGGTTCACCGTCGGGAGTCACGTCCATCGGTCTCACAGTCCTACGTCGCGC
    AACCATGGTGATGACTCCATTCATGACAAGACGATTCATCAACATCTGTTTGCCCG
    TCTTCCTCTGGAGAACAACGACGACCATCGTTCTGTGGATCTTCCTGCAGTGTATG
    CGCCGGGCCAGGCACGTGTGCGTTCTACTTTTGTTCTTGACCTCATTGCAGATAGG
    GGTTGGTGCAGACGACATGAAACTACAGCGCCAAAGACGTCAAGGTTTCTGTTGCG
    TCGTTATCCCGATTCTTTGGTTCTGTTGTGGGGGTTACCGCACAAATGGCACTGCA
    CTGGCCGATTGAAAGAACTGCAATAAACGGAATGGCAAGAAGGAATAAAAAAAAAA
    AAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVVGSPSGVTSIGLTVLRRATMVMTPFMTRRFINICLPVFLWRTT (SEQ ID NO:146)
    TTIVLWIFLQCMRRARHVCVLLLFLTSLQIGVGADDMKLQRQRRQGFCCVVIPILW
    FCCGGYRTNGTALAD
    Toxin Sequence:
    Xaa2-Gly-Phe-Cys-Cys-Val-Val-Ile-Xaa3-Ile-Leu-Xaa4-Phe- (SEQ ID NO:147)
    Cys-Cys-Gly-Gly-Xaa5-Arg-Thr-Asn-Gly-Thr-Ala-Leu-Ala-
    Asp-{circumflex over ( )}
    Name: Mu14.1
    Species: muriculatus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTTT (SEQ ID NO:148)
    GTCTGAAGGTGGTAAACTGAACGATGTAATTCGGGGTTTCGCGCTAGATGACTTAG
    CCCAAAGCCGTATTATGCAAAGTCTGGTTTTCAGTCATCAGCCTCTTCCAACGGCA
    TCCATATGTATCTGGAAGATATGTCCACCAGACCCATGGAGACGACATGATCTTCA
    GAAAAGTAACAAATGACGTCAGACAACCGCCACAACTTGAATACAACATCATTAAT
    ACGACTTCAGCAAATATTTTAACATCACTGTGATTGTTCGGAAGTCAGTTGCTTTA
    AAGGATTGGATTTGTCCCTGTTGTATTGATGTCAACTCTGCACTATGAAATAAAGC
    TGATGTGACAAACAAGAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCG
    AG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGFALDDLAQSRIMQSLVFSHQPLPTA (SEQ ID NO:149)
    SICIWKICPPDPWRRHDLQKSNK
    Toxin Sequence:
    Ile-Met-Gln-Ser-Leu-Val-Phe-Ser-His-Gln-Xaa3-Leu-Xaa3- (SEQ ID NO:150)
    Thr-Ala-Ser-Ile-Cys-Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Asp-
    Xaa3-Xaa4-Arg-Arg-His-Asp-Leu-Gln-Lys-Ser-Asn-Lys-{circumflex over ( )}
    Name: Ms14.1
    Species: musicus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGATGATGACGATGATGGTGTGGATGACAGCCCC (SEQ ID NO:151)
    TCTGTCTGAAGGTCGTCCACTGAGCGACGAAGTTCGGGGTATGGTGCCAGGCGACT
    TGGTCCTACAGTATCTGTTCCCAAGTCTGGCTTTCAGTCCTCCGGACATATGTACG
    TGGAAGGTATGTCCACCACCCCCATGGAGACGACCAAAAAAAATAACAGACGTCAG
    ACAGCCGCCACAACTGTAGTACGACATCGTTGATACGGCTTCAGCAAATATTTTCA
    ACATCACTGCGGTTGTGAAGAAATCAGTTGCTTTAAAATGTTGGATTTTTCCTTGT
    TTAAAAGAGCTGTACTGATGTCAGCCCTGCATTACGAAATAAAGCTGATGTGACAA
    ACAAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMMMTMMVWMTAPLSEGRPLSDEVRGMVPGDLVLQYLFPSLAFSPPDICT (SEQ ID NO:152)
    WKVCPPPPWRRPKXITDVRQPPQL
    Toxin Sequence:
    Gly-Met-Val-Xaa3-Gly-Asp-Leu-Val-Leu-Gln-Xaa5-Leu-Phe- (SEQ ID NO:153)
    Xaa3-Ser-Leu-Ala-Phe-Ser-Xaa3-Xaa3-Asp-Ile-Cys-Thr-Xaa4-
    Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Xaa3-Lys-
    Lys-Ile-Thr-Asp-Val-Arg-Gln-Xaa3-Xaa3-Gln-Leu-{circumflex over ( )}
    Name: Ms14.2
    Species: musicus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGATGATGATGATGATGGTGTGGATGACAGCCCC (SEQ ID NO:154)
    TCTGTCTGAAGGTCGTAAACTGATCGACAAAGTTCGGGGTATGGGGCCAGGCGACT
    TATCCCTACAGAAAATGTTCCCAAGTCTGGCTTTAGGTCCTGGGGGAGACGTAATA
    TGTAGGTGGAAGGTATGTCCACCAACCCCATGGAAACGACTAATAAAATAACTGAC
    GTCAGACAGCCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATAT
    TTCAACATCACTGCGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCC
    TTGTTTAAAGAGTTGTACTGATATCAGCTCTGCATTACGAAATAAAGCTGATGTGA
    CAAACAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMMMMMMVWMTAPLSEGRKLIDKVRGMGPGDLSLQKMFPSLALGPGGD (SEQ ID NO:155)
    VICRWKVCPPTPWKRLIK
    Toxin Sequence:
    Gly-Met-Gly-Xaa3-Gly-Asp-Leu-Ser-Leu-Gln-Lys-Met-Phe- (SEQ ID NO:156)
    Xaa3-Ser-Leu-Ala-Leu-Gly-Xaa3-Gly-Gly-Asp-Val-Ile-Cys-
    Arg-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Thr-Xaa3-Xaa4-Lys-Arg-
    Leu-Ile-Lys-{circumflex over ( )}
    Name: Ms14.3
    Species: musicus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGATGATGATGACGATGATGGTGTGGATGACAGC (SEQ ID NO:157)
    CCCTCTGTCTGAAGGTCGTCCACTGAGCGACAAAGTTCGGGGTATGGTGCCAGGCG
    ACTTAGCCCTGCAGTATCTGTTCCCAAGTCTGGCTTTCAATCCCCCGGACATATGT
    ACGTGGAAGGTATGTCCACCACCCCCATGGAGACGACCAAAAAAAATAACTGACGT
    CGGACAGCCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTT
    TCAACATCACTGCGGTTGTGAAGAAATCAGTTGTTTTAAAAGGTTGGATTTTTCCT
    TGTTTAAAAGAGCTGTACTGATGTCAGCTCTGCATTACGAAATAAAGCTGATGTGA
    CAAACGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGA
    G
    Translation:
    MQTAYWVMMMMTMMVWMTAPLSEGRPLSDKVRGMVPGDLALQYLFPSLAFNPPDIC (SEQ ID NO:158)
    TWKVCPPPPWRRPKKITDVGQPPQL
    Toxin Sequence:
    Gly-Met-Val-Xaa3-Gly-Asp-Leu-Ala-Leu-Gln-Xaa5-Leu-Phe- (SEQ ID NO:159)
    Xaa3-Ser-Leu-Ala-Phe-Asn-Xaa3-Xaa3-Asp-Ile-Cys-Thr-Xaa4-
    Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Xaa3-Lys-
    Lys-Ile-Thr-Asp-Val-Gly-Gln-Xaa3-Xaa3-Gln-Leu-{circumflex over ( )}
    Name: Ms14.4
    Species: musicus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGATGATGACGATGATGGTGTGGATGACAGCCCC (SEQ ID NO:160)
    TCTGTCTGAAGGTCGTCCACTGAGCGACAAAGTTCGGGGTATGGTGCCAGGCGACT
    TAGTCCTGCAGTATCTGTTCCCAAGTCTGGCTTTCAATCCTCCGGACATATGTACG
    TGGAAGGTATGTCCACCACCCCCATGGAGACGACCAAAAAAAATAACTGACGTCAG
    ACAGCCGCCACAACTGTAGTACGACATCGTTGATACGACTTCAGCAAATATTTTCA
    ACATCACTGCGGTTGTGAAGAAATCAGTTGTTTTAAAAGGTTGGATTTTTCCTTGT
    TTAAAAGAGCTGTACTGATGTCAGCTCTGCATTACGAAATAAAGCTGATGTGACAA
    GCAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMMMTMMVWMTAPLSEGRPLSDKVRGMVPGDLVLQYLFPSLAFNPPDICT (SEQ ID NO:161)
    WKVCPPPPWRRPKKITDVRQPPQL
    Toxin Sequence:
    Gly-Met-Val-Xaa3-Gly-Asp-Leu-Val-Leu-Gln-Xaa5-Leu-Phe- (SEQ ID NO:162)
    Xaa3-Ser-Leu-Ala-Phe-Asn-Xaa3-Xaa3-Asp-Ile-Cys-Thr-Xaa4-
    Lys-Val-Cys-Xaa3-Xaa3-Xaa3-Xaa3-Xaa4-Arg-Arg-Xaa3-Lys-
    Lys-Ile-Thr-Asp-Val-Arg-Gln-Xaa3-Xaa3-Gln-Leu-{circumflex over ( )}
    Name: Mt14.2
    Species: mustelinus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGCGTGGTATACAACCCCTGT (SEQ ID NO:163)
    GTCTGAATGTGGGAAATTGAACAACGTAATTCGGGGTTTTGTGCCAAAGGACTGGA
    CCCCAATGCTTCCCTGGCGTCGTCTAGTTTCCCATACCAGCAGCAAGTATCCAGGT
    GTGACTTTTTGTCCATGGAAGGTGTGTCCGCCAGCGCCATGGAGAATACTTGGGGT
    CTAACGCAAAAAAATACATGACGTCAGACAACCGCCACCGCTTTAGTACGACATCG
    TTCATACGTCTCCAGCAAGTATTTTAACATCACTGTGGTTGTGAAGAAGTCAGTAG
    CTTTAAAAGATTGGATTTTTTCCTTGTTTAAGAGTTGTACTGACATGAGTTCTGCA
    CTATGAAATAAAGTTGATGTGACGAACGAAAAAAAAAAAAAAAAAAAAGTACTCTG
    CGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMMMAWYTTPVSECGKLNNVIRGFVPKDWTPMLPWRRLVSHTSSKYP (SEQ ID NO:164)
    GVTFCPWKVCPPAPWRILGV
    Toxin Sequence:
    Leu-Val-Ser-His-Thr-Ser-Ser-Lys-Xaa5-Xaa3-Gly-Val-Thr- (SEQ ID NO:165)
    Phe-Cys-Xaa3-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ala-Xaa3-Xaa4-
    Arg-Ile-Leu-Gly-Val-{circumflex over ( )}
    Name: Nb14.1
    Species: nobilis
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGATGGTGGTG (SEQ ID NO:166)
    GTGATGATGGTGGGGGTTACTGTCGCTGGCTCACTGTCTGTGTTTGATGATGACAA
    CGACTCTGACCCAGCTGTCAAGCGCGCCATCACGTGGTCTCGATTCCTGGGCGCGT
    CTCCAGCCTTCCTGGCACAGCAGCGAGCGCTGGCTCCCTTCGCCAACCGACCCATC
    AATGAGCAGAAACGTTTCCGACCTGCCGTGAAGAGCCGATCACGACGAGCGCCGCC
    GTGCGTGTGGAAGGTGTGTCCCGCTCCCCCCTGGCTGGTCACCAAACGTAAACAGG
    AAACCAGCGACTACTGACGTCATACCTCAATAGACCGACTCATGACTTCAACGCTG
    AATTGACGTCACCGAGAGCTCCAACGTCACAGCAGGAGCGAGAGAGAGAGAGAGAG
    AGAGAGAAAGAGAGAGAGAAAGGCTGGAGTATTTCTCTTTCTTTTGGTTTTTCGTG
    TTGAAGTGTGATCAGCTGGGCTGGTTCAAAATTGTTGAATAAAGTTGAATGAAAAT
    CAAAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAA
    TTC
    Translation:
    MQTAYWVMMMVVVMMVGVTVAGSLSVFDDDNDSDPAVKRAITWSRFLGASPAFLA (SEQ ID NO:167)
    QQRALAPFANRPINEQKRFRPAVKSRSRRAPPCVWKVCPAPPWLVTKRKQETSDY
    Toxin Sequence:
    Phe-Arg-Xaa3-Ala-Val-Lys-Ser-Arg-Ser-Arg-Arg-Ala-Xaa3- (SEQ ID NO:168)
    Xaa3-Cys-Val-Xaa4-Lys-Val-Cys-Xaa3-Ala-Xaa3-Xaa3-Xaa4-
    Leu-Val-Thr-Lys-Arg-Lys-Gln-Xaa1-Thr-Ser-Asp-Xaa5-{circumflex over ( )}
    Name: Nb14.2
    Species: nobilis
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:169)
    GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCACACTTCTTAACCCCACAGCATATCTTGCAAAGTCTGACTTCCCGTA
    ATGGTTCTGGCAGCAGTAATCAGAAAGAAGCGCAACTATGCATCTGGAAGGTATGT
    CCACCAACCCCATGGAGATGATCACAAGGAAAAAGATGAACGGCGTCAGACAACCG
    CCACAACTGTAGTGGGACATCGTTGATACGACTTCAGCAAATATTTTAACATCACT
    GTGGTTGTGAAGAAATCAGTTGTTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGT
    TGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAGCAAAAAAAA
    AAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHFLTPQHILQSLTSRNGSGSSN (SEQ ID NO:170)
    QKEAQLCIWKVCPPTPWR
    Toxin Sequence:
    Asn-Gly-Ser-Gly-Ser-Ser-Asn-Gln-Lys-Xaa1-Ala-Gln-Leu- (SEQ ID NO:171)
    Cys-Ile-Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Thr-Xaa3-Xaa4-Arg-{circumflex over ( )}
    Name: Nb14.3
    Species: nobilis
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGATGGTGGTG (SEQ ID NO:172)
    GTGATGATGGTGGGGGTTACTGTCGCTGGCTCACTGTCTGTGTTTGATGACGACAA
    TGACTCTGACCCAGCTGTCAAGCGCGCCATCACGTGGTCTCGATTCCTGGGCGCGT
    CTCCAGCCTTCCTGGCACAGCAGCGAGCGCTGGCTCCCTTCGCCAACCGACCCATC
    AATGAGCAGAAACGTTTCCGACCTGCCGTGAAGAGCCGATCACGACGAGCGCCGCC
    GTGCGTATGGAAGGTGTGTCCCGCTCCCCCCTGGCTGGTCACCAAACGTAAACAGG
    AAACCAGCGACTACTGACGTCATACCTCAATAGACCGACTCATGACTTCAACGCTG
    AATTGACCTCACCGAGAGCTCCAACGTCACAGCAGGAGCGAGAGAGAGAGAGAGAG
    AGAGAGAGAGAGAAAGGCTGGAGTATTTCTCTTTCTTTCGGTTTTTCGTGTTGAAG
    TGTGATCAGCTGGGCTGGTTCAAAATTGTTGAATAAAGTTGAATAAAAAAAAAAAA
    AAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMMMVVVMMVGVTVAGSLSVFDDDNDSDPAVKRITWSRFLGASPAFLA (SEQ ID NO:173)
    QQRALAPFANRPINEQKRFRPAVKSRSRRAPPCVWKVCPAPPWLVTKRKQETSDY
    Toxin Sequence:
    Phe-Arg-Xaa3-Ala-Val-Lys-Ser-Arg-Ser-Arg-Arg-Ala-Xaa3- (SEQ ID NO:174)
    Xaa3-Cys-Val-Xaa4-Lys-Val-Cys-Xaa3-Ala-Xaa3-Xaa3-Xaa4-
    Leu-Val-Thr-Lys-Arg-Lys-Gln-Xaa1-Thr-Ser-Asp-Xaa5-{circumflex over ( )}
    Name: Pr14.1
    Species: parius
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:175)
    GTGGTGTGGATTACAGCCCCTTTGTCTGAAGGTGGTAAACCGAAGCACGCAATTCG
    GGGTTTGGTGCCAGACGACTTAACCCCACAGCTTATCTTGCGAAGTCTGATTTCCC
    GTCGTAGTTCTTTCGGCAAGGATGCGAAACCCCCCTTTAGTTGTTCAGGCCTCCGA
    GGGGGTTGCGTCCTACCTCCCAATCTCAGGCCAAAGTTCAACAAAGGTGGATAACA
    AACCCAAGCGTTCCTAGTTATACGAATGCCAGCAAATAAAAGCAGTTTGATTGTGA
    AAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVVWITAPLSEGGKPKHAIRGLVPDDLTPQLILRSLISRRSSFGK (SEQ ID NO:176)
    DAKPPFSCSGLRGGCVLPPNLRPKFNKGG
    Toxin Sequence:
    Xaa3-Xaa3-Phe-Ser-Cys-Ser-Gly-Leu-Arg-Gly-Gly-Cys-Val- (SEQ ID NO:177)
    Leu-Xaa3-Xaa3-Asn-Leu-Arg-Xaa3-Lys-Phe-Asn-Lys-Gly-#
    Name: Pr14.2
    Species: parius
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGT (SEQ ID NO:178)
    GATGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAACCGAAGCTCATAATTCGGG
    GTTTGGTGCCAAACGACTTAACCCCACAGCGTATCTTGCGAAGTCTGATTTCCGGG
    CGTACTTATGGCATCTATGATGCGAAACCCCCCTTTAGTTGTGCAGGCCTCCGAGG
    GGGTTGCGTCCTACCTCCCAATCTCAGGCCAAAGTTCAAGGAAGGTCGATAAAAAA
    CCCAAGCGTTCCTAGTTATACGAATGCCAGCAAATAAAAGCAGTTTGATTGCGAAA
    AAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVMWITAPLSEGGKPKLIIRGLVPNDLTPQRILRSLISGRTYGIY (SEQ ID NO:179)
    DAKPPFSCAGLRGGCVLPPNLRPKFKEGR
    Toxin Sequence:
    Xaa3-Xaa3-Phe-Ser-Cys-Ala-Gly-Leu-Arg-Gly-Gly-Cys-Val- (SEQ ID NO:180)
    Leu-Xaa3-Xaa3-Asn-Leu-Arg-Xaa3-Lys-Phe-Lys-Xaa1-#
    Name: Pl14.1
    Species: planorbis
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGATGATGATGATG (SEQ ID NO:181)
    GTGTGGATTACAGGCCATCTGTCTGAAGGTGGCAAATTGAAGGATGCAATTAGGGG
    TTTGGTGCCAGACGACTTGACCTCAATGTTTGCGTTGCATCTTCCGGTTTCCCATT
    CTCGGTCTAGCAGCAATGGTCTGAAGAGAGCTGACCTATGTATCCACAAGATTTGT
    CCACCACGGTATCACCAAAGCCAACAATAAAAGACGTCAGACAACCACCACAACTT
    TAGTATGACATCGTTAATAGGACTTCAGCAAGTATTTTAACATCACTGTGGTTGTG
    ATGAAATCAGTCGCCTTAAAAGATTGGCTTTTTCCTTGTTTAAGAGTTGTACTTGT
    ATCAGCTTTGCACTTCGAAATAAAGTTGATGTGATGAACCAAAAAAAAAAAAAAAA
    AAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMMMMMVWITGHLSEGGKLKDAIRGLVPDDLTSMFALHLPVSHSRSSSNG (SEQ ID NO:182)
    LKRADLCIHKICPPRYHQSQQ
    Toxin Sequence:
    Ser-Ser-Ser-Asn-Gly-Leu-Lys-Arg-Ala-Asp-Leu-Cys-Ile-His- (SEQ ID NO:183)
    Lys-Ile-Cys-Xaa3-Xaa3-Arg-Xaa5-His-Gln-Ser-Gln-Gln-{circumflex over ( )}
    Name: Pu14.1
    Species: pulicarius
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGATGGTGTGGGTTACAGCGCC (SEQ ID NO:184)
    TGTGTCTGAAGGTGGTAAATTGAGCGACGTAATTCGGGGTTTGGTGCCAGACGACA
    TAACCCCACAGATTATTTTGCAAAGTCTGAATGCCAGTCGTCATGCTTACAGACGT
    GTTCGTCTGAGAGGACAGATATGTATCTGGAAGGTATGTCCACCACTACTACAATG
    GATACATCCATTAGTAAAAAGATGAATGACATCAGACAACCGCCACAACTGTAGTA
    CGACATCGTTAACACGACTTCAGCAAATATTCTAACATCACAGTGGGTTGTGAAGA
    NATCGGGTTGGCTTTAAAAAAAANAATGGGGGNTTTTCCCCNTGGGTTTAAAAAAA
    NNTNGGNNCCGGGNAANNNCCCNNNNTNNNCCCCCCCCNNTNGGGAGAAAAAAAAA
    ANNCCNNTNNNGGGGGGNNNNCNAAAAAAAAAAAAAAAAAAAAAAAAAAAAAANCC
    CCNGGGGGGNTGNTTTNNCCCCCCNCCCCNGGGGGGGGGGGNGNTTTNNCCCCCCC
    CCCGNGGGGGGGGGGGNTTTTNNTTTNNGGGGGNGCCCCCCCCCCCCCCNNNCNNN
    NNAANAANNNNNGGGGGGGGGGAANAAAAANANNNNNNNNNNNNNNNNNNTTTTNT
    CNNTCNNCCGNGNNGNNAAAAAAAAAANTTNATTTNTNNANNNCNNCNNNCCNNCN
    NCNNACCCNNCCCCNNCCNCNNCANNCNNAGANNANGAGGGGGGGGNGNNNNGGNG
    NANNNNNANNNNNNNGAANNNGAGGNGNGNNNCNCGNCNNCGCNCNNGNC
    Translation:
    MQTAYWVMVMMMMVWVTAPVSEGGKLSDVIRGLVPDDITPQIILQSLNASRHAYRR (SEQ ID NO:185)
    VRLRGQICIWKVCPPLLQWIHPLVKR
    Toxin Sequence:
    Val-Arg-Leu-Arg-Gly-Gln-Ile-Cys-Ile-Xaa4-Lys-Val-Cys- (SEQ ID NO:186)
    Xaa3-Xaa3-Leu-Leu-Gln-Xaa4-Ile-His-Xaa3-Leu-Val-Lys-
    Arg-{circumflex over ( )}
    Name: Pu14.2
    Species: pulicarius
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGATGGTGTGGGTTACAGCGCC (SEQ ID NO:187)
    TGTGTCTGAAGGTGGTAAATTGAGCGACGTAATTCGGGGTTTGGTGCCAGACGACT
    TAACCCCACAGATTATCTTGCAAAGTCTGAATGCCAGTCGTCATGCTTACAGACGT
    GTTCGTCCGAGAGGACAGATATGTATCTGGAAGGTATGTCCACCACTACTACAATG
    GATACATCCATTAGTAAAAAGATGAATGACATCAGACAACCGCCACAACTGTAGTA
    CGGCATCGTTAACACGACTTCAGCAAATATTTTAACATCACAGTGGTTGTGAAGAA
    ATCGGTTGCTTTAAAAAAAGATTGGGTTTTTCCTTGTTTAAGAGTTGTACTGATAT
    CAGTTCTGCACTATGAAATAAAGCTGATGTGACGAACAAAAAAAAAAAAAAAAAAA
    AGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMMMMVWVTAPVSEGGKLSDVIRGLVPDDLTPQIILQSLNASRHAYRR (SEQ ID NO:188)
    VRPRGQICIWKVCPPLLQWIHPLVKR
    Toxin Sequence:
    Val-Arg-Xaa3-Arg-Gly-Gln-Ile-Cys-Ile-Xaa4-Lys-Val-Cys- (SEQ ID NO:189)
    Xaa3-Xaa3-Leu-Leu-Gln-Xaa4-Ile-His-Xaa3-Leu-Val-Lys-Arg-{circumflex over ( )}
    Name: Pu14.3
    Species: pulicarius
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGATGGTGTGGGTTACAGCGCC (SEQ ID NO:190)
    TGTGTCTGAAGGTGGTAAATTGAGCGACGTAATTCGGGGTTTGGTGCCAGACGACA
    TAACCCCACAGATTATCTTGCAAAGTCTGAATGCCAGTCGTCATGCTTACAGACCT
    GTTCGTCTGAGAGGACAGATATGTATCTGGAAGGTATGTCCACCACTACTACAATG
    GATACATCCATTAGTAAAAAGATGAATGACATCAGACAACCGCCACAACTGTAGTA
    CGACATCGTTAACACGACTTCAGCAAATATTTTAACATCACAGTGGTTGTGAAGAA
    ATCGGTTGCTTTAAAAAAAGATTGGGTTTTTCCTTGTTTAAGAGTTGTACTGATAT
    CAGTTCTGCACTATGAAATAAAGCTGATGTGACGAACAAAAAAAAAAAAAAAAAAA
    AGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMMMMVWVTAPVSEGGKLSDVIRGLVPDDITPQIILQSLNASRHAYRP (SEQ ID NO:191)
    VRLRGQICIWKVCPPLLQWIHPLVKR
    Toxin Sequence:
    Xaa3-Val-Arg-Leu-Arg-Gly-Gln-Ile-Cys-Ile-Xaa4-Lys-Val- (SEQ ID NO:192)
    Cys-Xaa3-Xaa3-Leu-Leu-Gln-Xaa4-Ile-His-Xaa3-Leu-Val-Lys-
    Arg-{circumflex over ( )}
    Name: Ra14.1
    Species: rattus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGGTGGTGGTGGGGTTCACCGTCGG (SEQ ID NO:193)
    GGGTCACGTCCATCAATCTCACAGTCCTACATCGCGCAGCCATGGTGATGACTCCA
    TTCATGACAAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCTGGAGAACAAC
    GACGACCATCGTTCTGTGGATCTTCCTGCAGGGACCAGCGCAGGCGACATGAAACC
    ACAACGCCAAAGACGTCTCTGCTGCATCTTTGCCATTCTTTGGTTCTGTTGTCTCG
    GTTAACAGTACAAATTGCAATGCACTGGCCGATTGAAAGAACTGCAATAAACGGAA
    AAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMMVVVGFTVGGHVHQSHSPTSRSHGDDSIHDKTIHQHLFARLPLENN (SEQ ID NO:194)
    DDHRSVDLPAGTSAGDMKPQRQRRLCCIFAILWFCCLG
    Toxin Sequence:
    Leu-Cys-Cys-Ile-Phe-Ala-Ile-Leu-Xaa4-Phe-Cys-Cys-Leu-# (SEQ ID NO:195)
    Name: S14.2
    Species: striatus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:196)
    GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGTCTGATTTCCCCTC
    TTCGTTCTAACAACGGTCGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGT
    CCACCATCCCCATGGAGACAACCACAAGAAATGATGAATGACATCAGACAACCGCC
    ACAACTGTAGTACGACATCGTTGATACGACTTTAGCAAATATTTTAACATCACTGT
    GGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTG
    TACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAA
    AAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGRLNDVIRGLVPHILTPQHILQSLISPLRSNNGR (SEQ ID NO:197)
    SSGAQICIWKVCPPSPWRQPQEMMNDIRQPPQL
    Toxin Sequence:
    Ser-Asn-Asn-Gly-Arg-Ser-Ser-Gly-Ala-Gln-Ile-Cys-Ile- (SEQ ID NO:198)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Gln-Xaa3-
    Gln-Xaa1-Met-Met-Asn-Asp-Ile-Arg-Gln-Xaa3-Xaa3-Gln-Leu-{circumflex over ( )}
    Name: Sx14.1
    Species: striolatus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGACCCTCT (SEQ ID NO:199)
    GTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACGCATCTTAA
    CCCCACAGCATACCTTGCGAAGTCCGACTTCCCTTCTTCGTTCTAACACCGGTGGT
    TCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATGGAGACG
    ATCACAAGGAAAAAGATGAATGACGTCAGACAAGCGCCACAACTGTAGTACGACAT
    CGTTGATACGACTTCAGCAAGTATTTTAACATCACTGTGGTTGTGAAGAAATCAGT
    TGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGC
    CCTGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITDPLSEGGKLNDVIRGLVPRILTPQHTLRSPTSLLRSNTGG (SEQ ID NO:200)
    SSGAQICIWKVCPPSPWRRSQGKR
    Toxin Sequence:
    Ser-Asn-Thr-Gly-Gly-Ser-Ser-Gly-Ala-Gln-Ile-Cys-Ile- (SEQ ID NO:201)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Ser-
    Gln-#
    Name: Sx14.2
    Species: striolatus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:202)
    GTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGGTTTGGTGCCACACATCTTAA
    CCCCACAGCATATCTTGCAAAGTCTGATTTCCCCTCTTCGTTCTAACAACGGTCGT
    TCGAGTGGAGCACAAATATGCATCTGGAAGGTATGTCCACCATCCCCATGGAGACG
    ATCACAAGGAAAAAGATGAATGACGTCAGACAAGCGCCACAACTGTAGTACGACAT
    CGTTGATACGACTTCAGCAAGTATTTTAACATCACTGTGGTTGTGAAGAAATCAGT
    TGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGTACTGATATCAGCTCTGC
    ACTGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHILTPQHILQSLISPLRSNNGR (SEQ ID NO:203)
    SSGAQICIWKVCPPSPWRRSQGKR
    Toxin Sequence:
    Ser-Asn-Asn-Gly-Arg-Ser-Ser-Gly-Ala-Gln-Ile-Cys-Ile- (SEQ ID NO:204)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Ser-
    Gln-#
    Name: Sx14.3
    Species: striolatus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:205)
    GTGTGGATTAAAGACCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGTCTGATTTCCCCTC
    TTCGTTCTAACAACGGTCGTTCGAGTGGAGCACAAATATGCAACTGGAAGGTATGT
    CCACCATCCCCATGGAGACGACCACGAGGAAAATGATGAATGACATCAGACAACCG
    CCACAACTGTAGTACGACTTCGTTGATACGACTTTAGCAAATATTTTAACATCACT
    GTGGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGT
    TGTACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAA
    AAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWIKDPLSEGGKLNDVIRGLVPHILTPQHILQSLISPLRSNNGR (SEQ ID NO:206)
    SSGAQICNWKVCPPSPWRRPRGK
    Toxin Sequence:
    Ser-Asn-Asn-Gly-Arg-Ser-Ser-Gly-Ala-Gln-Ile-Cys-Asn- (SEQ ID NO:207)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-Xaa3-
    Arg-#
    Name: Sx14.4
    Species: striolatus
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:208)
    GTGTGGATTACAGCCCCTCTGTCTGAAGGTGGTAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCACACATCTTAACCCCACAGCATATCTTGCAAAGTCTGATTTCCCCTC
    TTCGTTCTAACAACGGTCGTTCGAGTGGAGCACAAATATGCATCTGGAAGGTATGT
    CCACCATCCCCATGGAGACAACCACAAGAAATGATGAATGACATCAGACAACCGCC
    ACAACTGTAGTACGACATCGTTGATACGACTTTAGCAAATATTTTAACATCACTGT
    GGTTGTGAAGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTG
    TACTGATATCAGCTCTGCACTATGAAATAAAGCTGATGTGACAAACGAAAAAAAAA
    AAAAAAAAAAAGTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGLVPHILTPQHILQSLISPLRSNNGR (SEQ ID NO:209)
    SSGAQICIWKVCPPSPWRQPQEMMNDIRQPPQL
    Toxin Sequence:
    Ser-Asn-Asn-Gly-Arg-Ser-Ser-Gly-Ala-Gln-Ile-Cys-Ile- (SEQ ID NO:210)
    Xaa4-Lys-Val-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Gln-Xaa3-
    Gln-Xaa1-Met-Met-Asn-Asp-Ile-Arg-Gln-Xaa3-Xaa3-Gln-Leu-{circumflex over ( )}
    Name: Sl14.1
    Species: sulcatus
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCTCTCT (SEQ ID NO:211)
    GTCTGAAGGTGGTAAACCGAACGACGTCATTCGGGGTTTTGTGCCAGACGACTTAA
    CCCCACAGCTTATCTTGCGAAGTCTGATTTCCCGTCGTCGTTCTGACAAGGATGTT
    GGGAAGAGAATGGAATGTTACTGGAAGGCATGTAGACCCACGCTATCGAGACGACA
    TGATCTTGGGTAAAAGATGAATGACGTCAGACAACAGCCACAACTATAGTATGACA
    TCGTTAATACGACTTCAGCAAATATTTTAACATCACTGTGGTTGTGAAGAAATCAG
    TTGCTTTAAAAGATTGGATTTTTCCGTGTTTAAGAGTTGTACTGATATCAGCTCTG
    CCCTGTGAAATAAAGCTGATG
    Translation:
    MQTAYWVMVMMMVWITASLSEGGKPNDVIRGFVPDDLTPQLILRSLISRRRSDKDV (SEQ ID NO:212)
    GKRMECYWKACRPTLSRRHDLG
    Toxin Sequence:
    Arg-Ser-Asp-Lys-Asp-Val-Gly-Lys-Arg-Met-Xaa1-Cys-Xaa5- (SEQ ID NO:213)
    Xaa4-Lys-Ala-Cys-Arg-Xaa3-Thr-Leu-Ser-Arg-Arg-His-Asp-
    Leu-#
    Name: Tr14.1
    Species: terebra
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:214)
    GTCTGAAGGTGATAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATAACTTAG
    CCCCACAGCTTGTTTTGCAAAGTCTGGATTCCCGTCGTCATCCTCACGGCATTCGT
    CAGGATGGAGCCCAAATATGTATCTGGAAGATATGTCCACCATCCCCATGGAAACG
    ACTTGGATCTTAAGAAAAGAAACAATTGACGTCAGACAACCGCCACAACTTGAGTA
    CGACATCGTTAATACAACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGT
    GAAGAAATCAGTTGCTTTAAAAGATTGGATTTGTCCTTGTTTAAGAGTTGTACTGA
    TGTCATCTCTGCACTGTGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAA
    AAGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGDKLNDVIRGLVPDNLAPQLVLQSLDSRRHPHGIR (SEQ ID NO:215)
    QDGAQICIWKICPPSPWKRLGS
    Toxin Sequence:
    His-Xaa3-His-Gly-Ile-Arg-Gln-Asp-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:216)
    Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Lys-Arg-
    Leu-Gly-Ser-{circumflex over ( )}
    Name: Tr14.2
    Species: terebra
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGTGGATTACAGCCCCTCT (SEQ ID NO:217)
    GTCTGAAGGTGATAAATTGAACGACGTAATTCGGGGTTTGGTGCCAGATAACTTAG
    CCCCACAGCTTGTTTTGCATAGTCTGGATTCCCGTCGTCATCCTCACGGCATTCGT
    CAGGATGGAGCCCAAATATGTATCTGGAAGATATGTCCACCATCCCCATGGAGACG
    ACTTGGATCTTAAGAAAAGAAACAATTGACGTCAGACAACCGCCACATCTTGAGTA
    CGACATCGTTAATACGACTTCAGCAAATATGAAATTTTCAGCATCACTGTGGTTGT
    GAAGAAATCAGTTGCCTTAAAAGATTGGATTTGTCCTTGTTTAAGAGTTGTACTGA
    TGTCATCTCTGCACTATGAAATAAAGCTGATGTGACAAACAAAAAAAAAAAAAAAA
    AAAAGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMMMVWITAPLSEGDKLNDVIRGLVPDNLAPQLVLHSLDSRRHPHGIR (SEQ ID NO:218)
    QDGAQICIWKICPPSPWRRLGS
    Toxin Sequence:
    His-Xaa3-His-Gly-Ile-Arg-Gln-Asp-Gly-Ala-Gln-Ile-Cys- (SEQ ID NO:219)
    Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Ser-Xaa3-Xaa4-Arg-Arg-
    Leu-Gly-Ser-{circumflex over ( )}
    Name: Vx14.1
    Species: vexillum
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGATGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:220)
    GTGTGGATTAAAGGCCCTGTGTCCGAAGGTGGTAAATTGAACGACGTAATTCGGGG
    TTTGGTGCCAGACGACTTGACCCCAGTGTCTGCCTTGCATCATCCGGTTTCCCATC
    GTCGGTCTCACAGCAGTAGTTTGTGGTGTGTATGTCCATTCAGGGTGTGTCCACCA
    TGCCATGGAAGATGACCTGGTCCCAAACCAACAAAATAACGTCAGACAACCGCCAC
    AACTTTAGTACGACATCCCTTAATACGACTTCAGCAAGTATTTTAACATCACTATG
    GTGTGATGAAATCAGTTGCTTTAAAAGATTGGATTTTTCCTTGTTTAAGAGTTGCA
    CTGATAACAGCCCAGCAGTATGAAATAAAGTTGATGTGGCAAAAAAAAAAAAAAAA
    GTACTCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQMAYWVMVMMMVWIKGPVSEGGKLNDVIRGLVPDDLTPVSALHHPVSHRRSHSSS (SEQ ID NO:221)
    LWCVCPFRVCPPCHGR
    Toxin Sequence:
    Ser-His-Ser-Ser-Ser-Leu-Xaa4-Cys-Val-Cys-Xaa3-Phe-Arg- (SEQ ID NO:222)
    Val-Cys-Xaa3-Xaa3-Cys-His-#
    Name: Vx14.2
    Species: vexillum
    Cloned: Yes
    DNA Sequence:
    GAATTCGCCCTTATGGATCCATGCAGACGGCCTACTGGGTGATGGTGATGATGATG (SEQ ID NO:223)
    GTGTGGATTACAGCCCCTTTGTCTGAAGGTGGTAAACTGAACGATGTAATTCGGGG
    TTTCGCGCTAGATGACTTAGCCCAAAGCCGTATTATGCAAAGTCTGGTTTTCAGTC
    ATCAGCCTCTTCCAACGGCATCCATATGTATCTGGAAGATATGTCCACCAGACCCA
    TGGAGACGACATGATCTTCAGAAAAGTAACAAATGACGTCAGACAACCGCCACAAC
    TTGAATACAACATCATTAATACGACTTCAGCAAATATTTTAGCATCACTGTGATTG
    TTCGGAAGTCAGTTGCTTTAAAAGATTGGATTTGTCCCTGTTGTATTGATGTCAAC
    TCTGCACTATGAAATAAAGCTGATGTGACAAGCAAAAAAAAAAAAAAAAAAAGTAC
    TCTGCGTTGTTACTCGAGCTTAAGGGCGAATTC
    Translation:
    MQTAYWVMVMMMVWITAPLSEGGKLNDVIRGFALDDLAQSRIMQSLVFSHQPLPTA (SEQ ID NO:224)
    SICIWKICPPDPWRRHDLQKSNKT
    Toxin Sequence:
    Ile-Met-Gln-Ser-Leu-Val-Phe-Ser-His-Gln-Xaa3-Leu-Xaa3- (SEQ ID NO:225)
    Thr-Ala-Ser-Ile-Cys-Ile-Xaa4-Lys-Ile-Cys-Xaa3-Xaa3-Asp-
    Xaa3-Xaa4-Arg-Arg-His-Asp-Leu-Gln-Lys-Ser-Asn-Lys-{circumflex over ( )}
    Name: Vx14.3
    Species: vexillum
    Cloned: Yes
    DNA Sequence:
    ATGCAGACGGCCTACTGGGTGATGGTGATGATGATGGTGGTGGGGTTCACCGTCGA (SEQ ID NO:226)
    GAGTCACGTCCATCAGTCTCACAGTCCTACATCGCGCAGCCATGGTGATGACTCCA
    TTCATGACAAGACGATTCATCAACATCTGTTTGCCCGTCTTCCTCTGGAGAACAAC
    GACGACCATCGTTCTGTGGATCTTCCTGCAGGGACTAGCGCAGGCGACATGAAACC
    ACAACGCCAGAAACGTTTCTGCTGCATCTTTGCCCCGATTCTTTTGTTCTGTTGTT
    TCGGTTAACAGCACAAATTACACTGCACTGGCCGATTGAAAGAACTGCAATAAACG
    GTAAAGCAAAAAAAAAAAAAAAAAAAGTACTCTGCGTTGTTACTCGAG
    Translation:
    MQTAYWVMVMMMVVGFTVESHVHQSHSPTSRSHGDDSIHDKTIHQHLFARLPLENN (SEQ ID NO:227)
    DDHRSVDLPAGTSAGDMKPQRQKRFCCIFAPILLFCCFG
    Toxin Sequence:
    Phe-Cys-Cys-Ile-Phe-Ala-Xaa3-Ile-Leu-Leu-Phe-Cys-Cys- (SEQ ID NO:228)
    Phe-#
  • [0116]
    TABLE 2
    Alignment of β-Superfamily Conotoxins (SEQ ID NO:)*
    Type 2:
    T14.2 tulipa ----ZTDVLLEATLLTTPAPEQRLFCFWKSCWPRPYPWRRRDLN# (229)
    M14.1 magus ----ZTDVLLDATLLTTPAPEQRLFCFWKSCWPRPYPWRRRNLN# (230)
    G14.2 geographus ----ZTDVLLEATLLTTPAPEQRLFCFWKSCTWRPYPWRRRDLN# (231)
    T14.2 tulipa -----------------------LFCFWKSCWPRPYPWRRRDLN# (232)
    M14.1 magus -----------------------LFCFWKSCWPRPYPWRRRNLN# (233)
    G14.2 geographus -----------------------LFCFWKSCTWRPYPWRRRDLN# (234)
    Type 3:
    Ge14.1 generalis ----------------SHSSSLWCVCPFRVCPPCH# (235)
    Vx14.1 vexillum ----------------SHSSSLWCVCPFRVCPPCH# (236)
    Type 4:
    Fd14.1 flavidus ---HDHGIRPKR----------VDICNWRICAPNPLRRHDLKKGNN{circumflex over ( )} (237)
    Em14.1 emaciatus ---HTHGIRPKG----------DGICIWKVCPPDPWRRHRLKKRNN{circumflex over ( )} (238)
    A14.1 aurisiacus ---HTHGIRPKG----------DGICIWKVCPPDPWRRHHLKKRNN{circumflex over ( )} (239)
    Tr14.1 terebra ---HPHGIRQDG----------AQICIWKICPPSPWKRLGS{circumflex over ( )} (240)
    Tr14.2 terebra ---HPHGIRQDG----------AQICIWKICPPSPWRRLGS{circumflex over ( )} (241)
    Ly14.2 litoglyphus ---HPHGIRQDG----------AQICIWKICPPSPWKRLGS{circumflex over ( )} (242)
    Ly14.1 litoglyphus ---HPHGIRQDG----------AQICIWKICPPSPWRRLGS{circumflex over ( )} (243)
    Type 5:
    Cn14.1 consors ---DRSDNGGSSG---------AQITCIWKVCPPSP{circumflex over ( )} (244)
    Cn14.5 consors ---DRSDNGGSSG---------AQICIWKVCPPSPWK{circumflex over ( )} (245)
    Cn14.2 consors ---ARSDNGGSSG---------AQICIWKVCPPSPWRRPQ# (246)
    Sx14.1 striolatus -----SNTGGSSG---------AQICIWKVCPPSPWRRSQ# (247)
    Sx14.3 striolatus -----SNNGRSSG---------AQICNWKVCPPSPWRRPR# (248)
    Sx14.2 striolatus -----SNNGRSSG---------AQICIWKVCPPSPWRRSQ# (249)
    Sx14.4 striolatus -----SNNGRSSG---------AQICIWKVCPPSPWRQPQEMMNDIRQPPQL{circumflex over ( )} (250)
    S14.2 striatus -----SNNGRSSG---------AQICIWKVCPPSPWRQPQEMMNDIRQPPQL{circumflex over ( )} (251)
    A14.3 aurisiacus ---LHSDSSDQKG---------AQICIWKVCPPPPWR{circumflex over ( )} (252)
    A14.2 aurisiacus ---LHSDSSDQKGGMNAWTGAGAQICIWKVCPPPPWR{circumflex over ( )} (253)
    A14.4 aurisiacus ---LRSDSSDQKGGMNASTGAGAQICIWKVCPPSPWRRTQ# (254)
    Cr14.1 circumcisus ---LRSDSSGQKG---------AQICIWKVCPLSPWRRPQ# (255)
    Cr14.2 circumcisus ---LRSDSSGQKG---------AQICIWKVCPLSPWRRPQGKDE{circumflex over ( )} (256)
    Ac14.1 achatinus ---LRSDNGGSSG---------AQICIWKVCPPSPWRRPQ# (257)
    Sm14.1 stercusmuscarum ---LGIGSSDQN----------AQICIWKVCPPSP{circumflex over ( )} (258)
    Cn14.3 consors ---NGSGSSNQKE---------AQLCIWKVCPPSPWR{circumflex over ( )} (259)
    Cn14.4 consors ---NGSGSSNQKE---------AQLCIWKVCPPTPWR{circumflex over ( )} (260)
    M14.2 magus ---NGSGSSNQKE---------AQLCIWKVCPPSPWR{circumflex over ( )} (261)
    Nb14.2 nobilis ---NGSGSSNQKE---------AQLCIWKVCPPTPWR{circumflex over ( )} (262)
    Type 6:
    Sl14.1 sulcatus -------------RSDKDVGKRME-CYWKACRPTLSRRHDL# (263)
    Bk14.1 bocki -------------RSDKDDPGGQE-CYWNVCAPNQGDHMILRKKMNDDRQPPQL{circumflex over ( )} (264)
    Bt14.1 betulinus -------------RSDSDVREV-PVCSWKICPP{circumflex over ( )} (265)
    Ls14.1 loroisii -------------RSDSDVREVYILCIWKICPPLP{circumflex over ( )} (266)
    Type 7:
    Gd14.1 gladiator --------------HPANVRQQGKICVWKVCPPWPVRSPGPQPKNK{circumflex over ( )} (267)
    Gd14.2 gladiator --------------HPANVRQQGKICVWKVCPPSPVRSPGPLPKNK{circumflex over ( )} (268)
    Type 8:
    Ms14.2 musicus GMGPGDLSLQKMFPSLALGPGGDVICRWKVCPPTPWKRLIK{circumflex over ( )} (269)
    Ms14.3 musicus GMVPGDLALQYLFPSLAFNP-PD-ICTWKVCPPPPWRRPKKITDVGQPPQL{circumflex over ( )} (270)
    Ms14.1 musicus GMVPGDLVLQYLFPSLAFSP-PD-ICTWKVCPPPPWRRPKKITDVRQPPQL{circumflex over ( )} (271)
    Ms14.4 musicus GMVPGDLVLQYLFPSLAFNP-PD-ICTWKVCPPPPWRRPKKITDVRQPPQL{circumflex over ( )} (272)
    Type 9:
    Mi14.1 miles ZQDQSPHHVCCAIGPVLPFCCVSWLHKLH{circumflex over ( )} (273)
    Mi14.2 miles --------LCCIFAPILWFCCH# (274)
    Ra14.1 rattus --------LCCIFA-ILWFCCL# (275)
    Cp14.1 capitaneus -------GFCCDFPPIFWFCCI# (276)
    Mi14.4 miles ------ZGFCCVVIPILWFCCGGYRTNGTALAD{circumflex over ( )} (277)
    Vx14.3 vexillum --------FCCIFAPILLFCCF# (278)
    Type 10:
    Sl14.2 sulcatus --------------ZSGCRVPFELKCIWKFCTIYPSRPFASLEEKDECQTVTITVTWDF{circumflex over ( )} (279)
    Ci14.1 cinereus --------------SSGCSVSLGFKCFWKSCTVIPVRPFVSLEEENECQKVQISAVWGP{circumflex over ( )} (280)
    Type 11:
    Pr14.1 parius ---------------------PPFSCSGLRGGCVLPPNLRPKFNKG# (281)
    Pr14.2 parius ---------------------PPFSCAGLRGGCVLPPNLRPKFKE# (282)
    Type 12:
    Wi14.1 wittigi -------------SSDGSDPKAKKQCMWKRCIPDQSR---L-EEDE{circumflex over ( )} (283)
    Ci14.4 cinereus -------------SSDG---KAKKQCAWKTCVPTQWRRRDLKEKDE{circumflex over ( )} (284)
    Ci14.3 cinereus -------------SSDG---KAKRNCFWKACVPEQWRQRDPKEKDE{circumflex over ( )} (285)
    Ci14.2 cinereus -------------SSDG---KAKRNCFWKACVPEQWRQRDLKEKDE{circumflex over ( )} (286)
    Type 13:
    Nb14.1 nobilis victor -----------FRPAVKSRSRRAPPCVWKVCPAPPWLVTKRKQETSDY{circumflex over ( )} (287)
    Nb14.3 nobilis skinneri -----------FRPAVKSRSRRAPPCVWKVCPAPPWLVTKRKQETSDY{circumflex over ( )} (288)
    Mi14.3 miles -----------FRPAMQSRSGGMSLCLWKVCPAAPWLVAKRKQETSDY{circumflex over ( )} (289)
    Miscel-
    laneous:
    T14.1 tulipa --------------HFNSVVPTVYICMWKVCPPSP{circumflex over ( )} (290)
    P14.2 purpurascens ------------------ZSEEEKICLWKICPPPPWRRS{circumflex over ( )} (291)
    P14.1 purpurascens ------------------ESNGVEICMWKVCPPSPWRRS{circumflex over ( )} (292)
    Vx14.2 vexillum --------IMQSLVFSHQPLPTASICIWKICPPDPWRRHDLQKSNK{circumflex over ( )} (293)
    Mu14.1 muriculatus --------IMQSLVFSHQPLPTASICIWKICPPDPWRRHDLQKSNK{circumflex over ( )} (294)
    Pu14.1 pulicarius ------------------VRLRGQICIWKVCPPLLQWIHPLVKR{circumflex over ( )} (295)
    Pu14.2 pulicarius ------------------VRPRGQICIWKVCPPLLQWIHPLVKR{circumflex over ( )} (296)
    Pu14.3 pulicarius -----------------PVRLRGQICIWKVCPPLLQWIHPLVKR{circumflex over ( )} (297)
    Mt14.2 mustelinus -----------LVSHTSSKYPGVTFCPWKVCPPAPWRILGV{circumflex over ( )} (298)
    Ba14.1 baileyi ---------------HSDSIILRGLCIWKVCEPPPQR{circumflex over ( )} (299)
    Pl14.1 planorbis --------------SSSNGLKRADLCIHKICPPRYHQSQQ{circumflex over ( )} (300)
    Lt14.2 litteratus ----------HRVFHLDNTYLKIPICAWKVCPPTPWRRRDLKKRNK{circumflex over ( )} (301)
    Lt14.1 litteratus ----SPVSTPYPEFHLDEPYLKIPVCIWKICPPNLLRRRDLKKRNKVRQTTATT{circumflex over ( )} (302)
    Ct14.1 coronatus --------------LSDGRDWTGYICIWKACPRPPWIPPK# (303)
    Cd14.2 chaldaeus --------------LSEGRNSTVHICMWKVCPPPPWRRPHGQR{circumflex over ( )} (304)
    CD14.1 chaldaeus --------------LSEGRNSTVHICTWKVCPPPPWRRPHGQR{circumflex over ( )} (305)
    Eb14.1 ebraeus --------------LSGGTYSRVDTCIWKVCPQSP{circumflex over ( )} (340)
  • [0117]
    TABLE 3
    Analogs and Truncations of β-Superfamily Conotoxins (SEQ ID NO:)
    Q663             ZCMWKRCIPDQSR{circumflex over ( )} (306)
    F531           VDICNWRICAPNPLR{circumflex over ( )} (307)
    βG-C1325             LCFX1KSCRPYPWR{circumflex over ( )} (308)
    βM1            LFCFX1WKSCWPRPYWR{circumflex over ( )} (309)
    βM2            LFCFX1KSCWPRPYPWR{circumflex over ( )} (310)
    βM3            LX2CFWKSCWPRPYWR{circumflex over ( )} (311)
    βM4            LX2CFX1KSCWPRPYWR{circumflex over ( )} (312)
    βM5            LX2CFWKSCWPR{circumflex over ( )} (313)
    βM6            LFCFX1KSCWPR{circumflex over ( )} (314)
    βM7            LX2CFX1KSCWPR{circumflex over ( )} (315)
    βM8            LX2CFWKSCW{circumflex over ( )} (316)
    βM9            LFCFX1KSCW{circumflex over ( )} (317)
    βM10            LX2CFX1KSCW{circumflex over ( )} (318)
    βM11             FCFX1KSCWPR{circumflex over ( )} (319)
    βM12             FCFWX3SCWPR{circumflex over ( )} (320)
    βM13             FCFX1FSCWPR{circumflex over ( )} (321)
    βM14             FCFWKSCWPR{circumflex over ( )} (322)
    βP2       ESNGVEICMX1KVCPPSPWRRS{circumflex over ( )} (323)
    βS1            MECYX1KACRPTLSR{circumflex over ( )} (324)
    βS12           FELKCIX1KFCTIYPSR{circumflex over ( )} (325)
    βS12b           FELKCIX1KFCTIYPSRPF{circumflex over ( )} (326)
    βT           TVYICMX1KVCPPSP{circumflex over ( )} (327)
    βA-     SDSSDQKAQICIX1KVCPPPPWR{circumflex over ( )} (328)
    CTL03
    βCn2           GAQICIX1KVCPPSPWR{circumflex over ( )} (329)
    βMs14.5 MFPSLALGPGGDVICRX1KVCPPTPWKRLIK{circumflex over ( )} (330)
    βFd-            VDICNX1RICAPNPLRRRDLKKGNN{circumflex over ( )} (331)
    F531
    βF531-            VDICNX1RICAPNPLR{circumflex over ( )} (332)
    dW
    βG14.1            RLFCFX1KSCTWRPYPWRRRDLN# (333)
    βD919 SLWCVCPFRVCPPCHGR{circumflex over ( )} (334)
    [1-4]
    βD919 SLWCVCPFRVCPPCHGR{circumflex over ( )} (335)
    [2-4]
    βGe SLWCVCPX2RVCPPCH# (336)
    [1-4]
    βGe SLWCVCPX2RVCPPCH# (337)
    [2-4]
    • Example 2
  • Activity of Type 2 β-Superfamily Conopeptide on Tumor Cell Lines [0118]
  • Test Substance and Concentration: A β-M14.1 derivative, β-M14.1-D1 (LFCFXKSCWPRPYPWR (SEQ ID NO:309, where X is dW) was used for in vitro anti-tumor studies. The test compound was dissolved and diluted with sterile distilled water to obtain initial working solutions of 10000, 1000, 100, 10, and 1 μM. In testing, 100-fold dilution was made in culture media to get final assay concentrations of 100, 10, 1, 0.1, and 0.01 μM. [0119]
  • Cell Culture Media: The culture medium used for the MCF-7 cell line was Minimum Essential Medium, 90%; Fetal Bovine Serum, 10%. The culture medium used for the MIA PaCa-2 cell line was Dulbecco's Modified Eagle's Medium, 90%; Fetal Bovine Serum, 10%. All media were supplemented with 1% Antibiotic-Antimycotic. [0120]
  • Cell Lines: The cell line MCF-7, which is a breast adenocarcinoma, pleural effusion, human, was obtained from the American Type Culture Collection (ATCC HTB-22). The cell line MIA PaCa-2, which is a pancreatic carcinoma, human, was obtained form the American Type culture Collection (ATCC CRL-1420). The tumor cells were incubated in an air atmosphere of 5% CO[0121] 2 at 3° C.
  • Chemicals: The sources of the chemicals were as follows: AlamarBlue (Biosource, USA), Antibiotic-Antimycotic (GIBCO BRL, USA), Dulbecco's Modified Eagle's Medium (GIBCO BRL, USA), Fetal Bovine Serum (HyClone, USA), Minimum Essential medium (GIBCO BRL, USA) and Mitomycin (Kyowa, Japan). [0122]
  • Equipment: Centrifuge 5810R (Eppendorf, Germany), CO[0123] 2 Incubator (Forma Scientific Inc., USA), Hemacytometer(Hausser Scientific Horsham, USA), Inverted Microscope CK-40 (Olympus, Japan), Spectrafluor Plus (Tecan, Austria), System Microscope E-400 (Nikon, Japan) and Vertical Laminar Flow (Tsao-Hsin, Taiwan).
  • Reference Methods: Ahmed et al. (1994), Boyd et al. (1989), Boyd et al. (1992). [0124]
  • Aliquots of 100 μl of cell suspension (about 2.5×10[0125] 3/well) were placed in 96-well microtiter plates in an air atmosphere of 5% CO2 at 37° C. After 24 hours, 100 μl of growth medium and 2 μl of test solution, or mitomycin or vehicle (sterile distilled water), were added respectively per well in duplicate for an additional 72-hour incubation. The test compound, β-M14.1 derivative, was evaluated at concentrations of 100, 10, 1, 0.1 and 0.01 μM. At the end of incubation, the media in microplate were all removed, and then 200 μl of fresh media and 20 μl of 90% alamarBlue reagent were added to each well for another 6-hour incubation before detection of cell viability by fluorescent intensity. Fluorescent intensity was measured using a Spectraflour Plus plate reader with excitation at 530 nm and emission at 590 nm.
  • The measured results was calculated by the following formula: [0126]
  • PG (%)=100×(Mean F test −Mean F time0)/(Mean F ctrl −Mean F time0)
  • If (Mean F test −Mean F time0)<0, then PG (%)=100×(Mean F test −Mean F time0)/(Mean F time0 −Mean F blank)
  • Where: [0127]
  • PG: percent growth [0128]
  • Mean F[0129] time0=The average of 2 measured fluorescent intensities of reduced alamarBlue at the time just before exposure of cells to the test substance.
  • Mean F[0130] test=The average of 2 measured fluorescent intensities of alamarBlue after 72-hour exposure of cells to the test substance.
  • Mean F[0131] ctrl=The average of 2 measured fluorescent intensities of alamarBlue after 72-hour incubation without the test substance.
  • Mean F[0132] blank=The average of 2 measured fluorescent intensities of alamarBlue in medium without cells after 72-hour incubation.
  • A decrease of 50% or more (≧50%) in fluorescent intensity relative to vehicle-treated control indicated significant growth inhibition, cytostatic or cytotoxic activity, and a semi-quantitative IC[0133] 50, TGI and LC50 were then determined by nonlinear regression using GraphPad Prism (GraphPad Software, USA).
  • The assays were used to detect changes in cell proliferation based on the ability of viable cells to cause alamarBlue to change from its oxidized (non-fluorescent, blue) to a reduced (fluorescent, red) form. With the results obtained from the alamarBlue reaction, cell proliferation can be quantified and metabolic activity of viable cells can be examined. The β-M14.1-D1 was tested for its effect upon the proliferation of 2 different human tumor cell lines, MCF-7 (breast) and MIA PaCa-2 (pancreas), at five final assay concentrations from 0.01 to 100 μM through serial 10-fold dilutions. [0134]
  • Based on the results obtained, the β-M14.1-D1 exhibited significant growth inhibition (≧50%) relative to the respective vehicle treated control group at concentrations between 10 μM to 100 μM in the 2 human tumor cells lines (Table 4). Significant activity was observed for the concurrently tested standard reference agent Mitomycin at <10 μM (Table 1). Consequently, semi-quantitative determinations of estimated IC[0135] 50 (50% inhibition concentration), TGI (total growth inhibition) and LC50 (50% lethal concentration) by nonlinear regression analysis were calculated (Table 5).
    TABLE 4
    Effect of Test Substance Tumor Cells
    Percent Growth (Mean ± SEM, n = 2)
    Concentration (μM)
    Treatment Assay Name Blank Time0 Vehicle 100 10 1 0.1 0.01 0.001
    PT# 1018911-ADD 370000 Breast, −100 0 100 −43 ± 11 102 ± 14  87 ± 9  88 ± 12 100 ± 18 a —
    β-M14.1-D1 MCF-7
    Mitomycin 370000 Breast, −100 0 100 — −96 ± 0 −38 ± 16  5 ± 12  88 ± 8  95 ± 7
    MCF-7
    PT# 1018911-ADD 371700 Pancreas, −100 0 100 −14 ± 9 109 ± 2 100 ± 4 102 ± 6 102 ± 3 —
    β-M14.1-D1 MIA PaCa-2
    Mitomycin 371700 Pancreas, −100 0 100 — −93 ± 2 −44 ± 16  1 ± 6  76 ± 5 105 ± 10
    MIA PaCa-2
  • [0136]
    TABLE 5
    Estimated IC50, TGI and LC50 Values
    Treatment Prot. # Assay Name aIC50 bTGI cLC50
    PT# 1018911-ADD 370000 Tumor, Breast, MCF-7   62 μM   81 μM  >100 μM
    β-M14.1-D1
    Mitomycin 370000 Tumor, Breast, MCF-7 0.035 μM 0.18 μM   0.93 μM
    PT# 1018911-ADD 371700 Tumor Pancreas,   79 μM   95 μM  >100 μM
    β-M14.1-D1 MIA PaCa-2
    Mitomycin 371700 Tumor Pancreas, 0.028 μM 0.15 μM   0.78 μM
    MIA PaCa-2
    • EXAMPLE 3 In Vitro Functional Activity of Type 2 β-Superfamily Conopeptide
  • The in vitro functional activity of β-M14.1-D1 with respect to somatostatin sst[0137] 2 and sst5 was tested using the following assays.
    Somatostatin sst2 (Feniuk et al., 1993)
    Tissue: Duncan Hartley Guinea pig 325 ± 25 g
    Vehicle: 0.1 mL Distilled Water
    Incubation Time/Temp: 5 minutes @ 32° C.
    Incubation Buffer: Krebs, pH 7.4
    Administration Volume: 10 μL
    Bath Volume:  10 mL
    Time of Assessment: 5 minutes
    Quantitation Method: Isometric (gram changes)
    Significance Criteria-Ag: ≧50% Inhibition of contraction
    relative to somatostatin28-responses
    Significance Criteria-Ant: ≧50% Inhibition of somatostatin28 relaxant
    response
    Somatostatin sst5 (Feniuk et al., 1993)
    Tissue: Duncan Hartley Guinea pig 325 ± 25 g
    Vehicle: 0.1 mL Distilled Water
    Incubation Time/Temp: 5 minutes @ 32° C.
    Incubation Buffer: Krebs, pH 7.4
    Administration Volume: 10 μL
    Bath Volume:  10 mL
    Time of Assessment: 5 minutes
    Quantitation Method: Isometric (gram changes)
    Significance Criteria-Ag: ≧50% Inhibition of contraction
    relative to somatostatin28-responses
    Significance Criteria-Ant: ≧50% Inhibition of somatostatin28 relaxant
    response
  • Biochemical assay results are presented as the percent inhibition of specific binding or activity. All other results are expressed in terms of that assay's quantitation method. For primary assays, only the lowest concentration with a significant response judged by the assays' criteria, is shown. Primary screening in duplicate with quantitative data are shown where applicable for individual assays. Significant responses were noted in the primary assays shown in Table 6. [0138]
    TABLE 6
    Primary Testsa
    Primary
    Tissue Assay Tissue, gp Conc. Criteria AG ANT EC50/IC50
    Somatostatin ileum 1 μM ≧50% 68% ND 0.49 μM
    sst2
    Somatostatin vas deferens 1 μM ≧50% 61% ND 0.59 μM
    sst5
    • EXAMPLE 4 Radioligand Binding Assay of Type 2 β-Superfamily Conopeptide
  • The radioligand binding activity of β-M14.1-D1 with respect to somatostatin sst[0139] 1, sst2, sst3 and sst4 and sst5 was tested using the following assays.
    Somatostatin sst1 (Liapakis et al., 1996; Patel and Srikant, 1994)
    Source: Human recombinant CHO-K1
    Ligand: 0.1 nM 125I Somatostatin-14
    Vehicle: 0.4% DMSO
    Incubation Time/Temp: 2 hours @ 25° C.
    Incubation Buffer: 25 mM Hepes, pH 7.4, 5 mM MgCl2, 1 mM
    CaCl2, 0.5% BSA
    NonSpecific Ligand: 1 μM Somatostatin-14
    Kd: 1.9 nM (historical value)
    Bmax: 0.5 pmol/mg Protein (historical value)
    Specific Binding: 60% (historical value)
    Quantitation Method: Radioligand Binding
    Significance Criteria: ≧50% of max stimulation or inhibition
    Somatostatin sst2 (Patel and Srikant, 1994)
    Source: Human recombinant CHO-K1
    Ligand: 0.03 nM 125I Somatostatin-14
    Vehicle: 1% H2O
    Incubation Time/Temp: 4 hours @ 25° C.
    Incubation Buffer: 25 mM Hepes, pH 7.4, 5 mM MgCl2, 1 mM
    CaCl2, 0.5% BSA
    NonSpecific Ligand: 1 μM Somatostatin-14
    Kd: 0.034 nM (historical value)
    Bmax: 11 pmol/mg Protein (historical value)
    Specific Binding: 90% (historical value)
    Quantitation Method: Radioligand Binding
    Significance Criteria: ≧50% of max stimulation or inhibition
    Somatostatin sst3 (Liapakis et al., 1996; Patel and Srikant, 1994)
    Source: Human recombinant CHO-K1
    Ligand: 0.1 nM 125I Somatostatin-14
    Vehicle: 0.4% DMSO
    Incubation Time/Temp: 2 hours @ 25° C.
    Incubation Buffer: 25 mM Hepes, pH 7.4, 5 mM MgCl2, 1 mM
    CaCl2, 0.5% BSA
    NonSpecific Ligand: 1 μM Somatostatin-14
    Kd: 0.79 nM (historical value)
    Bmax: 1.1 pmol/mg Protein (historical value)
    Specific Binding: 78% (historical value)
    Quantitation Method: Radioligand Binding
    Significance Criteria: ≧50% of max stimulation or inhibition
    Somatostatin sst4 (Patel and Srikant, 1994)
    Source: Human recombinant CHO-K1
    Ligand: 0.12 nM 125I Somatostatin-14
    Vehicle: 0.4% DMSO
    Incubation Time/Temp: 2 hours @ 25° C.
    Incubation Buffer: 25 mM Hepes, pH 7.4, 5 mM MgCl2,
    1 mM CaCl2, 0.5% BSA
    NonSpecific Ligand: 1 μM Somatostatin-14
    Kd: 0.87 nM (historical value)
    Bmax: 0.5 pmol/mg Protein (historical value)
    Specific Binding: 60% (historical value)
    Quantitation Method: Radioligand Binding
    Significance Criteria: ≧50% of max stimulation or inhibition
    Somatostatin sst5 (Greenwood et al., 1997; Patel and Srikant, 1994)
    Source: Human recombinant HEK-293 EBNA cells
    Ligand: 0.1 nM 125I Somatostatin-14
    Vehicle: 1% H2O
    Incubation Time/Temp: 60 minutes @ 37° C.
    Incubation Buffer: 50 mM Hepes, pH 7.4, 5 mM MgCl2, 1 mM
    CaCl2, 0.5% BSA
    NonSpecific Ligand: 1 μM Somatostatin-14
    Kd: 0.5 nM (historical value)
    Bmax: 1.2 pmol/mg Protein (historical value)
    Specific Binding: 94% (historical value)
    Quantitation Method: Radioligand Binding
    Significance Criteria: ≧50% of max stimulation or inhibition
  • Biochemical assay results are presented as the percent inhibition of specific binding or activity. All other results are expressed in terms of that assay's quantitation method. For primary assays, only the lowest concentration with a significant response judged by the assays' criteria, is shown. Primary screening in duplicate with quantitative data (e.g., IC[0140] 50±SEM, Ki±SEM and nH) are shown where applicable for individual assays. In screening packages, primary screening in duplicate with semi-quantitative data (e.g., estimated IC50, Ki and nH) are shown where applicable (concentration range of 4 log units). Significant responses were noted in the primary assays shown in Table 7.
    TABLE 7
    Primary Test
    Primary
    Biochemical %
    Assay Species Conc. Inh. IC50 Ki nh
    Somatostatin hum 0.1 μM 61 0.053 μM 0.05 μM 0.736
    sst1
    Somatostatin hum 0.1 μM 90 0.018 μM 9.35 nM 1.24
    sst2
    Somatostatin hum  10 nM 61  6.14 nM 5.45 nM 0.714
    sst3
    Somatostatin hum  10 μM 67  5.63 μM 4.95 μM 1.26
    sst4
    Somatostatin hum 0.1 μM 61 0.082 μM 0.068 μM  0.961
    sst5
    • EXAMPLE 5 Radioligand Binding Assay of β-Superfamily Conopeptides
  • The radioligand binding activity of truncations of β-M14.1-D1 and other β-superfamily conopeptides with respect to somatostatin sst[0141] 1, sst2, sst3 and sst4 and sst5 was tested as described in Example 4. The peptides which were tested are set forth in Table 8. The significant responsers (≧50% inhibition or stimulation) are set forth in Table 9.
    TABLE 8
    Conopeptide Type Sequence (SEQ ID NO:)a
    β-M14.1-6 2 LFCFX1KSCWPR{circumflex over ( )} (314)
    β-M14.1-9 2 LFCFX1KSCW{circumflex over ( )} (317)
    β-M14.1-10 2 LX2CFX1KSCW{circumflex over ( )} (318)
    β-T14.1-D1 Misc TVYICMX1KVCPPSP{circumflex over ( )} (327)
    β-Sl14.1-D1 6 MECYX1KACRPTLSR{circumflex over ( )} (324)
    β-Cn14.2-D1 5 GAQICIX1KVCPPSPWR{circumflex over ( )} (329)
  • [0142]
    TABLE 9
    Primary Test
    Primary
    Biochemical Assay Species Peptide Conc. % Inh.
    Somatostatin sst1 hum β-Cn14.2-D1  10 μM 61
    Somatostatin sst3 hum β-M14.1-6 0.1 μM 63
    Somatostatin sst3 hum β-M14.1-9 0.1 μM 72
    Somatostatin sst3 hum β-Sl14.1-D1  10 μM 82
    Somatostatin sst3 hum β-Cn14.2-D1  10 μM 84
    Somatostatin sst4 hum β-Cn14.2-D1  10 μM 60
    Somatostatin sst5 hum β-M14.1-6 0.1 μM 57
    Somatostatin sst5 hum β-M14.1-9 0.1 μM 55
    Somatostatin sst5 hum β-M14.1-10 0.1 μM 65
    Somatostatin sst5 hum β-T14.1-D1  10 μM 65
    Somatostatin sst5 hum β-Sl14.1-D1  10 μM 86
    Somatostatin sst5 hum β-Cn14.2-D1  12 μM 56
    • EXAMPLE 6 Radioligand Binding Assay of Type 3 β-Superfamily Conopeptide
  • The radioligand binding activity of P-Gel4.1 D1 (SLWCVCPFRVCPPCH#; SEQ ID NO:335 with 1-3 fold), D919 (with 1-4 fold, SEQ ID NO:334) and D919 (with 2-4 fold, SEQ ID NO:335) with respect to melanocortin MC[0143] 3, MC4, MC5 and MCH (h) was tested using the following assays.
    Melanocortin MC3 (Schioth et al., 1995)
    Source: Human recombinant HEK-293 cells
    Ligand: 0.035 nM 125I NDP-αMSH
    Vehicle: 0.4% DMSO
    Incubation Time/Temp: 60 min @ 37° C.
    Incubation Buffer: 25 mM HEPES-KOH, 0.2% BSA, pH 7.0,
    100 mM NaCl, 1 mM 1,10-phenanthroline,
    1.5 mM CaCl2, 1 mM MgSO4, and one
    complete protease inhibitor tablet/
    100 ml
    NonSpecific Ligand: 3 μM NDP-αMSH
    Kd: 0.53 nM (historical value)
    Bmax: 6 pmol/mg Protein (historical value)
    Specific Binding: 85% (historical value)
    Quantitation Method: Radioligand Binding
    Significance Criteria: ≧50% of max stimulation or inhibition
    Melanocortin MC4 (Schioth et al., 1995)
    Source: Human recombinant HEK-293 cells
    Ligand: 0.02 nM 125I NDP-αMSH
    Vehicle: 01% H20
    Incubation Time/Temp: 2 hours @ 37° C.
    Incubation Buffer: 25 mM-HEPES-KOH, 0.2% BSA, pH 7.0,
    100 mM NaCl, 1 mM 1,10-phenanthroline,
    1.5 mM CaCl2, 1 mM MgSO4, and one
    complete protease inhibitor tablet/
    100 ml
    NonSpecific Ligand: 3 μM NDP-αMSH
    Kd: 0.5 nM (historical value)
    Bmax: 3.9 pmol/mg Protein (historical value)
    Specific Binding: 90% (historical value)
    Quantitation Method: Radioligand Binding
    Significance Criteria: ≧50% of max stimulation or inhibition
    Melanocortin MC5 (Schioth et al., 1995)
    Source: Human recombinant HEK-293 cells
    Ligand: 0.035 nM 125I NDP-αMSH
    Vehicle: 1% H20
    Incubation Time/Temp: 2 hours @ 37° C.
    Incubation Buffer: 25 mM HEPES-KOH, 0.2% BSA, pH 7.0,
    100 mM NaCl, 1 mM 1,10-phenanthroline,
    1.5 mM CaCl2, 1 mM MgSO4, and one
    complete protease inhibitor tablet/
    100 ml
    NonSpecific Ligand: 3 μM NDP-αMSH
    Kd: 0.53 nM (historical value)
    Bmax: 6 pmol/mg Protein (historical value)
    Specific Binding: 85% (historical value)
    Quantitation Method: Radioligand Binding
    Significance Criteria: ≧50% of max stimulation or inhibition
    MCH (h) (Chambers et al., 1999)
    Source: Human recombinant CHO cells
    Ligand: 0.1 nM 125I [Phe13, Tyr19]-MCH
    Incubation Time/Temp: 60 min @ 22° C.
    NonSpecific Ligand: 1 μM NDP-αMSH
    Kd: 0.05 nM (historical value)
    Quantitation Method: Radioligand Binding
    Significance Criteria: ≧50% of max stimulation or inhibition
    Melanocortin MC1 (Siegrist et al., 1988)
    Source: Human recombinant CHO cells
    Ligand: 0.05 nM 125I NDP-αMSH
    Incubation Time/Temp: 90 min @ 22° C.
    NonSpecific Ligand: 0.1 μM MCH
    Kd: 0.62 nM (historical value)
    Quantitation Method: Radioligand Binding
    Significance Criteria: ≧50% of max stimulation or inhibition
  • Biochemical assay results are presented as the percent inhibition of specific binding or activity. All other results are expressed in terms of that assay's quantitation method. For primary assays, only the lowest concentration with a significant response judged by the assays' criteria, is shown. Primary screening in duplicate with quantitative data (e.g., IC[0144] 50±SEM, Ki±SEM and nH) are shown where applicable for individual assays. In screening packages, primary screening in duplicate with semi-quantitative data (e.g., estimated IC50, Ki and nH) are shown where applicable (concentration range of 4 log units). Significant responses were noted in the primary assays shown in Tables 10 and 11.
    TABLE 10
    Primary Test for β-Ge14.1-D1
    Primary
    Biochemical
    Assay Species Conc. % Inh. IC50 Ki nh
    Melanocortin hum 1 μM 71 0.294 μM 0.276 μM 0.762
    MC5
  • [0145]
    TABLE 11
    Primary Test
    Primary
    Biochemical Assay Species Peptide Conc. % Inh.
    Melanocortin MC3 hum D919 [2, 4] 10 μM 67
    Melanocortin MC4 hum D919 [2, 4] 10 μM 67
    Melanocortin MC4 hum D919 [1, 4] 10 μM 58
    Melanocortin MC5 hum D919 [2, 4] 10 μM 96
    Melanocortin MC5 hum D919 [1, 4] 10 μM 89
    Melanocortin MC1 hum D919 [2, 4] 10 μM 60
    Melanocortin MC1 hum D919 [1, 4] 10 μM 66
    MCH (h) hum D919 [2, 4] 10 μM 83
    MCH (h) hum D919 [1, 4] 10 μM 65
  • 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. [0146]
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  • 1 340 1 456 DNA Conus flavidus CDS (7)..(255) 1 ggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp 1 5 10 att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att cgg 96 Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg 15 20 25 30 ggt ttg gtg cca gat gac tta acc cca cag ctt att ttg caa agt ctg 144 Gly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Gln Ser Leu 35 40 45 gat tcc cgt cgt cat gat cac ggc att cgt ccg aag aga gtc gac ata 192 Asp Ser Arg Arg His Asp His Gly Ile Arg Pro Lys Arg Val Asp Ile 50 55 60 tgt aac tgg agg ata tgt gca cca aac cca ttg aga cga cat gat ctt 240 Cys Asn Trp Arg Ile Cys Ala Pro Asn Pro Leu Arg Arg His Asp Leu 65 70 75 aag aaa gga aac aat tgacgtcaga caaccgccac aacttgagta cgacatcgtt 295 Lys Lys Gly Asn Asn 80 aatacgactt cagcaaatat gaaattttca gcatcactgt ggttgtgaag aaatcagttg 355 ctttaaaagg ttggatttgt ccttgtttaa gccgttgtac tgatgacatc tctgcactat 415 gaaataaagc tgatgtgaca aactaaaaaa aaaaaaaaaa a 456 2 83 PRT Conus flavidus 2 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Gln Ser Leu Asp Ser 35 40 45 Arg Arg His Asp His Gly Ile Arg Pro Lys Arg Val Asp Ile Cys Asn 50 55 60 Trp Arg Ile Cys Ala Pro Asn Pro Leu Arg Arg His Asp Leu Lys Lys 65 70 75 80 Gly Asn Asn 3 33 PRT Conus flavidus PEPTIDE (1)..(33) Xaa at residues 7, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residue 15 may be Trp (Dor L) or bromo-Trp (Dor L) 3 His Asp His Gly Ile Arg Xaa Lys Arg Val Asp Ile Cys Asn Xaa Arg 1 5 10 15 Ile Cys Ala Xaa Asn Xaa Leu Arg Arg His Asp Leu Lys Lys Gly Asn 20 25 30 Asn 4 374 DNA Conus miles CDS (7)..(315) 4 ggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg gtg 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val 1 5 10 ggg ctc acc gtc ggg agt cac gtc cat cgg tct cac agt cct aca tcg 96 Gly Leu Thr Val Gly Ser His Val His Arg Ser His Ser Pro Thr Ser 15 20 25 30 cgc agc cat ggt gat gac tcc att cat gac aag acg att cat caa cat 144 Arg Ser His Gly Asp Asp Ser Ile His Asp Lys Thr Ile His Gln His 35 40 45 ctg ttt gcc cgt ctt cct ctg gag aac aac gac gac cat cgt tct gtg 192 Leu Phe Ala Arg Leu Pro Leu Glu Asn Asn Asp Asp His Arg Ser Val 50 55 60 gat ctt cct gca ggg aat ggt gca ggc aac acc aag caa caa gac caa 240 Asp Leu Pro Ala Gly Asn Gly Ala Gly Asn Thr Lys Gln Gln Asp Gln 65 70 75 agt cct cat cat gtg tgt tgt gct att ggt ccg gtt ctt cca ttc tgt 288 Ser Pro His His Val Cys Cys Ala Ile Gly Pro Val Leu Pro Phe Cys 80 85 90 tgt gtc agt tgg ctg cac aaa ctc cat tgaactggcc aatgaaaata 335 Cys Val Ser Trp Leu His Lys Leu His 95 100 actcaggaat agacagaaag gcaaaaaaaa aaaaaaaaa 374 5 103 PRT Conus miles 5 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val Gly Leu 1 5 10 15 Thr Val Gly Ser His Val His Arg Ser His Ser Pro Thr Ser Arg Ser 20 25 30 His Gly Asp Asp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 40 45 Ala Arg Leu Pro Leu Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 Pro Ala Gly Asn Gly Ala Gly Asn Thr Lys Gln Gln Asp Gln Ser Pro 65 70 75 80 His His Val Cys Cys Ala Ile Gly Pro Val Leu Pro Phe Cys Cys Val 85 90 95 Ser Trp Leu His Lys Leu His 100 6 29 PRT Conus miles PEPTIDE (1)..(29) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residues 6, 15 and 18 may be Pro or hydroxy-Pro; Xaa at residue 24 may be Trp (D or L) or bromo-Trp (D or L) 6 Xaa Gln Asp Gln Ser Xaa His His Val Cys Cys Ala Ile Gly Xaa Val 1 5 10 15 Leu Xaa Phe Cys Cys Val Ser Xaa Leu His Lys Leu His 20 25 7 359 DNA Conus miles CDS (7)..(291) 7 ggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg gtg 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val 1 5 10 ggg ttc acc gtc ggg ggt cac gtc cat cgg tct cac agt cct aca tcg 96 Gly Phe Thr Val Gly Gly His Val His Arg Ser His Ser Pro Thr Ser 15 20 25 30 cgc agc cat ggt gat gac tcc att cat gac aag acg att cat caa cat 144 Arg Ser His Gly Asp Asp Ser Ile His Asp Lys Thr Ile His Gln His 35 40 45 ctg ttt gcc cgt ctt cct cag gag aac aac gac gac cat cgt tct gtg 192 Leu Phe Ala Arg Leu Pro Gln Glu Asn Asn Asp Asp His Arg Ser Val 50 55 60 gat ctt cct gca ggg act agc gca ggc gac atg aaa cca caa cgc caa 240 Asp Leu Pro Ala Gly Thr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln 65 70 75 aga cgt ctc tgc tgc atc ttt gcc ccg att ctt tgg ttc tgt tgt cac 288 Arg Arg Leu Cys Cys Ile Phe Ala Pro Ile Leu Trp Phe Cys Cys His 80 85 90 ggt taacagctca aattacactg cactggccga ttgaaagaac tgcaataaac 341 Gly 95 ggaaaaaaaa aaaaaaaa 359 8 95 PRT Conus miles 8 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val Gly Phe 1 5 10 15 Thr Val Gly Gly His Val His Arg Ser His Ser Pro Thr Ser Arg Ser 20 25 30 His Gly Asp Asp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 40 45 Ala Arg Leu Pro Gln Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 Pro Ala Gly Thr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln Arg Arg 65 70 75 80 Leu Cys Cys Ile Phe Ala Pro Ile Leu Trp Phe Cys Cys His Gly 85 90 95 9 14 PRT Conus miles PEPTIDE (1)..(14) Xaa at residue 7 may be Pro or hydroxy-Pro; Xaa at residue 10 may be Trp (D or L) or bromo-Trp (D or L) 9 Leu Cys Cys Ile Phe Ala Xaa Ile Leu Xaa Phe Cys Cys His 1 5 10 10 351 DNA Conus capitaneus CDS (7)..(291) 10 ggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg gtg 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val 1 5 10 ggg ttc acc gtc ggg ggt cac gtc cat cgg tct cac agt cct aca tcg 96 Gly Phe Thr Val Gly Gly His Val His Arg Ser His Ser Pro Thr Ser 15 20 25 30 cgc agc cat ggt gat gac tcc att cat gac gag acg att cat caa cat 144 Arg Ser His Gly Asp Asp Ser Ile His Asp Glu Thr Ile His Gln His 35 40 45 ctg ttt gcc cgt ctt cct cag gag aac aac gac gac cat cgt tct gtg 192 Leu Phe Ala Arg Leu Pro Gln Glu Asn Asn Asp Asp His Arg Ser Val 50 55 60 gat ctt cct gca ggg act agc gca ggc gac atg aaa cca caa cgc caa 240 Asp Leu Pro Ala Gly Thr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln 65 70 75 aga ggt ttc tgc tgc gac ttt ccc ccg att ttt tgg ttc tgt tgt atc 288 Arg Gly Phe Cys Cys Asp Phe Pro Pro Ile Phe Trp Phe Cys Cys Ile 80 85 90 ggt taacagcaca aattacactg cactggccga ttgaaagaac tgcaataaac 341 Gly 95 ggaaaaaaaa 351 11 95 PRT Conus capitaneus 11 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val Gly Phe 1 5 10 15 Thr Val Gly Gly His Val His Arg Ser His Ser Pro Thr Ser Arg Ser 20 25 30 His Gly Asp Asp Ser Ile His Asp Glu Thr Ile His Gln His Leu Phe 35 40 45 Ala Arg Leu Pro Gln Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 Pro Ala Gly Thr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln Arg Gly 65 70 75 80 Phe Cys Cys Asp Phe Pro Pro Ile Phe Trp Phe Cys Cys Ile Gly 85 90 95 12 15 PRT Conus capitaneus PEPTIDE (1)..(15) Xaa at residues 7 and 8 may be Pro or hydroxy-Pro; Xaa at residue 11 may be Trp (D or L) or bromo-Trp (D or L) 12 Gly Phe Cys Cys Asp Phe Xaa Xaa Ile Phe Xaa Phe Cys Cys Ile 1 5 10 15 13 348 DNA Conus generalis CDS (7)..(222) 13 ggatcc atg cag acg gcc tac tgg gta atg gtg atg atg atg gtg tgg 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp 1 5 10 att aaa ggc cct gtg tct gaa ggt ggt aaa ttg aac gac gta att cgg 96 Ile Lys Gly Pro Val Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg 15 20 25 30 ggt ttg gtg cca gac gac ttg acc cca gtg ttt gcc ttg cat cat ccg 144 Gly Leu Val Pro Asp Asp Leu Thr Pro Val Phe Ala Leu His His Pro 35 40 45 gtt tcc cat cgt cgg tct cac agc agt agt ttg tgg tgt gta tgt cca 192 Val Ser His Arg Arg Ser His Ser Ser Ser Leu Trp Cys Val Cys Pro 50 55 60 ttc agg gtg tgt cca cca tgc cat gga aga tgacctggtc ccaaaccaac 242 Phe Arg Val Cys Pro Pro Cys His Gly Arg 65 70 aaaataacgt cagacaaccg ccacaacttt agtacgacat cccttaatac gacttcagca 302 agtattttaa catcactatg gtgtgatgaa atcagttgct ttaaaa 348 14 72 PRT Conus generalis 14 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Lys 1 5 10 15 Gly Pro Val Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Val Phe Ala Leu His His Pro Val Ser 35 40 45 His Arg Arg Ser His Ser Ser Ser Leu Trp Cys Val Cys Pro Phe Arg 50 55 60 Val Cys Pro Pro Cys His Gly Arg 65 70 15 19 PRT Conus generalis PEPTIDE (1)..(19) Xaa at residue 7 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 11, 16 and 17 may be Pro or hydroxy-Pro 15 Ser His Ser Ser Ser Leu Xaa Cys Val Cys Xaa Phe Arg Val Cys Xaa 1 5 10 15 Xaa Cys His 16 405 DNA Conus wittigi CDS (1)..(210) misc_feature (1)..(405) n may be any base 16 atg atg ttg gtg tgg att aca gcc cct ctg cct gaa ggt ggt aaa ctg 48 Met Met Leu Val Trp Ile Thr Ala Pro Leu Pro Glu Gly Gly Lys Leu 1 5 10 15 aag cac gta att cgg ggt ttg gtg cca gac gac tta acc cca cag ctt 96 Lys His Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu 20 25 30 atc ttg cga agt ctg att tcc cgt cgt agt tct gac ggc agt gat ccg 144 Ile Leu Arg Ser Leu Ile Ser Arg Arg Ser Ser Asp Gly Ser Asp Pro 35 40 45 aag gca aaa aaa cag tgt atg tgg aag aga tgt ata cca gac caa tcg 192 Lys Ala Lys Lys Gln Cys Met Trp Lys Arg Cys Ile Pro Asp Gln Ser 50 55 60 aga cta gaa gaa gat gaa tgatgtcaga caaccgccat cactgtagta 240 Arg Leu Glu Glu Asp Glu 65 70 tgacatcgtt aatacgactt aagcaaatat tttaacatca ctgtggttct gaagacatca 300 gttgctttaa aagattggat tcttccttgt ttaagagttg tactganatc attcctgccc 360 tgtgaaataa agctgatgtt gacanncaaa caaaaaaaaa aaaaa 405 17 70 PRT Conus wittigi misc_feature (1)..(405) n may be any base 17 Met Met Leu Val Trp Ile Thr Ala Pro Leu Pro Glu Gly Gly Lys Leu 1 5 10 15 Lys His Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu 20 25 30 Ile Leu Arg Ser Leu Ile Ser Arg Arg Ser Ser Asp Gly Ser Asp Pro 35 40 45 Lys Ala Lys Lys Gln Cys Met Trp Lys Arg Cys Ile Pro Asp Gln Ser 50 55 60 Arg Leu Glu Glu Asp Glu 65 70 18 29 PRT Conus wittigi PEPTIDE (1)..(29) Xaa at residues 7 and 20 may be Pro or hydroxy-Pro; Xaa at residue 15 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 26, 27 and 29 may be Glu or Gla 18 Ser Ser Asp Gly Ser Asp Xaa Lys Ala Lys Lys Gln Cys Met Xaa Lys 1 5 10 15 Arg Cys Ile Xaa Asp Gln Ser Arg Leu Xaa Xaa Asp Xaa 20 25 19 463 DNA Conus consors CDS (7)..(222) 19 ggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp 1 5 10 att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att cgg 96 Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg 15 20 25 30 ggt ttg gtg tca cac atc tta atc cca cag cat acc ttg cga agt ctg 144 Gly Leu Val Ser His Ile Leu Ile Pro Gln His Thr Leu Arg Ser Leu 35 40 45 act tcc cgt gat cgt tct gac aac ggt ggt tcg agt gga gca caa ata 192 Thr Ser Arg Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile 50 55 60 tgc atc tgg aag gta tgt cca cca tcc cca tagagacgac cacgaggaaa 242 Cys Ile Trp Lys Val Cys Pro Pro Ser Pro 65 70 aagatgaacg gcgtcagaca accgccacaa ctgtagtacg acatcgttga tacgacttca 302 gcaactattt taacatcact gtggttgtga agaaatcagt cgctttaaaa gattggattt 362 ttccttgttt aagagttgta ctgatatcag ctctgcacta tgaaataaag ctgatgtgac 422 ataaaaaaaa aaaaaaaaag tactctgcgt tgttactcga g 463 20 72 PRT Conus consors 20 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Ser His Ile Leu Ile Pro Gln His Thr Leu Arg Ser Leu Thr Ser 35 40 45 Arg Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro 65 70 21 23 PRT Conus consors PEPTIDE (1)..(23) Xaa at residue 16 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 21 and 23 may be Pro or hydroxy-Pro 21 Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Ser Xaa 20 22 470 DNA Conus consors CDS (7)..(246) 22 ggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp 1 5 10 att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gca att cgg 96 Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Ala Ile Arg 15 20 25 30 ggt ttg gtg tca cac atc tta atc cca cag cat acc ttg cga agt ctg 144 Gly Leu Val Ser His Ile Leu Ile Pro Gln His Thr Leu Arg Ser Leu 35 40 45 act tcc cgt gct cgt tct gac aac ggt ggt tcg agt gga gca caa ata 192 Thr Ser Arg Ala Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile 50 55 60 tgc atc tgg aag gta tgt cca cca tcc cca tgg aga cga cca caa gga 240 Cys Ile Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Pro Gln Gly 65 70 75 aaa aga tgaatgacgt cagacaaccg ccacaactgt agtacgacat cgttgatacg 296 Lys Arg 80 acttcagcaa atattttaac atcactgtgg ttgtgaagaa atcagttgct ttaaaagatt 356 ggatttttcc ttgtttaaga gttgtactga tatcagctct gcactatgaa ataaagctga 416 tgtgacaaac aataaaaaag aaaaaaaaaa aagtactctg cgttgttact cgag 470 23 80 PRT Conus consors 23 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Ala Ile Arg Gly Leu 20 25 30 Val Ser His Ile Leu Ile Pro Gln His Thr Leu Arg Ser Leu Thr Ser 35 40 45 Arg Ala Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Pro Gln Gly Lys Arg 65 70 75 80 24 28 PRT Conus consors PEPTIDE (1)..(28) Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 21, 23 and 27 may be Pro or hydroxy-Pro 24 Ala Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Ser Xaa Xaa Arg Arg Xaa Gln 20 25 25 469 DNA Conus consors CDS (7)..(228) 25 ggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp 1 5 10 att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att cgg 96 Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg 15 20 25 30 ggt ttg gtg cca cac ttc tta acc cca cag cat atc ttg caa agt ctg 144 Gly Leu Val Pro His Phe Leu Thr Pro Gln His Ile Leu Gln Ser Leu 35 40 45 act tcc cgt aat ggt tct ggc agc agt aat cag aaa gaa gca caa cta 192 Thr Ser Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu Ala Gln Leu 50 55 60 tgc atc tgg aag gta tgt cca cca tcc cca tgg aga tgaccacaag 238 Cys Ile Trp Lys Val Cys Pro Pro Ser Pro Trp Arg 65 70 gaaaaagatg aacggcgtca gacaaccgcc acaactgtag tgggacatcg ttgatacgac 298 ttcagcaaat attttaacat cactgtggtt gtgaagaaat cagttgcttt aaaagattgg 358 atttttcctt gtttaagaat tgtactgata tcagctctgc actatgaaat aaagctgatg 418 tgacaaccca aaaaaaaaaa aaaaaaaaag tactctgcgt tgttactcga g 469 26 74 PRT Conus consors 26 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Phe Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu Ala Gln Leu Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg 65 70 27 25 PRT Conus consors PEPTIDE (1)..(25) Xaa at residue 10 may be Glu or Gla; Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 21 and 23 may be Pro or hydroxy-Pro 27 Asn Gly Ser Gly Ser Ser Asn Gln Lys Xaa Ala Gln Leu Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Ser Xaa Xaa Arg 20 25 28 472 DNA Conus tulipa CDS (7)..(231) misc_feature (1)..(472) n may be any base 28 ggatcc atg cag acg gcc tac tgg gtg atg ctg atg atg atg gtg tgg 48 Met Gln Thr Ala Tyr Trp Val Met Leu Met Met Met Val Trp 1 5 10 att aca gcc cct ctg tct gaa ggt ggt aaa ctg aac gac gta att cgg 96 Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg 15 20 25 30 ggt ttg gtg cca cac gtc tta acc cca cag cat atc ttg caa agt ctg 144 Gly Leu Val Pro His Val Leu Thr Pro Gln His Ile Leu Gln Ser Leu 35 40 45 gtt tcc cgt cgt cat ttt aac agc gtt gtt ccg acg gta tac ata tgc 192 Val Ser Arg Arg His Phe Asn Ser Val Val Pro Thr Val Tyr Ile Cys 50 55 60 atg tgg aag gta tgt cca cca tcg cca tag aga cga cca taaggaaaaa 241 Met Trp Lys Val Cys Pro Pro Ser Pro Arg Arg Pro 65 70 gatgaatgac gtcagacaac cgccacaact gtagtacgac atcgttaata cgacttcagc 301 aaatatttta acatcactgt ggttgtgaag aaatcagttg ctttaaaaga ttggattttt 361 ccttgtttca gagttgtact gatatcagct ctgcactatc aaataaagct gaagtgacaa 421 accnnaaaaa aaaaaaaaaa aaaaaaaaag tactctgcgt tgttactcga g 472 29 71 PRT Conus tulipa misc_feature (1)..(472) n may be any base 29 Met Gln Thr Ala Tyr Trp Val Met Leu Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Val Leu Thr Pro Gln His Ile Leu Gln Ser Leu Val Ser 35 40 45 Arg Arg His Phe Asn Ser Val Val Pro Thr Val Tyr Ile Cys Met Trp 50 55 60 Lys Val Cys Pro Pro Ser Pro 65 70 30 21 PRT Conus tulipa PEPTIDE (1)..(21) Xaa at residues 7, 18, 19 and 21 may be Pro or hydroxy-Pro; Xaa aT residue 10 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residue 14 may be Trp or bromo-Trp 30 His Phe Asn Ser Val Val Xaa Thr Val Xaa Ile Cys Met Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa 20 31 451 DNA Conus tulipa CDS (1)..(279) 31 atg cag acg gcc tac tgg gtg atg ctg ttg atg atg gtg ggc att aca 48 Met Gln Thr Ala Tyr Trp Val Met Leu Leu Met Met Val Gly Ile Thr 1 5 10 15 gcc cct ctg cct gaa ggt ggt aaa ccg aac agc gta att cgg ggt ttg 96 Ala Pro Leu Pro Glu Gly Gly Lys Pro Asn Ser Val Ile Arg Gly Leu 20 25 30 gtg cca aac gac tta act cca cag cat acc ttg cga agt ctg att tcc 144 Val Pro Asn Asp Leu Thr Pro Gln His Thr Leu Arg Ser Leu Ile Ser 35 40 45 cgt cgt caa act gac gtt ctt ctg gag gct acc ctt ttg aca aca cca 192 Arg Arg Gln Thr Asp Val Leu Leu Glu Ala Thr Leu Leu Thr Thr Pro 50 55 60 gcc ccc gag cag aga ttg ttc tgc ttc tgg aag tca tgt tgg cca agg 240 Ala Pro Glu Gln Arg Leu Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg 65 70 75 80 ccc tac cct tgg aga cga cgt gat ctt aat gga aaa cga tgaatgacgt 289 Pro Tyr Pro Trp Arg Arg Arg Asp Leu Asn Gly Lys Arg 85 90 cagacaaccg ccacaactgt agtacgacat cattaatacg acttcagcaa atattttaac 349 attactgtgg ttgtgaagaa atcacttgct ttaaaagatt ggttttttcc ttgtttcaga 409 gttgtactga tatcagctct gccctatgaa ataaagctga tg 451 32 93 PRT Conus tulipa 32 Met Gln Thr Ala Tyr Trp Val Met Leu Leu Met Met Val Gly Ile Thr 1 5 10 15 Ala Pro Leu Pro Glu Gly Gly Lys Pro Asn Ser Val Ile Arg Gly Leu 20 25 30 Val Pro Asn Asp Leu Thr Pro Gln His Thr Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Gln Thr Asp Val Leu Leu Glu Ala Thr Leu Leu Thr Thr Pro 50 55 60 Ala Pro Glu Gln Arg Leu Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg 65 70 75 80 Pro Tyr Pro Trp Arg Arg Arg Asp Leu Asn Gly Lys Arg 85 90 33 40 PRT Conus tulipa PEPTIDE (1)..(40) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 7 and 17 may be Glu or Gla; Xaa at residue 14, 16, 29, 31 and 33 may be Pro or hydroxy-Pro; Xaa at residues 24, 28 and 34 may be Trp (D or L) or bromo-Trp (D or L) 33 Xaa Thr Asp Val Leu Leu Xaa Ala Thr Leu Leu Thr Thr Xaa Ala Xaa 1 5 10 15 Xaa Gln Arg Leu Phe Cys Phe Xaa Lys Ser Cys Xaa Xaa Arg Xaa Xaa 20 25 30 Xaa Xaa Arg Arg Arg Asp Leu Asn 35 40 34 414 DNA Conus sulcatus CDS (1)..(285) 34 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ccg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Pro Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca gac gac tta acc cca cag cgt gtc ttg cga agt ctg att tcc 144 Val Pro Asp Asp Leu Thr Pro Gln Arg Val Leu Arg Ser Leu Ile Ser 35 40 45 cgt cgt caa tct ggc tgc aga gtc ccg ttt gaa ttg aaa tgc atc tgg 192 Arg Arg Gln Ser Gly Cys Arg Val Pro Phe Glu Leu Lys Cys Ile Trp 50 55 60 aag ttc tgt aca ata tac cca tcg aga cca ttt gct tct ctg gaa gaa 240 Lys Phe Cys Thr Ile Tyr Pro Ser Arg Pro Phe Ala Ser Leu Glu Glu 65 70 75 80 aaa gac gaa tgt cag aca gtc acc ata act gta aca tgg gat ttt 285 Lys Asp Glu Cys Gln Thr Val Thr Ile Thr Val Thr Trp Asp Phe 85 90 95 taatacgtct ccagcaagta ttttaacatc actgtggttg tgaagaaatc agttgcttta 345 aaagattgga tttttccttg tttaagagtt gtactgatat cagctctgcc ctgtgaaata 405 aagctgatg 414 35 95 PRT Conus sulcatus 35 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Pro Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Arg Val Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Gln Ser Gly Cys Arg Val Pro Phe Glu Leu Lys Cys Ile Trp 50 55 60 Lys Phe Cys Thr Ile Tyr Pro Ser Arg Pro Phe Ala Ser Leu Glu Glu 65 70 75 80 Lys Asp Glu Cys Gln Thr Val Thr Ile Thr Val Thr Trp Asp Phe 85 90 95 36 45 PRT Conus sulcatus PEPTIDE (1)..(45) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residues 7, 21 and 24 may be Pro or hydroxy-Pro; Xaa at residues 9, 29, 30 and 33 may be Glu or Gla; Xaa at residues 14 and 43 may be Trp (D or L) or bromo-Trp (D or L) 36 Xaa Ser Gly Cys Arg Val Xaa Phe Xaa Leu Lys Cys Ile Xaa Lys Phe 1 5 10 15 Cys Thr Ile Xaa Xaa Ser Arg Ser Phe Ala Ser Leu Xaa Xaa Lys Asp 20 25 30 Xaa Cys Gln Thr Val Thr Ile Thr Val Thr Xaa Asp Phe 35 40 45 37 413 DNA Conus sulcatus CDS (1)..(234) 37 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc tct ctg tct gaa ggt ggt aaa ccg aac gac gtc att cgg ggt ttt 96 Ala Ser Leu Ser Glu Gly Gly Lys Pro Asn Asp Val Ile Arg Gly Phe 20 25 30 gtg cca gac gac tta acc cca cag ctt atc ttg cga agt ctg att tcc 144 Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile Ser 35 40 45 cgt cgt cgt tct gac aag gat gtt ggg aag aga atg gaa tgt tac tgg 192 Arg Arg Arg Ser Asp Lys Asp Val Gly Lys Arg Met Glu Cys Tyr Trp 50 55 60 aag gca tgt aga ccc acg cta tcg aga cga cat gat ctt ggg 234 Lys Ala Cys Arg Pro Thr Leu Ser Arg Arg His Asp Leu Gly 65 70 75 taaaagatga atgacgtcag acaacagcca caactatagt atgacatcgt taatacgact 294 tcagcaaata ttttaacatc actgtggttg tgaagaaatc agttgcttta aaagattgga 354 tttttccgtg tttaagagtt gtactgatat cagctctgcc ctgtgaaata aagctgatg 413 38 78 PRT Conus sulcatus 38 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Ser Leu Ser Glu Gly Gly Lys Pro Asn Asp Val Ile Arg Gly Phe 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Arg Ser Asp Lys Asp Val Gly Lys Arg Met Glu Cys Tyr Trp 50 55 60 Lys Ala Cys Arg Pro Thr Leu Ser Arg Arg His Asp Leu Gly 65 70 75 39 27 PRT Conus sulcatus PEPTIDE (1)..(27) Xaa at residue 11 may be Glu or Gla; Xaa at residue 13 may be Pro or hydroxy-Pro; Xaa at residue 14 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 19 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 39 Arg Ser Asp Lys Asp Val Gly Lys Arg Met Xaa Cys Xaa Xaa Lys Ala 1 5 10 15 Cys Arg Xaa Thr Leu Ser Arg Arg His Asp Leu 20 25 40 451 DNA Conus magus CDS (1)..(279) 40 atg cag acg gcc tac tgg gtg atg ctg atg atg atg gtg tgc atc aca 48 Met Gln Thr Ala Tyr Trp Val Met Leu Met Met Met Val Cys Ile Thr 1 5 10 15 gcc cct ctg cct gaa ggt ggt aaa ccg aac agc gga att cgg ggt ttg 96 Ala Pro Leu Pro Glu Gly Gly Lys Pro Asn Ser Gly Ile Arg Gly Leu 20 25 30 gtg cca aac gac tta act cca cag cat acc ttg cga agt ctg att tcc 144 Val Pro Asn Asp Leu Thr Pro Gln His Thr Leu Arg Ser Leu Ile Ser 35 40 45 cgt cgt caa act gac gtt ctt ctg gat gct acc ctt ttg aca aca cca 192 Arg Arg Gln Thr Asp Val Leu Leu Asp Ala Thr Leu Leu Thr Thr Pro 50 55 60 gcc ccc gag cag aga ttg ttc tgc ttc tgg aag tca tgt tgg cca agg 240 Ala Pro Glu Gln Arg Leu Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg 65 70 75 80 ccc tac cct tgg aga cga cgt aat ctt aat gga aaa cga tgaatgacgt 289 Pro Tyr Pro Trp Arg Arg Arg Asn Leu Asn Gly Lys Arg 85 90 cagacaaccg ccacaactgt agtacgacat cgttaatacg acttcagcaa atattttaac 349 ataactgtgg ttgtgaagaa atcggttgct ttaaaagatt ggatttttcc ttgtttcaga 409 gttgtactga tatgagctct gccctgtgaa ataaagctga tg 451 41 93 PRT Conus magus 41 Met Gln Thr Ala Tyr Trp Val Met Leu Met Met Met Val Cys Ile Thr 1 5 10 15 Ala Pro Leu Pro Glu Gly Gly Lys Pro Asn Ser Gly Ile Arg Gly Leu 20 25 30 Val Pro Asn Asp Leu Thr Pro Gln His Thr Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Gln Thr Asp Val Leu Leu Asp Ala Thr Leu Leu Thr Thr Pro 50 55 60 Ala Pro Glu Gln Arg Leu Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg 65 70 75 80 Pro Tyr Pro Trp Arg Arg Arg Asn Leu Asn Gly Lys Arg 85 90 42 40 PRT Conus magus PEPTIDE (1)..(40) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residues 14, 16, 29, 31 and 33 may be Pro or hydroxy-Pro; Xaa at residue 17 may be Glu or Gla; Xaa at residues 24, 28 and 34 may be Trp (D or L) or bromo-Trp (D or L) 42 Xaa Thr Asp Val Leu Leu Asp Ala Thr Leu Leu Thr Thr Xaa Ala Xaa 1 5 10 15 Xaa Gln Arg Leu Phe Cys Phe Xaa Lys Ser Cys Xaa Xaa Arg Xaa Xaa 20 25 30 Xaa Xaa Arg Arg Arg Asn Leu Asn 35 40 43 423 DNA Conus emaciatus CDS (1)..(249) 43 atg cag acg gcc tac tgg gtg atg gcg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Ala Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca gat gac tta acc cca cag ctt gtt ttg caa agt ctg gat tcc 144 Val Pro Asp Asp Leu Thr Pro Gln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 cgt cgt cat act cac ggc att cgt ccg aag gga gac ggc ata tgt atc 192 Arg Arg His Thr His Gly Ile Arg Pro Lys Gly Asp Gly Ile Cys Ile 50 55 60 tgg aag gta tgt cca cca gac cca tgg aga cga cat cgt ctt aag aaa 240 Trp Lys Val Cys Pro Pro Asp Pro Trp Arg Arg His Arg Leu Lys Lys 65 70 75 80 aga aac aat tgacgtcaga caaccgccac aacttgagta cgacatcgtt 289 Arg Asn Asn aatacgactt cagcaaatat gaaattttca gcatcactgt ggttgtcaag aaatcagttg 349 ctttaaaaga ttggatttgt ccttgtttaa gagttgtact gatgtcagct ctgccctgtg 409 aaataaagct gatg 423 44 83 PRT Conus emaciatus 44 Met Gln Thr Ala Tyr Trp Val Met Ala Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 Arg Arg His Thr His Gly Ile Arg Pro Lys Gly Asp Gly Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Asp Pro Trp Arg Arg His Arg Leu Lys Lys 65 70 75 80 Arg Asn Asn 45 33 PRT Conus emaciatus PEPTIDE (1)..(33) Xaa at residues 7, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residues 15 and 23 may be Trp (D or L) or bromo-Trp (D or L) 45 His Thr His Gly Ile Arg Xaa Lys Gly Asp Gly Ile Cys Ile Xaa Lys 1 5 10 15 Val Cys Xaa Xaa Asp Xaa Xaa Arg Arg His Arg Leu Lys Lys Arg Asn 20 25 30 Asn 46 412 DNA Conus circumcisus CDS (1)..(240) 46 atg cag acg gcc tac tgg gtg atg gtg atg atg gtg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Val Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa tcg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Ser Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca cac atc tta acc cca cag cat atc ttg caa agt ctg act tcc 144 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 cgt ctt cgt tct gac agc agt ggt cag aaa gga gca caa ata tgc atc 192 Arg Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala Gln Ile Cys Ile 50 55 60 tgg aag gta tgt cca cta tcc cca tgg aga cga cca caa gga aaa aga 240 Trp Lys Val Cys Pro Leu Ser Pro Trp Arg Arg Pro Gln Gly Lys Arg 65 70 75 80 tgaatgacgt cagacaaccg ctacaactgt agtacgacat cgttgatacg acttcagcaa 300 atattttaac atcactgtgg ttgtgaagaa atcagttgct ttaaaagatt ggatttttcc 360 ttgtttaaga gttgtactga tatcagctct gccctgtgaa ataaagctga tg 412 47 80 PRT Conus circumcisus 47 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Val Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Ser Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Leu Ser Pro Trp Arg Arg Pro Gln Gly Lys Arg 65 70 75 80 48 28 PRT Conus circumcisus PEPTIDE (1)..(28) Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 23 and 27 may be Pro or hydroxy-Pro 48 Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Leu Ser Xaa Xaa Arg Arg Xaa Gln 20 25 49 410 DNA Conus betulinus CDS (1)..(207) 49 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tcc gaa ggt ggt aaa ctg aac gat gta att cgg gct ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Ala Leu 20 25 30 gcg cca gac gac gta acc cca cag ttt atc ttg cga agt ctg att tcc 144 Ala Pro Asp Asp Val Thr Pro Gln Phe Ile Leu Arg Ser Leu Ile Ser 35 40 45 cgt cgt cgt tct gac agc gat gtt cgg gag gta ccc gta tgt tcc tgg 192 Arg Arg Arg Ser Asp Ser Asp Val Arg Glu Val Pro Val Cys Ser Trp 50 55 60 aag ata tgt cca cca tagccataga gacgacatga tcttaaggaa aaagagaaat 247 Lys Ile Cys Pro Pro 65 gacgtcagac aaccgccaca actgtagtac ggcatcgtta atacgacttc agcaaatgtt 307 ttaacatcac tgtggttgtg aagaaatcag ctgctttaaa agattggatt tttccttaag 367 agttgcactg atgtcagttc tgccctgtga aataaagctg atg 410 50 69 PRT Conus betulinus 50 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Ala Leu 20 25 30 Ala Pro Asp Asp Val Thr Pro Gln Phe Ile Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Arg Ser Asp Ser Asp Val Arg Glu Val Pro Val Cys Ser Trp 50 55 60 Lys Ile Cys Pro Pro 65 51 19 PRT Conus betulinus PEPTIDE (1)..(19) Xaa at residue 8 may be Glu or Gla; Xaa at residues 10, 18 and 19 may be Pro or hydroxy-Pro; Xaa at residue 14 may be Trp (D or L) or bromo-Trp (D or L) 51 Arg Ser Asp Ser Asp Val Arg Xaa Val Xaa Val Cys Ser Xaa Lys Ile 1 5 10 15 Cys Xaa Xaa 52 423 DNA Conus aurisiacus CDS (1)..(249) 52 atg cag acg gcc tac tgg gtg atg gcg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Ala Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca gat gac tta acc cca cag ctt gtt ttg caa agt ctg gat tcc 144 Val Pro Asp Asp Leu Thr Pro Gln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 cgt cgt cat act cac ggc att cgt ccg aag gga gac ggc ata tgt atc 192 Arg Arg His Thr His Gly Ile Arg Pro Lys Gly Asp Gly Ile Cys Ile 50 55 60 tgg aag gta tgt cca cca gac cca tgg aga cga cat cat ctt aag aaa 240 Trp Lys Val Cys Pro Pro Asp Pro Trp Arg Arg His His Leu Lys Lys 65 70 75 80 aga aac aat tgacgtcaga caaccgccac aacttgagta cgacatcgtt 289 Arg Asn Asn aatacgactt cagcaaatat gaaattttca gcatcactgt ggttgtcaag aaatcagttg 349 ctttaaaaga ttggatttgt ccttgtttaa gagttgtact gatgtcagct ctgccctatg 409 aaataaagct gatg 423 53 83 PRT Conus aurisiacus 53 Met Gln Thr Ala Tyr Trp Val Met Ala Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 Arg Arg His Thr His Gly Ile Arg Pro Lys Gly Asp Gly Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Asp Pro Trp Arg Arg His His Leu Lys Lys 65 70 75 80 Arg Asn Asn 54 33 PRT Conus aurisiacus PEPTIDE (1)..(33) Xaa at residues 7, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residues 1 and 24 may be Trp (D or L) or bromo-Trp (D or L) 54 His Thr His Gly Ile Arg Xaa Lys Gly Asp Gly Ile Cys Ile Xaa Lys 1 5 10 15 Val Cys Xaa Xaa Asp Xaa Xaa Arg Arg His His Leu Lys Lys Arg Asn 20 25 30 Asn 55 439 DNA Conus aurisiacus CDS (1)..(249) 55 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att tgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Trp Gly Leu 20 25 30 gtg cca cac atc tta acc cca cag cat atc ttg caa agc ctg act tcc 144 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 cgt ctt cat tct gac agc agt gat cag aaa gga ggc atg aac gca tgg 192 Arg Leu His Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Trp 50 55 60 aca gga gca gga gca caa ata tgc atc tgg aag gta tgt cca cca ccc 240 Thr Gly Ala Gly Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Pro 65 70 75 80 cca tgg aga tgaacacaag gaaaaagatg aatgacgtca gacaaccgcc 289 Pro Trp Arg acaactgtag tacgacatcg ttgatacgac ttcagcaaat attttaacat cactgtggtt 349 gtgaagaaat cagttgcttt aaaagattgg atttttcctt gtttaagagt tgtactgata 409 tcagctctgc cctgtgaagt aaagctgatg 439 56 83 PRT Conus aurisiacus 56 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Trp Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Leu His Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Trp 50 55 60 Thr Gly Ala Gly Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Pro 65 70 75 80 Pro Trp Arg 57 34 PRT Conus aurisiacus PEPTIDE (1)..(34) Xaa at residues 15, 25 and 33 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 29, 30, 31 and 32 may be Pro or hydroxy-Pro 57 Leu His Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Xaa Thr 1 5 10 15 Gly Ala Gly Ala Gln Ile Cys Ile Xaa Lys Val Cys Xaa Xaa Xaa Xaa 20 25 30 Xaa Arg 58 412 DNA Conus aurisiacus CDS (1)..(222) 58 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att tgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Trp Gly Leu 20 25 30 gtg cca cac atc tta acc cca cag cat atc ttg caa agc ctg act tcc 144 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 cgt ctt cat tct gac agc agt gat cag aaa gga gca caa ata tgc atc 192 Arg Leu His Ser Asp Ser Ser Asp Gln Lys Gly Ala Gln Ile Cys Ile 50 55 60 tgg aag gta tgt cca cca ccc cca tgg aga tgaacacaag gaaaaagatg 242 Trp Lys Val Cys Pro Pro Pro Pro Trp Arg 65 70 aatgacgtca gacaaccgcc acaactgtag tacgacatcg ttgatacgac ttcagcaaat 302 attttaacat cactgtggtt gtgaagaaat cagttgcttt aaaagattgg atttttcctt 362 gtttaggagt tgtattgata tcagctctgc cctgtgaaat aaagctgatg 412 59 74 PRT Conus aurisiacus 59 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Trp Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Leu His Ser Asp Ser Ser Asp Gln Lys Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Pro Pro Trp Arg 65 70 60 25 PRT Conus aurisiacus PEPTIDE (1)..(25) Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 21, 22 and 23 may be Pro or hydroxy-Pro 60 Leu His Ser Asp Ser Ser Asp Gln Lys Gly Ala Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Xaa Xaa Xaa Arg 20 25 61 439 DNA Conus aurisiacus CDS (1)..(267) 61 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg ttt gaa ggt ggt aaa ttg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Phe Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca cac atc tta acc cca cag cat atc ttg caa agc ctg act tcc 144 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 cgt ctt cgt tct gac agc agt gat cag aaa gga ggc atg aac gca tcg 192 Arg Leu Arg Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Ser 50 55 60 aca gga gca gga gca caa ata tgc atc tgg aag gta tgt cca cca tcc 240 Thr Gly Ala Gly Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Ser 65 70 75 80 cca tgg aga cga aca caa gga aaa aga tgaatgacgt cagacaaccg 287 Pro Trp Arg Arg Thr Gln Gly Lys Arg 85 ccacaactgt agtacgacat cgttgatacg acttcagcaa atattttaac atcactgtgg 347 ttgtgaagaa atcagttgct ttaaaagatt ggatttttcc ttgtttaaga gttgtactga 407 tatcagctct gcactgtgaa ataaagctga tg 439 62 89 PRT Conus aurisiacus 62 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Phe Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Leu Arg Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Ser 50 55 60 Thr Gly Ala Gly Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Ser 65 70 75 80 Pro Trp Arg Arg Thr Gln Gly Lys Arg 85 63 37 PRT Conus aurisiacus PEPTIDE (1)..(37) Xaa at residues 25 and 33 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 29, 30 and 32 may be Pro or hydroxy-Pro 63 Leu Arg Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Ser Thr 1 5 10 15 Gly Ala Gly Ala Gln Ile Cys Ile Xaa Lys Val Cys Xaa Xaa Ser Xaa 20 25 30 Xaa Arg Arg Thr Gln 35 64 412 DNA Conus achatinus CDS (1)..(240) 64 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca cac atc tta acc cca cag cat atc ttg caa agt ctg act tcc 144 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 cgt ctt cgt tct gac aac ggt ggt tcg agt gga gca caa ata tgc atc 192 Arg Leu Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 tgg aag gtg tgt cca cca tcc cca tgg aga cga cca caa gga aaa aga 240 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Pro Gln Gly Lys Arg 65 70 75 80 tgaacggcgt cagacaaccg ccacaactgt agtgggacat cgttgatacg acttcagcaa 300 atattttaac atcactgtgg ttgtgaagaa atcagttgct ttaaaagatt ggatttttcc 360 ttgtttaaga gttgtactga tatcagctct gccctatgaa ataaagctga tg 412 65 80 PRT Conus achatinus 65 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Leu Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Pro Gln Gly Lys Arg 65 70 75 80 66 28 PRT Conus achatinus PEPTIDE (1)..(28) Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 21, 23 and 27 may be Pro or hydroxy-Pro 66 Leu Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Ser Xaa Xaa Arg Arg Xaa Gln 20 25 67 399 DNA Conus purpurascens CDS (1)..(213) 67 atg cag acg gcc tac tgg gtg atg gtg atg acg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Thr Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt gga aaa ctg aac gat gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca gac gac tta gcc cta cag ctt atc ttg caa agt ccg gtt ttc 144 Val Pro Asp Asp Leu Ala Leu Gln Leu Ile Leu Gln Ser Pro Val Phe 35 40 45 cgt cgt caa tct gaa gag gaa aaa ata tgc ctc tgg aag ata tgt cca 192 Arg Arg Gln Ser Glu Glu Glu Lys Ile Cys Leu Trp Lys Ile Cys Pro 50 55 60 cca ccc cca tgg aga cga tca taaggaaaaa aaaatgaatg acgtcagaca 243 Pro Pro Pro Trp Arg Arg Ser 65 70 accaccacaa ctgtaatacg acatcgttaa tacgacttca gcaaacattt taacatcact 303 gtggttgtga agaaatcagt tgctttagaa gcttggattt ttccttgttt aagagttgta 363 ctgatatcag ctctgcccta tgaaataaag ctgatg 399 68 71 PRT Conus purpurascens 68 Met Gln Thr Ala Tyr Trp Val Met Val Met Thr Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Ala Leu Gln Leu Ile Leu Gln Ser Pro Val Phe 35 40 45 Arg Arg Gln Ser Glu Glu Glu Lys Ile Cys Leu Trp Lys Ile Cys Pro 50 55 60 Pro Pro Pro Trp Arg Arg Ser 65 70 69 21 PRT Conus purpurascens PEPTIDE (1)..(21) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residues 3,4 adn 5 may be Glu or Gla; Xaa at residues 10 and 18 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 14, 15, 16 and 17 may be Pro or hydroxy-Pro 69 Xaa Ser Xaa Xaa Xaa Lys Ile Cys Leu Xaa Lys Ile Cys Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Arg Arg Ser 20 70 398 DNA Conus purpurascens CDS (1)..(213) 70 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gag ggt aga aaa ccg aac gat gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Arg Lys Pro Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca gat gac tta gcc cta cag ctt atc ttg caa agt cag gtt tcc 144 Val Pro Asp Asp Leu Ala Leu Gln Leu Ile Leu Gln Ser Gln Val Ser 35 40 45 cgt cgt gaa tct aat ggg gtg gaa ata tgc atg tgg aag gta tgt cca 192 Arg Arg Glu Ser Asn Gly Val Glu Ile Cys Met Trp Lys Val Cys Pro 50 55 60 cca tcc cca tgg aga cga tca taaggaaaaa aaatgaatga cgtcagacaa 243 Pro Ser Pro Trp Arg Arg Ser 65 70 ccaccacaac tgtaatacga catcgttaat acgacttcag caaacatttt aacatcactg 303 tggttgtgaa gaaatcagtt gctttaaaag attggatttt tccttgttta agagttgtac 363 tgatatcagc tctgccctat gaaataaagc tgatg 398 71 71 PRT Conus purpurascens 71 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Arg Lys Pro Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Ala Leu Gln Leu Ile Leu Gln Ser Gln Val Ser 35 40 45 Arg Arg Glu Ser Asn Gly Val Glu Ile Cys Met Trp Lys Val Cys Pro 50 55 60 Pro Ser Pro Trp Arg Arg Ser 65 70 72 21 PRT Conus purpurascens PEPTIDE (1)..(21) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 6 may be Glu or Gla; Xaa at residues 10 and 18 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 14, 15 and 17 may be Pro or hydroxy-Pro 72 Xaa Ser Asn Gly Val Xaa Ile Cys Met Xaa Lys Val Cys Xaa Xaa Ser 1 5 10 15 Xaa Xaa Arg Arg Ser 20 73 409 DNA Conus stercusmuscarum CDS (1)..(213) 73 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ttg acc gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Thr Asp Val Ile Arg Gly Leu 20 25 30 gtg cca cac atc tta acc cca cag cat atc ttg caa agt atg act tcc 144 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Met Thr Ser 35 40 45 cgt ctt ggt att ggc agc agt gat caa aat gca caa ata tgc atc tgg 192 Arg Leu Gly Ile Gly Ser Ser Asp Gln Asn Ala Gln Ile Cys Ile Trp 50 55 60 aag gta tgt cca cca tcc cca tagagacgac cataaggaaa aagatgaatg 243 Lys Val Cys Pro Pro Ser Pro 65 70 acgtcagaca accgccacaa ctgtagtacg acatcgttga tacgacttca gcaaatattt 303 taacatcact gtggttgtga agaaatcagt tgctttaaaa gattggattt ttccttgttt 363 aagagttgta ctgatatcag ctctgccctg tgaaataaag ctgatg 409 74 71 PRT Conus stercusmuscarum 74 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Thr Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Met Thr Ser 35 40 45 Arg Leu Gly Ile Gly Ser Ser Asp Gln Asn Ala Gln Ile Cys Ile Trp 50 55 60 Lys Val Cys Pro Pro Ser Pro 65 70 75 22 PRT Conus stercusmuscarum PEPTIDE (1)..(22) Xaa at residue 15 may be Trp or bromo-Trp; Xaa at residue 19, 20 and 22 may be Pro or hydroxy-Pro 75 Leu Gly Ile Gly Ser Ser Asp Gln Asn Ala Gln Ile Cys Ile Xaa Lys 1 5 10 15 Val Cys Xaa Xaa Ser Xaa 20 76 433 DNA Conus baileyi CDS (1)..(216) 76 atg cag acg gcc tac tgg gtg atg gtg atg ata atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Ile Met Val Trp Ile Thr 1 5 10 15 gtc cct ctg tct gaa ggt ggt aaa ttg aac gac ata att cgg ggt ttg 96 Val Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Ile Ile Arg Gly Leu 20 25 30 ttg cca gac aac ttc ccc cca cag ctt acc ttg cat cgt ctg gtt tcc 144 Leu Pro Asp Asn Phe Pro Pro Gln Leu Thr Leu His Arg Leu Val Ser 35 40 45 cgt cgt cat tct gac agc att att ctg agg ggc tta tgt atc tgg aag 192 Arg Arg His Ser Asp Ser Ile Ile Leu Arg Gly Leu Cys Ile Trp Lys 50 55 60 gtg tgt gaa cct ccg cca caa aga tgatctggtc caaagccaaa aaacgaatga 246 Val Cys Glu Pro Pro Pro Gln Arg 65 70 tgtcagacaa ccgccacagc tttagtacga catggttaat acgacttcag caaatatttc 306 aacatcactg tggttgtgaa gaaatcagtt actttaaaag attggaatga tgtcagctgt 366 gcactatcaa ataaagttga tgtgacaaaa aaaaaaaaaa aaaaagtact ctgcgttgtt 426 actcgag 433 77 72 PRT Conus baileyi 77 Met Gln Thr Ala Tyr Trp Val Met Val Met Ile Met Val Trp Ile Thr 1 5 10 15 Val Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Ile Ile Arg Gly Leu 20 25 30 Leu Pro Asp Asn Phe Pro Pro Gln Leu Thr Leu His Arg Leu Val Ser 35 40 45 Arg Arg His Ser Asp Ser Ile Ile Leu Arg Gly Leu Cys Ile Trp Lys 50 55 60 Val Cys Glu Pro Pro Pro Gln Arg 65 70 78 22 PRT Conus baileyi PEPTIDE (1)..(22) Xaa at residue 13 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 17 may be Glu or Gla; Xaa at residues 18, 19 and 20 may be Pro or hydroxy-Pro 78 His Ser Asp Ser Ile Ile Leu Arg Gly Leu Cys Ile Xaa Lys Val Cys 1 5 10 15 Xaa Xaa Xaa Xaa Gln Arg 20 79 413 DNA Conus bocki CDS (1)..(270) 79 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa agt gat aaa ctg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Ser Asp Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca gac aac tta acc cca cag ctt atc ttg cga agt ctg att tcc 144 Val Pro Asp Asn Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile Ser 35 40 45 cgt cgt cgt tct gac aag gat gat ccg gga gga caa gaa tgt tac tgg 192 Arg Arg Arg Ser Asp Lys Asp Asp Pro Gly Gly Gln Glu Cys Tyr Trp 50 55 60 aac gta tgt gca cca aac cag gga gac cac atg atc tta aga aaa aag 240 Asn Val Cys Ala Pro Asn Gln Gly Asp His Met Ile Leu Arg Lys Lys 65 70 75 80 atg aat gac gac aga caa ccg cca caa ctg taatacgaca tcgttaatac 290 Met Asn Asp Asp Arg Gln Pro Pro Gln Leu 85 90 gacttcagca aatattttaa catcactgtg gttgtgaaga aatcagttgc tttaaaagat 350 tggatttttc cgtgtttaag agctgtactg atatctgctc tgccctgtga aataaagctg 410 atg 413 80 90 PRT Conus bocki 80 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Ser Asp Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asn Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Arg Ser Asp Lys Asp Asp Pro Gly Gly Gln Glu Cys Tyr Trp 50 55 60 Asn Val Cys Ala Pro Asn Gln Gly Asp His Met Ile Leu Arg Lys Lys 65 70 75 80 Met Asn Asp Asp Arg Gln Pro Pro Gln Leu 85 90 81 40 PRT Conus bocki PEPTIDE (1)..(40) Xaa at residues 7, 19, 37, 38 may be Pro or hydroxy-Pro; Xaa at residue 11 may be Glu or Gla; Xaa at residue 14 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 13 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 81 Arg Ser Asp Lys Asp Asp Xaa Gly Gly Gln Xaa Cys Xaa Xaa Asn Val 1 5 10 15 Cys Ala Xaa Asn Gln Gly Asp His Met Ile Leu Arg Lys Lys Met Asn 20 25 30 Asp Asp Arg Gln Xaa Xaa Gln Leu 35 40 82 496 DNA Conus chaldaeus CDS (21)..(260) 82 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg atg ggg atg 53 Met Gln Thr Ala Tyr Trp Val Met Met Gly Met 1 5 10 atg atg gtg tgg att aca gcc cct ctg tct gga ggt ggt aaa ctg aac 101 Met Met Val Trp Ile Thr Ala Pro Leu Ser Gly Gly Gly Lys Leu Asn 15 20 25 gac gta att cgg ggt ttg gtg cca gac gac tta acc cta cag cgt atg 149 Asp Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met 30 35 40 ttc gaa act ccg gtt tcc cat cgt ctt tct gag ggc aga aat tcg acg 197 Phe Glu Thr Pro Val Ser His Arg Leu Ser Glu Gly Arg Asn Ser Thr 45 50 55 gta cac ata tgt acg tgg aag gta tgt cca cct ccc cca tgg aga cga 245 Val His Ile Cys Thr Trp Lys Val Cys Pro Pro Pro Pro Trp Arg Arg 60 65 70 75 cca cat gga caa aga tgaatgacgt cagacaacct ccacaactgt agtacgacat 300 Pro His Gly Gln Arg 80 cgttaacacg acgtcagcta atcttttaac atcactgtgg ctgtgaagaa ctcggttgct 360 ttaaaagatt ggatttttcc ttgtttaaga gttgtgctga tatgaactct gcactacgaa 420 ataaagctga tgtgacaaac aaaaaaaaga aaaaaaaaag tactctgcgt tgttactcga 480 gcttaagggc gaattc 496 83 80 PRT Conus chaldaeus 83 Met Gln Thr Ala Tyr Trp Val Met Met Gly Met Met Met Val Trp Ile 1 5 10 15 Thr Ala Pro Leu Ser Gly Gly Gly Lys Leu Asn Asp Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met Phe Glu Thr Pro Val 35 40 45 Ser His Arg Leu Ser Glu Gly Arg Asn Ser Thr Val His Ile Cys Thr 50 55 60 Trp Lys Val Cys Pro Pro Pro Pro Trp Arg Arg Pro His Gly Gln Arg 65 70 75 80 84 29 PRT Conus chaldaeus PEPTIDE (1)..(29) Xaa at residue 3 may be Glu or Gla; Xaa at residues 14 and 22 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 18, 19, 20, 21 and 25 may be Pro or hydroxy-Pro 84 Leu Ser Xaa Gly Arg Asn Ser Thr Val His Ile Cys Thr Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Xaa Xaa Xaa Arg Arg Xaa His Gly Gln Arg 20 25 85 499 DNA Conus chaldaeus CDS (21)..(260) 85 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg atg ggg atg 53 Met Gln Thr Ala Tyr Trp Val Met Met Gly Met 1 5 10 atg atg gtg tgg att aca gcc cct ctg tct gga ggt ggt aaa ctg aac 101 Met Met Val Trp Ile Thr Ala Pro Leu Ser Gly Gly Gly Lys Leu Asn 15 20 25 gac gta att cgg ggt ttg gtg cca gac gac tta acc cta cag cgt atg 149 Asp Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met 30 35 40 ttc gaa act ccg gtt tcc cat cgt ctt tct gag ggc aga aat tcg acg 197 Phe Glu Thr Pro Val Ser His Arg Leu Ser Glu Gly Arg Asn Ser Thr 45 50 55 gta cac ata tgt atg tgg aag gta tgt cca cct ccc cca tgg aga cga 245 Val His Ile Cys Met Trp Lys Val Cys Pro Pro Pro Pro Trp Arg Arg 60 65 70 75 cca cat gga caa aga tgaatgacgt cagacaacct ccacaactgt agtacgacat 300 Pro His Gly Gln Arg 80 cgttaacacg acgtcagcta atcttttaac atcactgtgg ttgtgaagaa atcggttgct 360 ttaaaagatt ggatttttcc ttgtttaaga gttgtgctga tatgaactct gcactacgaa 420 ataaagctga tgtgacaaac ggaaaaaaaa aaaaaaaaaa aagtactctg cgttgttact 480 cgagcttaag ggcgaattc 499 86 80 PRT Conus chaldaeus 86 Met Gln Thr Ala Tyr Trp Val Met Met Gly Met Met Met Val Trp Ile 1 5 10 15 Thr Ala Pro Leu Ser Gly Gly Gly Lys Leu Asn Asp Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met Phe Glu Thr Pro Val 35 40 45 Ser His Arg Leu Ser Glu Gly Arg Asn Ser Thr Val His Ile Cys Met 50 55 60 Trp Lys Val Cys Pro Pro Pro Pro Trp Arg Arg Pro His Gly Gln Arg 65 70 75 80 87 29 PRT Conus chaldaeus PEPTIDE (1)..(29) Xaa at residue 3 may be Glu or Gla; Xaa at residues 14 and 22 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 18, 19, 20, 21 and 25 may be Pro or hydroxy-Pro 87 Leu Ser Xaa Gly Arg Asn Ser Thr Val His Ile Cys Met Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Xaa Xaa Xaa Arg Arg Xaa His Gly Gln Arg 20 25 88 490 DNA Conus cinereus CDS (21)..(305) 88 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 ttg gtg tgg att aca gcc cct ctg cct gag ggt ggt aaa ccg aag cac 101 Leu Val Trp Ile Thr Ala Pro Leu Pro Glu Gly Gly Lys Pro Lys His 15 20 25 gta att cgg ggt ttg gta cca gac gac tta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Gln His Ile Leu 30 35 40 cga agt ttg att tcc cgt cgt tca tct ggc tgc agt gtt tcg ttg ggc 197 Arg Ser Leu Ile Ser Arg Arg Ser Ser Gly Cys Ser Val Ser Leu Gly 45 50 55 ttc aaa tgc ttc tgg aag agc tgt aca gta atc cca gtg aga cca ttt 245 Phe Lys Cys Phe Trp Lys Ser Cys Thr Val Ile Pro Val Arg Pro Phe 60 65 70 75 gta tct ctg gaa gaa gaa aat gaa tgc cag aaa gtc caa ata agt gca 293 Val Ser Leu Glu Glu Glu Asn Glu Cys Gln Lys Val Gln Ile Ser Ala 80 85 90 gta tgg ggt cct tgatacgact tcagcaagga tcactgtggt tgtgaagaaa 345 Val Trp Gly Pro 95 tcagttgctt taaaagattt gatttttcct tgtttaagag ttgtactgat atcagctctg 405 tactatgaaa taaagctgat gtgacaaaca aaaaaaaaaa aaaaaaaagt actctgcgtt 465 gttactcgag cttaagggcg aattc 490 89 95 PRT Conus cinereus 89 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Leu Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Pro Glu Gly Gly Lys Pro Lys His Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln His Ile Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Ser Ser Gly Cys Ser Val Ser Leu Gly Phe Lys Cys Phe Trp 50 55 60 Lys Ser Cys Thr Val Ile Pro Val Arg Pro Phe Val Ser Leu Glu Glu 65 70 75 80 Glu Asn Glu Cys Gln Lys Val Gln Ile Ser Ala Val Trp Gly Pro 85 90 95 90 45 PRT Conus cinereus PEPTIDE (1)..(45) Xaa at residues 14 and 43 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 21, 24 and 45 may be Pro or hydroxy-Pro; Xaa at residues 29, 30, 31 adn 33 may be Glu or Gla 90 Ser Ser Gly Cys Ser Val Ser Leu Gly Phe Lys Cys Phe Xaa Lys Ser 1 5 10 15 Cys Thr Val Ile Xaa Val Arg Xaa Phe Val Ser Leu Xaa Xaa Xaa Asn 20 25 30 Xaa Cys Gln Lys Val Gln Ile Ser Ala Val Xaa Gly Xaa 35 40 45 91 497 DNA Conus cinereus CDS (21)..(263) 91 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 gtg gtg gtg tgg att aca gcc cct ctg cct gaa ggt ggt aaa ccg gag 101 Val Val Val Trp Ile Thr Ala Pro Leu Pro Glu Gly Gly Lys Pro Glu 15 20 25 cac gta att cgg ggt ttg gtg cca gac gac tta acc cca cag ctt atc 149 His Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile 30 35 40 ttg cga agt ctg att tcc cgt cgt agt tct gac ggc aag gca aaa aga 197 Leu Arg Ser Leu Ile Ser Arg Arg Ser Ser Asp Gly Lys Ala Lys Arg 45 50 55 aat tgt ttc tgg aag gca tgt gta cca gaa caa tgg aga caa cgt gat 245 Asn Cys Phe Trp Lys Ala Cys Val Pro Glu Gln Trp Arg Gln Arg Asp 60 65 70 75 ctt aag gaa aaa gat gaa tgatgtcaga caaccgccat cactgtagta 293 Leu Lys Glu Lys Asp Glu 80 tgacatcgtt aatacgactt aagcaaatat tttaacatca ctgtggatct gaagaaatca 353 gttgctttaa aagattggat ttttcctcgt ttaagagttg tactgatgtc agctctgcac 413 tgtgaaataa agctgatgtg acaaacgaaa aaaaaaaaaa aaaaaaagta ctctgcgttg 473 ttactcgagc ttaagggcga attc 497 92 81 PRT Conus cinereus 92 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Val Val Val Trp Ile 1 5 10 15 Thr Ala Pro Leu Pro Glu Gly Gly Lys Pro Glu His Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile 35 40 45 Ser Arg Arg Ser Ser Asp Gly Lys Ala Lys Arg Asn Cys Phe Trp Lys 50 55 60 Ala Cys Val Pro Glu Gln Trp Arg Gln Arg Asp Leu Lys Glu Lys Asp 65 70 75 80 Glu 93 30 PRT Conus cinereus PEPTIDE (1)..(30) Xaa at residues 12 and 20 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 17 may be Pro or hydroxy-Pro; Xaa at residues 18, 27 and 30 may be Glu or Gla 93 Ser Ser Asp Gly Lys Ala Lys Arg Asn Cys Phe Xaa Lys Ala Cys Val 1 5 10 15 Xaa Xaa Gln Xaa Arg Gln Arg Asp Leu Lys Xaa Lys Asp Xaa 20 25 30 94 496 DNA Conus cinereus CDS (21)..(263) 94 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg gtg tgg att aca gcc cct ctg cct gaa ggt ggt aaa ccg aag 101 Met Val Val Trp Ile Thr Ala Pro Leu Pro Glu Gly Gly Lys Pro Lys 15 20 25 cac gta att cgg ggt ttg gtg cca gac gac tta acc cca cag ctt atc 149 His Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile 30 35 40 ttg cga agt ctg att tcc cgt cgt agt tct gac ggc aag gca aaa aga 197 Leu Arg Ser Leu Ile Ser Arg Arg Ser Ser Asp Gly Lys Ala Lys Arg 45 50 55 aat tgt ttc tgg aag gca tgt gta cca gaa caa tgg aga caa cgt gat 245 Asn Cys Phe Trp Lys Ala Cys Val Pro Glu Gln Trp Arg Gln Arg Asp 60 65 70 75 cct aag gaa aaa gat gaa tgatgtcaga caaccgccat cactgtagta 293 Pro Lys Glu Lys Asp Glu 80 tgacatcgtt aatacgactt aagcaaatat tttaacatca ctgtggatct gaagaaatca 353 gttgctttaa aagattggat ttttcctcgt ttaagagttg tactgatgtc agctctgcac 413 tgtgaaataa agctgacgtg acaagcaaaa aaaaaaaaaa aaaaaagtac tctgcgttgt 473 tactcgagct taagggcgaa ttc 496 95 81 PRT Conus cinereus 95 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val Trp Ile 1 5 10 15 Thr Ala Pro Leu Pro Glu Gly Gly Lys Pro Lys His Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile 35 40 45 Ser Arg Arg Ser Ser Asp Gly Lys Ala Lys Arg Asn Cys Phe Trp Lys 50 55 60 Ala Cys Val Pro Glu Gln Trp Arg Gln Arg Asp Pro Lys Glu Lys Asp 65 70 75 80 Glu 96 30 PRT Conus cinereus PEPTIDE (1)..(30) Xaa at residues 12 and 20 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 17 and 25 may be Pro or hydroxy-Pro; Xaa at residues 18, 27 and 30 may be Glu or Gla 96 Ser Ser Asp Gly Lys Ala Lys Arg Asn Cys Phe Xaa Lys Ala Cys Val 1 5 10 15 Xaa Xaa Gln Xaa Arg Gln Arg Asp Xaa Lys Xaa Lys Asp Xaa 20 25 30 97 493 DNA Conus cinereus CDS (21)..(260) 97 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg ata atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Ile Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ccg aag cac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Pro Lys His 15 20 25 gta att cgg ggt ttg gtg cca gtc gac tta acc cca cag ctt atc ttg 149 Val Ile Arg Gly Leu Val Pro Val Asp Leu Thr Pro Gln Leu Ile Leu 30 35 40 cga agt ctg att tcc cgt cgt agt tct gac ggc aag gca aaa aaa caa 197 Arg Ser Leu Ile Ser Arg Arg Ser Ser Asp Gly Lys Ala Lys Lys Gln 45 50 55 tgt gcc tgg aag aca tgt gta cca acc caa tgg aga cga cgt gat ctt 245 Cys Ala Trp Lys Thr Cys Val Pro Thr Gln Trp Arg Arg Arg Asp Leu 60 65 70 75 aag gaa aaa gat gaa tgatgtcaga caaccgccat cactgtagta tgacatcgtt 300 Lys Glu Lys Asp Glu 80 aatacgactt aagcaaatat tttaacatca ctgtggttct gaagaaatca gttgctttaa 360 aagattggat ttttccttgt ttaagagttg tactgatatc agctctgcac tgtgaaataa 420 agctgatgtg acaaacaaaa aaaaaaaaaa aaaaaagtac tctgcgttgt tactcgagct 480 taagggcgaa ttc 493 98 80 PRT Conus cinereus 98 Met Gln Thr Ala Tyr Trp Val Met Val Ile Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Pro Lys His Val Ile Arg Gly Leu 20 25 30 Val Pro Val Asp Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Ser Ser Asp Gly Lys Ala Lys Lys Gln Cys Ala Trp Lys Thr 50 55 60 Cys Val Pro Thr Gln Trp Arg Arg Arg Asp Leu Lys Glu Lys Asp Glu 65 70 75 80 99 30 PRT Conus cinereus PEPTIDE (1)..(30) Xaa at residues 12 and 20 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 17 may be Pro or hydroxy-Pro; Xaa at residues 27 and 30 may be Glu or Gla 99 Ser Ser Asp Gly Lys Ala Lys Lys Gln Cys Ala Xaa Lys Thr Cys Val 1 5 10 15 Xaa Thr Gln Xaa Arg Arg Arg Asp Leu Lys Xaa Lys Asp Xaa 20 25 30 100 496 DNA Conus circumcisus CDS (21)..(263) 100 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca cac atc tta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val Pro His Ile Leu Thr Pro Gln His Ile Leu 30 35 40 caa ggt ctg act tcc cgt ctt cgt tct gac agc agt ggt cag aaa gga 197 Gln Gly Leu Thr Ser Arg Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly 45 50 55 gca caa ata tgc atc tgg aag gta tgt cca cta tcc cca tgg aga cga 245 Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Leu Ser Pro Trp Arg Arg 60 65 70 75 cca caa gga aaa gat gaa tgacgtcaga caaccgctac aactgtagta 293 Pro Gln Gly Lys Asp Glu 80 cgacatcgtt gatacgactt cagcaaatat tttaacatca ctgtggttgt gaagaaatca 353 gctgctttaa aagattggat ttttccttgt ttaagagttg tactgatatc agctctgcac 413 tatgaaataa agctgatgtg acaaacaaaa aaaaaaaaaa aaaaaagtac tctgcgttgt 473 tactcgagct taagggcgaa ttc 496 101 81 PRT Conus circumcisus 101 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Gly Leu Thr Ser 35 40 45 Arg Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Leu Ser Pro Trp Arg Arg Pro Gln Gly Lys Asp 65 70 75 80 Glu 102 32 PRT Conus circumcisus PEPTIDE (1)..(32) Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 23 and 27 may be Pro or hydroxy-Pro; Xaa at residue 32 may be Glu or Gla 102 Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Leu Ser Xaa Xaa Arg Arg Xaa Gln Gly Lys Asp Xaa 20 25 30 103 496 DNA Conus consors CDS (21)..(242) 103 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca cac ttc tta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val Pro His Phe Leu Thr Pro Gln His Ile Leu 30 35 40 caa agt ctg act tcc cgt aat ggt tct ggc agc agt aat cag aaa gaa 197 Gln Ser Leu Thr Ser Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu 45 50 55 gca caa cta tgc atc tgg aag gta tgt cca cca acc cca tgg aga 242 Ala Gln Leu Cys Ile Trp Lys Val Cys Pro Pro Thr Pro Trp Arg 60 65 70 tgaccacaag gaaaaagatg aacggcgtca gacaaccgcc acaactgtag tgggacatcg 302 ttgatacgac ttcagcaaat attttaacat cactgtggtt gtgaagaaat cagttgtttt 362 aaaagattgg atttttcctt gtttaagagt tgtactgata tcagctctgc actatgaaat 422 aaagctgatg tgacaagcaa aaaaaaaaaa aaaaaaagta ctctgcgttg ttactcgagc 482 ttaagggcga attc 496 104 74 PRT Conus consors 104 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Phe Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu Ala Gln Leu Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Thr Pro Trp Arg 65 70 105 25 PRT Conus consors PEPTIDE (1)..(25) Xaa at residue 10 may be Glu or Gla ; Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 21 and 23 may be Pro or hydroxy-Pro 105 Asn Gly Ser Gly Ser Ser Asn Gln Lys Xaa Ala Gln Leu Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Thr Xaa Xaa Arg 20 25 106 496 DNA Conus consors CDS (21)..(242) 106 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ctg aac ggc 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Gly 15 20 25 gta att cgg ggt ttg gtg tca cac atc tta atc cca cag cat acc ttg 149 Val Ile Arg Gly Leu Val Ser His Ile Leu Ile Pro Gln His Thr Leu 30 35 40 cga agt ctg act tcc cgt gat cgt tct gac aac ggt ggt tcg agt gga 197 Arg Ser Leu Thr Ser Arg Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly 45 50 55 gca caa ata tgc atc tgg aag gta tgt cca cca tcc cca tgg aaa 242 Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Ser Pro Trp Lys 60 65 70 tgaccacaag gaaaaagatg aacggcgtca gacaaccacc acaactgtag tgggacatcg 302 ttgatacgac ttcagcaaat attttaacat cactgtggtc gtgaagaaat cagttgcttt 362 aaaagattgg atttttcctt gtttaagagt tgtactgata tcagctctgc actatgaaat 422 aaagctgatg tgacaaacaa aaaaaaaaaa aaaaaaagta ctctgcgttg ttactcgagc 482 ttaagggcga attc 496 107 74 PRT Conus consors 107 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Gly Val Ile Arg Gly Leu 20 25 30 Val Ser His Ile Leu Ile Pro Gln His Thr Leu Arg Ser Leu Thr Ser 35 40 45 Arg Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Lys 65 70 108 25 PRT Conus consors PEPTIDE (1)..(25) Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 21 and 23 may be Pro or hydroxy-Pro 108 Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Ser Xaa Xaa Lys 20 25 109 459 DNA Conus coronatus CDS (1)..(240) 109 atg cag acg gcc tac tgg gtg atg atg atg atg atg atg gtg tgg att 48 Met Gln Thr Ala Tyr Trp Val Met Met Met Met Met Met Val Trp Ile 1 5 10 15 aca gcc cct ctg tct gaa ggt ggt aaa ctg aac gac gta att cgg ggt 96 Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly 20 25 30 ttg gtg cca gac gac tta acc cta cag cgt atg ttc aaa gct ctg gtt 144 Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met Phe Lys Ala Leu Val 35 40 45 tcc cat cgt ctt tct gac ggc aga gat tgg acg gga tac ata tgt atc 192 Ser His Arg Leu Ser Asp Gly Arg Asp Trp Thr Gly Tyr Ile Cys Ile 50 55 60 tgg aag gca tgt cca cgt ccc cca tgg atc cca cca aag gga aaa aga 240 Trp Lys Ala Cys Pro Arg Pro Pro Trp Ile Pro Pro Lys Gly Lys Arg 65 70 75 80 tgaatgacgt cagacaaccg ccacaactgt agtacgacat cgttaacaca acttcagcta 300 atattttaac atcactgtgg ttgtgaagaa atcggttgct ttaaaagatt gaatttttcg 360 tttaagagtt gtgctgatac gagctctgca ctatgaaata aagctgatgt gacaaacaaa 420 aaaaaaaaaa aaaaaaagta ctctgcgttg ttactcgag 459 110 80 PRT Conus coronatus 110 Met Gln Thr Ala Tyr Trp Val Met Met Met Met Met Met Val Trp Ile 1 5 10 15 Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met Phe Lys Ala Leu Val 35 40 45 Ser His Arg Leu Ser Asp Gly Arg Asp Trp Thr Gly Tyr Ile Cys Ile 50 55 60 Trp Lys Ala Cys Pro Arg Pro Pro Trp Ile Pro Pro Lys Gly Lys Arg 65 70 75 80 111 26 PRT Conus coronatus PEPTIDE (1)..(26) Xaa at residues 7, 14 and 22 may be Trp or bromo-Trp; Xaa at residue 10 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 18, 29, 21, 24 and 25 may be Pro or hydroxy-Pro 111 Leu Ser Asp Gly Arg Asp Xaa Thr Gly Xaa Ile Cys Ile Xaa Lys Ala 1 5 10 15 Cys Xaa Arg Xaa Xaa Xaa Ile Xaa Xaa Lys 20 25 112 495 DNA Conus ebraeus CDS (21)..(236) 112 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg atg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Met Met Met 1 5 10 atg atg gtg tgg att aca gcc cct ctg tct gaa ggc ggt aaa ctg aac 101 Met Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn 15 20 25 gac gta att cgg ggt ttg gtg cca gac gac tta acc cta cag cgt atg 149 Asp Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met 30 35 40 ttc aaa agt ctg ttt tcc cat cgt ctt tct ggc ggc aca tat tcg agg 197 Phe Lys Ser Leu Phe Ser His Arg Leu Ser Gly Gly Thr Tyr Ser Arg 45 50 55 gta gac aca tgc atc tgg aag gta tgt cca caa tct cca tagggacgat 246 Val Asp Thr Cys Ile Trp Lys Val Cys Pro Gln Ser Pro 60 65 70 catatggaaa aagatgagtg acatcagaca actgccacaa ctgtagtacg acatcgttaa 306 cacgacttca gctaatattt taacatcact gtggttgtga agaaatcggt tgctttaaaa 366 gattggattt ttccttgttt aagagttgtg ctgatatgag ctctgcacta tgaaataaag 426 ctgatgtgac aaacaaaaaa aaaaaaaaaa aagtactctg cgttgttact cgagcttaag 486 ggcgaattc 495 113 72 PRT Conus ebraeus 113 Met Gln Thr Ala Tyr Trp Val Met Met Met Met Met Met Val Trp Ile 1 5 10 15 Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Leu Gln Arg Met Phe Lys Ser Leu Phe 35 40 45 Ser His Arg Leu Ser Gly Gly Thr Tyr Ser Arg Val Asp Thr Cys Ile 50 55 60 Trp Lys Val Cys Pro Gln Ser Pro 65 70 114 21 PRT Conus ebraeus PEPTIDE (1)..(21) Xaa at residue 6 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residue 14 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 18 and 21 may be Pro or hydroxy-Pro 114 Leu Ser Gly Gly Thr Xaa Ser Arg Val Asp Thr Cys Ile Xaa Lys Val 1 5 10 15 Cys Xaa Gln Ser Xaa 20 115 537 DNA Conus geographus CDS (21)..(299) 115 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg ctg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Leu Met Met 1 5 10 atg gtg tgc atc aca gcc cct ctg cct gaa ggt ggt aaa ccg aac agc 101 Met Val Cys Ile Thr Ala Pro Leu Pro Glu Gly Gly Lys Pro Asn Ser 15 20 25 gga att cgg ggt ttg gtg cca aac gac tta act cca cag cat acc ttg 149 Gly Ile Arg Gly Leu Val Pro Asn Asp Leu Thr Pro Gln His Thr Leu 30 35 40 cga agt ctg att tcc cgt cgt caa act gac gtt ctt ctg gag gct acc 197 Arg Ser Leu Ile Ser Arg Arg Gln Thr Asp Val Leu Leu Glu Ala Thr 45 50 55 ctt ttg aca aca cca gcc ccc gag cag aga ttg ttc tgc ttc tgg aag 245 Leu Leu Thr Thr Pro Ala Pro Glu Gln Arg Leu Phe Cys Phe Trp Lys 60 65 70 75 tca tgt acg tgg agg ccc tac cct tgg aga cga cgt gat ctt aat gga 293 Ser Cys Thr Trp Arg Pro Tyr Pro Trp Arg Arg Arg Asp Leu Asn Gly 80 85 90 aaa cga tgaatgacgc cagacaaccg ccacaactgt agtacgacat cgttaatacg 349 Lys Arg acttcagcaa acattttaac ataactgtgg ttgtgaagaa atcagttgct ttaaaagatt 409 ggatttttcc ttgtttcaga gttgtactga tatgagctct gcaccatgaa ataaagctga 469 agtgacgaac aaaaaaaaaa aaaaaaaaaa agtactctgc gttgttactc gagcttaagg 529 gcgaattc 537 116 93 PRT Conus geographus 116 Met Gln Thr Ala Tyr Trp Val Met Leu Met Met Met Val Cys Ile Thr 1 5 10 15 Ala Pro Leu Pro Glu Gly Gly Lys Pro Asn Ser Gly Ile Arg Gly Leu 20 25 30 Val Pro Asn Asp Leu Thr Pro Gln His Thr Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Gln Thr Asp Val Leu Leu Glu Ala Thr Leu Leu Thr Thr Pro 50 55 60 Ala Pro Glu Gln Arg Leu Phe Cys Phe Trp Lys Ser Cys Thr Trp Arg 65 70 75 80 Pro Tyr Pro Trp Arg Arg Arg Asp Leu Asn Gly Lys Arg 85 90 117 40 PRT Conus geographus PEPTIDE (1)..(40) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residues 7 and 17 may be Glu or Gla; Xaa at residues 14, 16, 31 and 33 may be Pro or hydroxy-Pro; Xaa at residues 24, 29 and 34 may be Trp (D or L) or bromo-Trp (D or L) 117 Xaa Thr Asp Val Leu Leu Xaa Ala Thr Leu Leu Thr Thr Xaa Ala Xaa 1 5 10 15 Xaa Gln Arg Leu Phe Cys Phe Xaa Lys Ser Cys Thr Xaa Arg Xaa Xaa 20 25 30 Xaa Xaa Arg Arg Arg Asp Leu Asn 35 40 118 457 DNA Conus gladiator CDS (1)..(246) 118 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg gtt aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Val Thr 1 5 10 15 gtc cct cga tct gaa ggt ggc acg tgg aac tac tta att cgg ggt ttg 96 Val Pro Arg Ser Glu Gly Gly Thr Trp Asn Tyr Leu Ile Arg Gly Leu 20 25 30 gtg cca gac gac cta acc cca cag ctt acc ttg cat cgt ctg gtt acc 144 Val Pro Asp Asp Leu Thr Pro Gln Leu Thr Leu His Arg Leu Val Thr 35 40 45 cgt cgt cat cct gcc aac gtt aga cag cag ggg aaa ata tgt gta tgg 192 Arg Arg His Pro Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Trp 50 55 60 aag gtg tgt cca cca tgg cca gta aga tca cct ggt cca cag cca aaa 240 Lys Val Cys Pro Pro Trp Pro Val Arg Ser Pro Gly Pro Gln Pro Lys 65 70 75 80 aac aaa tgacgtcaga caaccgccac aactttagta cgacatcgtt gatacaactt 296 Asn Lys cagcaagtat tttaacatca ctgtggctct gaagaaatca gttgctttaa aagattggat 356 ttttccttgt tttagagttt tactgatatc agctctgcac tatgaaataa agatgtgacg 416 aaaaaaaaaa aaaaaaaaag tactctgcgt tgttactcga g 457 119 82 PRT Conus gladiator 119 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Val Thr 1 5 10 15 Val Pro Arg Ser Glu Gly Gly Thr Trp Asn Tyr Leu Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu Thr Leu His Arg Leu Val Thr 35 40 45 Arg Arg His Pro Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Trp 50 55 60 Lys Val Cys Pro Pro Trp Pro Val Arg Ser Pro Gly Pro Gln Pro Lys 65 70 75 80 Asn Lys 120 32 PRT Conus gladiator PEPTIDE (1)..(32) Xaa at residues 3, 18, 19, 21, 25, 27 and 29 may be Pro or hydroxy-Pro; Xaa at residues 14 and 20 may be Trp (D or L) or bromo-Trp (D or L) 120 His Xaa Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Xaa Xaa Val Arg Ser Xaa Gly Xaa Gln Xaa Lys Asn Lys 20 25 30 121 459 DNA Conus gladiator CDS (1)..(246) 121 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg gtt aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Val Thr 1 5 10 15 gtc cct cga tct gaa ggt ggc acg tgg aac tac tta att cgg ggt ttg 96 Val Pro Arg Ser Glu Gly Gly Thr Trp Asn Tyr Leu Ile Arg Gly Leu 20 25 30 gtg cca gac gac cta acc cca cag ctt acc ttg cat cgt ctg gtt acc 144 Val Pro Asp Asp Leu Thr Pro Gln Leu Thr Leu His Arg Leu Val Thr 35 40 45 cgt cgt cat cct gcc aac gtt aga cag cag ggg aaa ata tgt gta tgg 192 Arg Arg His Pro Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Trp 50 55 60 aag gtg tgt cca cca tcg cca gta aga tca cct ggt cca ctg cca aaa 240 Lys Val Cys Pro Pro Ser Pro Val Arg Ser Pro Gly Pro Leu Pro Lys 65 70 75 80 aac aaa tgacgtcaga caaccgccac aactttagta cgacatcgtt gatacaactt 296 Asn Lys cagcaagtat tttaacatca ctgtggctct gaagaaatca gttgctttaa aagattggat 356 ttttccttgt tttagagttt tactgatatc agctctgcac tatgaaataa agatgtgacg 416 gacaaaaaaa aaaaaaaaaa agtactctgc gttgttactc gag 459 122 82 PRT Conus gladiator 122 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Val Thr 1 5 10 15 Val Pro Arg Ser Glu Gly Gly Thr Trp Asn Tyr Leu Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu Thr Leu His Arg Leu Val Thr 35 40 45 Arg Arg His Pro Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Trp 50 55 60 Lys Val Cys Pro Pro Ser Pro Val Arg Ser Pro Gly Pro Leu Pro Lys 65 70 75 80 Asn Lys 123 32 PRT Conus gladiator PEPTIDE (1)..(32) Xaa at residues 2, 18, 19, 21, 25, 27 and 29 may be Pro or hydroxy-Pro; Xaa at residue 14 may be Trp (D or L) or bromo-Trp (D or L) 123 His Xaa Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa Val Arg Ser Xaa Gly Xaa Leu Xaa Lys Asn Lys 20 25 30 124 499 DNA Conus litoglyphus CDS (21)..(254) 124 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt gat aaa ttg aac gac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca gat aac tta gcc cca cag ctt gtt ttg 149 Val Ile Arg Gly Leu Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu 30 35 40 caa agt ctg gat tcc cgt cgt cat cct cac ggc att cgt cag gat gga 197 Gln Ser Leu Asp Ser Arg Arg His Pro His Gly Ile Arg Gln Asp Gly 45 50 55 gcc caa ata tgt atc tgg aag ata tgt cca cca tcc cca tgg aga cga 245 Ala Gln Ile Cys Ile Trp Lys Ile Cys Pro Pro Ser Pro Trp Arg Arg 60 65 70 75 ctt gga tct taagaaaaga aacaattgac gtcagacaac cgccacatct 294 Leu Gly Ser tgagtacgac atcgttaata cgacttcagc aaatatgaaa ttttcagcat cactgtggtt 354 gtgaagaaat cagttgcttt aaaagattgg atttgtcctt gtttaagagt tgtactgatg 414 tcatctctgc actatgaaat aaagctgatg tgaaaaaaaa aaaaaaaagt actctgcgtt 474 gttactcgag cttaagggcg aattc 499 125 78 PRT Conus litoglyphus 125 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Ile Cys Pro Pro Ser Pro Trp Arg Arg Leu Gly Ser 65 70 75 126 28 PRT Conus litoglyphus PEPTIDE (1)..(28) Xaa at residues 2, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residues 15 and 23 may be Trp (D or L) or bromo-Trp (D or L) 126 His Xaa His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile Xaa Lys 1 5 10 15 Ile Cys Xaa Xaa Ser Xaa Xaa Arg Arg Leu Gly Ser 20 25 127 507 DNA Conus litoglyphus CDS (21)..(254) 127 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt gat aaa ttg aac gac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca gat aac tta gcc cca cag ctt gtt ttg 149 Val Ile Arg Gly Leu Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu 30 35 40 caa agt ctg gat tcc cgt cgt cat cct cac ggc att cgt cag gat gga 197 Gln Ser Leu Asp Ser Arg Arg His Pro His Gly Ile Arg Gln Asp Gly 45 50 55 gcc caa ata tgt atc tgg aag ata tgt cca cca tcc cca tgg aaa cga 245 Ala Gln Ile Cys Ile Trp Lys Ile Cys Pro Pro Ser Pro Trp Lys Arg 60 65 70 75 ctt gga tct taagaaaaga aacaattgac gtcagacaac cgccacaact 294 Leu Gly Ser tgagtacgac atcgttaata caacttcagc aaatatgaaa ttttcagcat cactgtggtt 354 gtgaagaaat cagttgcttt aaaggattgg atttgtcctt gtttaagagt tgtactgatg 414 tcatctctgc actatgaaat aaagctgatg tgacaagcaa aaaaaaaaaa aaaaaagtac 474 tctgcgttgt tactcgagct taagggcgaa ttc 507 128 78 PRT Conus litoglyphus 128 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Ile Cys Pro Pro Ser Pro Trp Lys Arg Leu Gly Ser 65 70 75 129 28 PRT Conus litoglyphus PEPTIDE (1)..(28) Xaa at residues 2, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residues 15 and 23 may be Trp (D or L) or bromo-Trp (D or L) 129 His Xaa His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile Xaa Lys 1 5 10 15 Ile Cys Xaa Xaa Ser Xaa Xaa Lys Arg Leu Gly Ser 20 25 130 507 DNA Conus litteratus CDS (21)..(299) 130 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg ggg att aca gcc cct ctg tct gaa ggt cgt aaa ttg aac gac 101 Met Val Gly Ile Thr Ala Pro Leu Ser Glu Gly Arg Lys Leu Asn Asp 15 20 25 gca att cgg ggt ttg gtg cca gat gac tta acc cca cag ctt ttg cga 149 Ala Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Leu Arg 30 35 40 agt ccg gtt tcg act cct tat cct gag ttt cat ctt gat gaa cct tat 197 Ser Pro Val Ser Thr Pro Tyr Pro Glu Phe His Leu Asp Glu Pro Tyr 45 50 55 ctg aag ata ccc gta tgt atc tgg aag ata tgt cca cca aac cta ttg 245 Leu Lys Ile Pro Val Cys Ile Trp Lys Ile Cys Pro Pro Asn Leu Leu 60 65 70 75 aga cga cgt gat ctt aag aaa aga aac aaa gta cgt cag aca acc gcc 293 Arg Arg Arg Asp Leu Lys Lys Arg Asn Lys Val Arg Gln Thr Thr Ala 80 85 90 aca act tgagtacgac atcgttcata caacttgagc aaatatttca gcatcactat 349 Thr Thr ggttgtgaag aaatcagttg ctttaaaaga ttggatcttt ccttgtttaa gagttgtatt 409 gatgtcagct ctgcactctg aaataaagct gatgtgacaa acaaaaaaaa aaaaaaaaaa 469 agtactctgc gttgttactc gagcttaagg gcgaattc 507 131 93 PRT Conus litteratus 131 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Gly Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Arg Lys Leu Asn Asp Ala Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu Leu Arg Ser Pro Val Ser Thr 35 40 45 Pro Tyr Pro Glu Phe His Leu Asp Glu Pro Tyr Leu Lys Ile Pro Val 50 55 60 Cys Ile Trp Lys Ile Cys Pro Pro Asn Leu Leu Arg Arg Arg Asp Leu 65 70 75 80 Lys Lys Arg Asn Lys Val Arg Gln Thr Thr Ala Thr Thr 85 90 132 50 PRT Conus litteratus PEPTIDE (1)..(50) Xaa at residues 2, 6, 8, 15, 20, 28 and 29 may be Pro or hydroxy-Pro; Xaa at residues 7 and 16 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 9 and 14 may be Glu or Gla 132 Ser Xaa Val Ser Thr Xaa Xaa Xaa Xaa Phe His Leu Asp Xaa Xaa Xaa 1 5 10 15 Leu Lys Ile Xaa Val Cys Ile Xaa Lys Ile Cys Xaa Xaa Asn Leu Leu 20 25 30 Arg Arg Arg Asp Leu Lys Lys Arg Asn Lys Val Arg Gln Thr Thr Ala 35 40 45 Thr Thr 50 133 508 DNA Conus litteratus CDS (21)..(275) 133 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg ggg att aca gcc cct ctg tct gaa ggt cgt aaa ttg aac gac 101 Met Val Gly Ile Thr Ala Pro Leu Ser Glu Gly Arg Lys Leu Asn Asp 15 20 25 gca att cgg ggt ttg gtg cca aat gac tta acc cca cag ctt ttg caa 149 Ala Ile Arg Gly Leu Val Pro Asn Asp Leu Thr Pro Gln Leu Leu Gln 30 35 40 agt ctg gtt tcc cgt cgt cat cgt gtg ttt cat ctt gac aac act tat 197 Ser Leu Val Ser Arg Arg His Arg Val Phe His Leu Asp Asn Thr Tyr 45 50 55 ctc aag ata ccc ata tgt gcc tgg aag gta tgt cca cca acc cca tgg 245 Leu Lys Ile Pro Ile Cys Ala Trp Lys Val Cys Pro Pro Thr Pro Trp 60 65 70 75 aga cga cgt gat ctt aag aaa aga aac aaa tgacgtcaga caaccgccac 295 Arg Arg Arg Asp Leu Lys Lys Arg Asn Lys 80 85 aacttgagta cgacattgtt aatgcgactt gagcaaattt ttcagcatca ctatggttgt 355 aaagaaatca gctgctttaa acgattggat ctttccttat ttaagagttg tattgatgtc 415 agctctgcac tctgaaataa agctgatgtg acaaacaaaa aaaaaaaaaa aaaaaagtac 475 tctgcgttgt tactcgagct taagggcgaa ttc 508 134 85 PRT Conus litteratus 134 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Gly Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Arg Lys Leu Asn Asp Ala Ile Arg Gly Leu 20 25 30 Val Pro Asn Asp Leu Thr Pro Gln Leu Leu Gln Ser Leu Val Ser Arg 35 40 45 Arg His Arg Val Phe His Leu Asp Asn Thr Tyr Leu Lys Ile Pro Ile 50 55 60 Cys Ala Trp Lys Val Cys Pro Pro Thr Pro Trp Arg Arg Arg Asp Leu 65 70 75 80 Lys Lys Arg Asn Lys 85 135 36 PRT Conus litteratus PEPTIDE (1)..(36) Xaa at residue 10 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 14, 22, 23 and 25 may be Pro or hydroxy-Pro; Xaa at residues 18 and 26 may be Trp (D or L) or bromo-Trp (D or L) 135 His Arg Val Phe His Leu Asp Asn Thr Xaa Leu Lys Ile Xaa Ile Cys 1 5 10 15 Ala Xaa Lys Val Cys Xaa Xaa Thr Xaa Xaa Arg Arg Arg Asp Leu Lys 20 25 30 Lys Arg Asn Lys 35 136 498 DNA Conus loroisii CDS (21)..(236) misc_feature (1)..(498) n may be any base 136 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aaa ggc cct gtg tct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Lys Gly Pro Val Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca gac gac tta acc cca cag ctt atc ttg 149 Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu 30 35 40 caa agt ctg atg tcc cgt cgt cgt tct gac agc gat gtt cgg gag gtg 197 Gln Ser Leu Met Ser Arg Arg Arg Ser Asp Ser Asp Val Arg Glu Val 45 50 55 tac ata tta tgc atc tgg aag ata tgt cca cca ttg cca tgaagacgac 246 Tyr Ile Leu Cys Ile Trp Lys Ile Cys Pro Pro Leu Pro 60 65 70 atgatcttaa ggaaaaggat aaacgacgtc agacaaccgc tacaactgta gtacgacatc 306 gttaatacga cttcagcaaa tatttgaaca tcactgtggt tgtgaagaaa tcagttgctt 366 taaacgattg gatttttcct taagagttgc actgatatca gctctgcact atgaaataaa 426 gctgatgtga ctaccaaaaa aaaaaaaaaa aaaaagtact ntgcgttgtt actcgagctt 486 aagggcgaat tc 498 137 72 PRT Conus loroisii misc_feature (1)..(498) n may be any base 137 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Lys 1 5 10 15 Gly Pro Val Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Gln Ser Leu Met Ser 35 40 45 Arg Arg Arg Ser Asp Ser Asp Val Arg Glu Val Tyr Ile Leu Cys Ile 50 55 60 Trp Lys Ile Cys Pro Pro Leu Pro 65 70 138 22 PRT Conus loroisii PEPTIDE (1)..(22) Xaa at residue 8 may be Glu or Gla; Xaa at residue 10 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residue 15 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 19, 20 and 22 may be Pro or hydroxy-Pro 138 Arg Ser Asp Ser Asp Val Arg Xaa Val Xaa Ile Leu Cys Ile Xaa Lys 1 5 10 15 Ile Cys Xaa Xaa Leu Xaa 20 139 495 DNA Conus magus CDS (21)..(242) 139 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca cac tcc tta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val Pro His Ser Leu Thr Pro Gln His Ile Leu 30 35 40 caa agt ctg act tcc cgt aat ggt tct ggc agc agc aat cag aaa gaa 197 Gln Ser Leu Thr Ser Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu 45 50 55 gca caa cta tgc atc tgg aag gta tgt cca cca tcc cca tgg aga 242 Ala Gln Leu Cys Ile Trp Lys Val Cys Pro Pro Ser Pro Trp Arg 60 65 70 tgaccacaag gaaaaagatg aacggcgtca gacaaccgcc acaactgtag tgggacatcg 302 ttgatacgac ttcaacaaat attttaacat cactgtggtt gtaaagaaat cagttgcttt 362 aaaagattgg atttttcctt gtttaagagt tgtactgata tcagctctgc actatgaaat 422 aaagctgatg tgacaaacaa aaaaaaaaaa aaaaaagtac tctgcgttgt tactcgagct 482 taagggcgaa ttc 495 140 74 PRT Conus magus 140 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ser Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu Ala Gln Leu Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg 65 70 141 25 PRT Conus magus PEPTIDE (1)..(25) Xaa at residue 10 may be Glu or Gla; Xaa at residues 16 and 24 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 20, 21 and 23 may be Pro or hydroxy-Pro 141 Asn Gly Ser Gly Ser Ser Asn Gln Lys Xaa Ala Gln Leu Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Ser Xaa Xaa Arg 20 25 142 587 DNA Conus miles CDS (21)..(347) misc_feature (1)..(587) n may be any nucleotide 142 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg atg atg gtg 53 Met Gln Thr Ala Tyr Trp Val Met Met Met Val 1 5 10 gtg atg atg gtg ggg gtt act gtc gct ggc tcc ctg cct gtg ttt gat 101 Val Met Met Val Gly Val Thr Val Ala Gly Ser Leu Pro Val Phe Asp 15 20 25 gac gac aac gac tct gac ccc gct gtc aag cgc gct atc acg tgg tcc 149 Asp Asp Asn Asp Ser Asp Pro Ala Val Lys Arg Ala Ile Thr Trp Ser 30 35 40 cgc atc ctg ggc gtg tct cca gcc ttc ctg gca cag cag cga gcg ctg 197 Arg Ile Leu Gly Val Ser Pro Ala Phe Leu Ala Gln Gln Arg Ala Leu 45 50 55 gtt ccc ttc gcc aac cga ttc atc agt gag cag aaa cgt ttc cga ccc 245 Val Pro Phe Ala Asn Arg Phe Ile Ser Glu Gln Lys Arg Phe Arg Pro 60 65 70 75 gcc atg cag agc cga tca gga gga atg tcg ctg tgc cta tgg aaa gtg 293 Ala Met Gln Ser Arg Ser Gly Gly Met Ser Leu Cys Leu Trp Lys Val 80 85 90 tgt cct gca gcc ccc tgg ctg gtc gcc aaa cgt aaa cag gaa acc agc 341 Cys Pro Ala Ala Pro Trp Leu Val Ala Lys Arg Lys Gln Glu Thr Ser 95 100 105 gac tac tgacgtcata cctctaaaga cccactcatg acgtcaacgc tgaactgacg 397 Asp Tyr tcaccgacag ctccaacgtc acagcaggag cgagagagag gctggagcat ttctctttct 457 tttggttttt cgagttgaag tgtgatcagc tgggctggtg aaaaaattgt tgagtaaagt 517 tgaatgaaaa tcaaaaaaaa aaaaaaaaaa agtactctgc gttggtactc gaggcttaaa 577 ggcgnaattc 587 143 109 PRT Conus miles misc_feature (1)..(587) n may be any nucleotide 143 Met Gln Thr Ala Tyr Trp Val Met Met Met Val Val Met Met Val Gly 1 5 10 15 Val Thr Val Ala Gly Ser Leu Pro Val Phe Asp Asp Asp Asn Asp Ser 20 25 30 Asp Pro Ala Val Lys Arg Ala Ile Thr Trp Ser Arg Ile Leu Gly Val 35 40 45 Ser Pro Ala Phe Leu Ala Gln Gln Arg Ala Leu Val Pro Phe Ala Asn 50 55 60 Arg Phe Ile Ser Glu Gln Lys Arg Phe Arg Pro Ala Met Gln Ser Arg 65 70 75 80 Ser Gly Gly Met Ser Leu Cys Leu Trp Lys Val Cys Pro Ala Ala Pro 85 90 95 Trp Leu Val Ala Lys Arg Lys Gln Glu Thr Ser Asp Tyr 100 105 144 37 PRT Conus miles PEPTIDE (1)..(37) Xaa at residues 3, 21 and 24 may be Pro or hydroxy-Pro; Xaa at residues 17 and 25 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 33 may be Glu or Gla; 144 Phe Arg Xaa Ala Met Gln Ser Arg Ser Gly Gly Met Ser Leu Cys Leu 1 5 10 15 Xaa Lys Val Cys Xaa Ala Ala Xaa Xaa Leu Val Ala Lys Arg Lys Gln 20 25 30 Xaa Thr Ser Asp Xaa 35 145 499 DNA Conus miles CDS (21)..(401) 145 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg gtg ggt tca ccg tcg gga gtc acg tcc atc ggt ctc aca gtc 101 Met Val Val Gly Ser Pro Ser Gly Val Thr Ser Ile Gly Leu Thr Val 15 20 25 cta cgt cgc gca acc atg gtg atg act cca ttc atg aca aga cga ttc 149 Leu Arg Arg Ala Thr Met Val Met Thr Pro Phe Met Thr Arg Arg Phe 30 35 40 atc aac atc tgt ttg ccc gtc ttc ctc tgg aga aca acg acg acc atc 197 Ile Asn Ile Cys Leu Pro Val Phe Leu Trp Arg Thr Thr Thr Thr Ile 45 50 55 gtt ctg tgg atc ttc ctg cag tgt atg cgc cgg gcc agg cac gtg tgc 245 Val Leu Trp Ile Phe Leu Gln Cys Met Arg Arg Ala Arg His Val Cys 60 65 70 75 gtt cta ctt ttg ttc ttg acc tca ttg cag ata ggg gtt ggt gca gac 293 Val Leu Leu Leu Phe Leu Thr Ser Leu Gln Ile Gly Val Gly Ala Asp 80 85 90 gac atg aaa cta cag cgc caa aga cgt caa ggt ttc tgt tgc gtc gtt 341 Asp Met Lys Leu Gln Arg Gln Arg Arg Gln Gly Phe Cys Cys Val Val 95 100 105 atc ccg att ctt tgg ttc tgt tgt ggg ggt tac cgc aca aat ggc act 389 Ile Pro Ile Leu Trp Phe Cys Cys Gly Gly Tyr Arg Thr Asn Gly Thr 110 115 120 gca ctg gcc gat tgaaagaact gcaataaacg gaatggcaag aaggaataaa 441 Ala Leu Ala Asp 125 aaaaaaaaaa aaaaaaaaaa agtactctgc gttgttactc gagcttaagg gcgaattc 499 146 127 PRT Conus miles 146 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val Gly Ser 1 5 10 15 Pro Ser Gly Val Thr Ser Ile Gly Leu Thr Val Leu Arg Arg Ala Thr 20 25 30 Met Val Met Thr Pro Phe Met Thr Arg Arg Phe Ile Asn Ile Cys Leu 35 40 45 Pro Val Phe Leu Trp Arg Thr Thr Thr Thr Ile Val Leu Trp Ile Phe 50 55 60 Leu Gln Cys Met Arg Arg Ala Arg His Val Cys Val Leu Leu Leu Phe 65 70 75 80 Leu Thr Ser Leu Gln Ile Gly Val Gly Ala Asp Asp Met Lys Leu Gln 85 90 95 Arg Gln Arg Arg Gln Gly Phe Cys Cys Val Val Ile Pro Ile Leu Trp 100 105 110 Phe Cys Cys Gly Gly Tyr Arg Thr Asn Gly Thr Ala Leu Ala Asp 115 120 125 147 27 PRT Conus miles PEPTIDE (1)..(27) Xaa at residue 1 is Gln or pyro-Glu; Xaa at residue 9 may be Pro or hydroxy-Pro; Xaa at residue 12 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 18 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr 147 Xaa Gly Phe Cys Cys Val Val Ile Xaa Ile Leu Xaa Phe Cys Cys Gly 1 5 10 15 Gly Xaa Arg Thr Asn Gly Thr Ala Leu Ala Asp 20 25 148 450 DNA Conus muriculatus CDS (1)..(237) 148 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ttg tct gaa ggt ggt aaa ctg aac gat gta att cgg ggt ttc 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Phe 20 25 30 gcg cta gat gac tta gcc caa agc cgt att atg caa agt ctg gtt ttc 144 Ala Leu Asp Asp Leu Ala Gln Ser Arg Ile Met Gln Ser Leu Val Phe 35 40 45 agt cat cag cct ctt cca acg gca tcc ata tgt atc tgg aag ata tgt 192 Ser His Gln Pro Leu Pro Thr Ala Ser Ile Cys Ile Trp Lys Ile Cys 50 55 60 cca cca gac cca tgg aga cga cat gat ctt cag aaa agt aac aaa 237 Pro Pro Asp Pro Trp Arg Arg His Asp Leu Gln Lys Ser Asn Lys 65 70 75 tgacgtcaga caaccgccac aacttgaata caacatcatt aatacgactt cagcaaatat 297 tttaacatca ctgtgattgt tcggaagtca gttgctttaa aggattggat ttgtccctgt 357 tgtattgatg tcaactctgc actatgaaat aaagctgatg tgacaaacaa gaaaaaaaaa 417 aaaaaaaaaa agtactctgc gttgttactc gag 450 149 79 PRT Conus muriculatus 149 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Phe 20 25 30 Ala Leu Asp Asp Leu Ala Gln Ser Arg Ile Met Gln Ser Leu Val Phe 35 40 45 Ser His Gln Pro Leu Pro Thr Ala Ser Ile Cys Ile Trp Lys Ile Cys 50 55 60 Pro Pro Asp Pro Trp Arg Arg His Asp Leu Gln Lys Ser Asn Lys 65 70 75 150 38 PRT Conus muriculatus PEPTIDE (1)..(38) Xaa at residues 11, 13, 24, 25 and 27 may be Pro or hydroxy-Pro; Xaa at residue 20 and 28 may be Trp or bromo-Trp 150 Ile Met Gln Ser Leu Val Phe Ser His Gln Xaa Leu Xaa Thr Ala Ser 1 5 10 15 Ile Cys Ile Xaa Lys Ile Cys Xaa Xaa Asp Xaa Xaa Arg Arg His Asp 20 25 30 Leu Gln Lys Ser Asn Lys 35 151 437 DNA Conus musicus CDS (1)..(240) 151 atg cag acg gcc tac tgg gtg atg atg atg acg atg atg gtg tgg atg 48 Met Gln Thr Ala Tyr Trp Val Met Met Met Thr Met Met Val Trp Met 1 5 10 15 aca gcc cct ctg tct gaa ggt cgt cca ctg agc gac gaa gtt cgg ggt 96 Thr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser Asp Glu Val Arg Gly 20 25 30 atg gtg cca ggc gac ttg gtc cta cag tat ctg ttc cca agt ctg gct 144 Met Val Pro Gly Asp Leu Val Leu Gln Tyr Leu Phe Pro Ser Leu Ala 35 40 45 ttc agt cct ccg gac ata tgt acg tgg aag gta tgt cca cca ccc cca 192 Phe Ser Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro Pro 50 55 60 tgg aga cga cca aaa aaa ata aca gac gtc aga cag ccg cca caa ctg 240 Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Arg Gln Pro Pro Gln Leu 65 70 75 80 tagtacgaca tcgttgatac ggcttcagca aatattttca acatcactgc ggttgtgaag 300 aaatcagttg ctttaaaatg ttggattttt ccttgtttaa aagagctgta ctgatgtcag 360 ccctgcatta cgaaataaag ctgatgtgac aaacaaaaaa aaaaaaaaaa aaaaagtact 420 ctgcgttgtt actcgag 437 152 80 PRT Conus musicus 152 Met Gln Thr Ala Tyr Trp Val Met Met Met Thr Met Met Val Trp Met 1 5 10 15 Thr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser Asp Glu Val Arg Gly 20 25 30 Met Val Pro Gly Asp Leu Val Leu Gln Tyr Leu Phe Pro Ser Leu Ala 35 40 45 Phe Ser Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro Pro 50 55 60 Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Arg Gln Pro Pro Gln Leu 65 70 75 80 153 49 PRT Conus musicus PEPTIDE (1)..(49) Xaa at residues 4, 14, 20, 21, 30, 31, 32, 33, 37, 46 and 47 may be Pro or hydroxy-Pro; Xaa at residue 11 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 26 and 34 may be Trp (D or L) or bromo-Trp (D or L) 153 Gly Met Val Xaa Gly Asp Leu Val Leu Gln Xaa Leu Phe Xaa Ser Leu 1 5 10 15 Ala Phe Ser Xaa Xaa Asp Ile Cys Thr Xaa Lys Val Cys Xaa Xaa Xaa 20 25 30 Xaa Xaa Arg Arg Xaa Lys Lys Ile Thr Asp Val Arg Gln Xaa Xaa Gln 35 40 45 Leu 154 436 DNA Conus musicus CDS (1)..(216) 154 atg cag acg gcc tac tgg gtg atg atg atg atg atg atg gtg tgg atg 48 Met Gln Thr Ala Tyr Trp Val Met Met Met Met Met Met Val Trp Met 1 5 10 15 aca gcc cct ctg tct gaa ggt cgt aaa ctg atc gac aaa gtt cgg ggt 96 Thr Ala Pro Leu Ser Glu Gly Arg Lys Leu Ile Asp Lys Val Arg Gly 20 25 30 atg ggg cca ggc gac tta tcc cta cag aaa atg ttc cca agt ctg gct 144 Met Gly Pro Gly Asp Leu Ser Leu Gln Lys Met Phe Pro Ser Leu Ala 35 40 45 tta ggt cct ggg gga gac gta ata tgt agg tgg aag gta tgt cca cca 192 Leu Gly Pro Gly Gly Asp Val Ile Cys Arg Trp Lys Val Cys Pro Pro 50 55 60 acc cca tgg aaa cga cta ata aaa taactgacgt cagacagccg ccacaactgt 246 Thr Pro Trp Lys Arg Leu Ile Lys 65 70 agtacgacat cgttgatacg acttcagcaa atatttcaac atcactgcgg ttgtgaagaa 306 atcagttgct ttaaaagatt ggatttttcc ttgtttaaag agttgtactg atatcagctc 366 tgcattacga aataaagctg atgtgacaaa caaaaaaaaa aaaaaaaagt actctgcgtt 426 gttactcgag 436 155 72 PRT Conus musicus 155 Met Gln Thr Ala Tyr Trp Val Met Met Met Met Met Met Val Trp Met 1 5 10 15 Thr Ala Pro Leu Ser Glu Gly Arg Lys Leu Ile Asp Lys Val Arg Gly 20 25 30 Met Gly Pro Gly Asp Leu Ser Leu Gln Lys Met Phe Pro Ser Leu Ala 35 40 45 Leu Gly Pro Gly Gly Asp Val Ile Cys Arg Trp Lys Val Cys Pro Pro 50 55 60 Thr Pro Trp Lys Arg Leu Ile Lys 65 70 156 41 PRT Conus musicus PEPTIDE (1)..(41) Xaa at residues 4, 14, 20, 32, 33 and 35 may be Pro or hydroxy-Pro; Xaa at residues 28 and 36 may be Trp (D or L) or bromo-Trp (D or L) 156 Gly Met Gly Xaa Gly Asp Leu Ser Leu Gln Lys Met Phe Xaa Ser Leu 1 5 10 15 Ala Leu Gly Xaa Gly Gly Asp Val Ile Cys Arg Xaa Lys Val Cys Xaa 20 25 30 Xaa Thr Xaa Xaa Lys Arg Leu Ile Lys 35 40 157 449 DNA Conus musicus CDS (1)..(243) 157 atg cag acg gcc tac tgg gtg atg atg atg atg acg atg atg gtg tgg 48 Met Gln Thr Ala Tyr Trp Val Met Met Met Met Thr Met Met Val Trp 1 5 10 15 atg aca gcc cct ctg tct gaa ggt cgt cca ctg agc gac aaa gtt cgg 96 Met Thr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser Asp Lys Val Arg 20 25 30 ggt atg gtg cca ggc gac tta gcc ctg cag tat ctg ttc cca agt ctg 144 Gly Met Val Pro Gly Asp Leu Ala Leu Gln Tyr Leu Phe Pro Ser Leu 35 40 45 gct ttc aat ccc ccg gac ata tgt acg tgg aag gta tgt cca cca ccc 192 Ala Phe Asn Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro 50 55 60 cca tgg aga cga cca aaa aaa ata act gac gtc gga cag ccg cca caa 240 Pro Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Gly Gln Pro Pro Gln 65 70 75 80 ctg tagtacgaca tcgttgatac gacttcagca aatattttca acatcactgc 293 Leu ggttgtgaag aaatcagttg ttttaaaagg ttggattttt ccttgtttaa aagagctgta 353 ctgatgtcag ctctgcatta cgaaataaag ctgatgtgac aaacgaaaaa aaaaaaaaaa 413 aaaaaaaaaa aaaagtactc tgcgttgtta ctcgag 449 158 81 PRT Conus musicus 158 Met Gln Thr Ala Tyr Trp Val Met Met Met Met Thr Met Met Val Trp 1 5 10 15 Met Thr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser Asp Lys Val Arg 20 25 30 Gly Met Val Pro Gly Asp Leu Ala Leu Gln Tyr Leu Phe Pro Ser Leu 35 40 45 Ala Phe Asn Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro 50 55 60 Pro Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Gly Gln Pro Pro Gln 65 70 75 80 Leu 159 49 PRT Conus musicus PEPTIDE (1)..(49) Xaa at residues 4, 14, 20, 21, 30, 31, 32, 33, 37, 46 and 47 may be Pro or hydroxy-Pro; Xaa at residue 11 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 26 and 34 may be Trp (D or L) or bromo-Trp (D or L) 159 Gly Met Val Xaa Gly Asp Leu Ala Leu Gln Xaa Leu Phe Xaa Ser Leu 1 5 10 15 Ala Phe Asn Xaa Xaa Asp Ile Cys Thr Xaa Lys Val Cys Xaa Xaa Xaa 20 25 30 Xaa Xaa Arg Arg Xaa Lys Lys Ile Thr Asp Val Gly Gln Xaa Xaa Gln 35 40 45 Leu 160 436 DNA Conus musicus CDS (1)..(240) 160 atg cag acg gcc tac tgg gtg atg atg atg acg atg atg gtg tgg atg 48 Met Gln Thr Ala Tyr Trp Val Met Met Met Thr Met Met Val Trp Met 1 5 10 15 aca gcc cct ctg tct gaa ggt cgt cca ctg agc gac aaa gtt cgg ggt 96 Thr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser Asp Lys Val Arg Gly 20 25 30 atg gtg cca ggc gac tta gtc ctg cag tat ctg ttc cca agt ctg gct 144 Met Val Pro Gly Asp Leu Val Leu Gln Tyr Leu Phe Pro Ser Leu Ala 35 40 45 ttc aat cct ccg gac ata tgt acg tgg aag gta tgt cca cca ccc cca 192 Phe Asn Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro Pro 50 55 60 tgg aga cga cca aaa aaa ata act gac gtc aga cag ccg cca caa ctg 240 Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Arg Gln Pro Pro Gln Leu 65 70 75 80 tagtacgaca tcgttgatac gacttcagca aatattttca acatcactgc ggttgtgaag 300 aaatcagttg ttttaaaagg ttggattttt ccttgtttaa aagagctgta ctgatgtcag 360 ctctgcatta cgaaataaag ctgatgtgac aagcaaaaaa aaaaaaaaaa aaaagtactc 420 tgcgttgtta ctcgag 436 161 80 PRT Conus musicus 161 Met Gln Thr Ala Tyr Trp Val Met Met Met Thr Met Met Val Trp Met 1 5 10 15 Thr Ala Pro Leu Ser Glu Gly Arg Pro Leu Ser Asp Lys Val Arg Gly 20 25 30 Met Val Pro Gly Asp Leu Val Leu Gln Tyr Leu Phe Pro Ser Leu Ala 35 40 45 Phe Asn Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro Pro 50 55 60 Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Arg Gln Pro Pro Gln Leu 65 70 75 80 162 49 PRT Conus musicus PEPTIDE (1)..(49) Xaa at residues 4, 14, 20, 21, 30, 31, 32, 33, 37, 46 and 47 may be Pro or hydroxy-Pro; Xaa at residue 11 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 26 and 34 may be Trp (D or L) or bromo-Trp (D or L) 162 Gly Met Val Xaa Gly Asp Leu Val Leu Gln Xaa Leu Phe Xaa Ser Leu 1 5 10 15 Ala Phe Asn Xaa Xaa Asp Ile Cys Thr Xaa Lys Val Cys Xaa Xaa Xaa 20 25 30 Xaa Xaa Arg Arg Xaa Lys Lys Ile Thr Asp Val Arg Gln Xaa Xaa Gln 35 40 45 Leu 163 462 DNA Conus mustelinus CDS (1)..(225) 163 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gcg tgg tat aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Ala Trp Tyr Thr 1 5 10 15 acc cct gtg tct gaa tgt ggg aaa ttg aac aac gta att cgg ggt ttt 96 Thr Pro Val Ser Glu Cys Gly Lys Leu Asn Asn Val Ile Arg Gly Phe 20 25 30 gtg cca aag gac tgg acc cca atg ctt ccc tgg cgt cgt cta gtt tcc 144 Val Pro Lys Asp Trp Thr Pro Met Leu Pro Trp Arg Arg Leu Val Ser 35 40 45 cat acc agc agc aag tat cca ggt gtg act ttt tgt cca tgg aag gtg 192 His Thr Ser Ser Lys Tyr Pro Gly Val Thr Phe Cys Pro Trp Lys Val 50 55 60 tgt ccg cca gcg cca tgg aga ata ctt ggg gtc taacgcaaaa aaatacatga 245 Cys Pro Pro Ala Pro Trp Arg Ile Leu Gly Val 65 70 75 cgtcagacaa ccgccaccgc tttagtacga catcgttcat acgtctccag caagtatttt 305 aacatcactg tggttgtgaa gaagtcagta gctttaaaag attggatttt ttccttgttt 365 aagagttgta ctgacatgag ttctgcacta tgaaataaag ttgatgtgac gaacgaaaaa 425 aaaaaaaaaa aaaaagtact ctgcgttgtt actcgag 462 164 75 PRT Conus mustelinus 164 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Ala Trp Tyr Thr 1 5 10 15 Thr Pro Val Ser Glu Cys Gly Lys Leu Asn Asn Val Ile Arg Gly Phe 20 25 30 Val Pro Lys Asp Trp Thr Pro Met Leu Pro Trp Arg Arg Leu Val Ser 35 40 45 His Thr Ser Ser Lys Tyr Pro Gly Val Thr Phe Cys Pro Trp Lys Val 50 55 60 Cys Pro Pro Ala Pro Trp Arg Ile Leu Gly Val 65 70 75 165 30 PRT Conus mustelinus PEPTIDE (1)..(30) Xaa at residue 9 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residues 10, 16, 21, 22 and 24 may be Pro or hydroxy-Pro; Xaa at residues 17 and 25 may be Trp (D or L) or bromo-Trp (D or L) 165 Leu Val Ser His Thr Ser Ser Lys Xaa Xaa Gly Val Thr Phe Cys Xaa 1 5 10 15 Xaa Lys Val Cys Xaa Xaa Ala Xaa Xaa Arg Ile Leu Gly Val 20 25 30 166 619 DNA Conus nobilis CDS (21)..(350) 166 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg atg atg gtg 53 Met Gln Thr Ala Tyr Trp Val Met Met Met Val 1 5 10 gtg gtg atg atg gtg ggg gtt act gtc gct ggc tca ctg tct gtg ttt 101 Val Val Met Met Val Gly Val Thr Val Ala Gly Ser Leu Ser Val Phe 15 20 25 gat gat gac aac gac tct gac cca gct gtc aag cgc gcc atc acg tgg 149 Asp Asp Asp Asn Asp Ser Asp Pro Ala Val Lys Arg Ala Ile Thr Trp 30 35 40 tct cga ttc ctg ggc gcg tct cca gcc ttc ctg gca cag cag cga gcg 197 Ser Arg Phe Leu Gly Ala Ser Pro Ala Phe Leu Ala Gln Gln Arg Ala 45 50 55 ctg gct ccc ttc gcc aac cga ccc atc aat gag cag aaa cgt ttc cga 245 Leu Ala Pro Phe Ala Asn Arg Pro Ile Asn Glu Gln Lys Arg Phe Arg 60 65 70 75 cct gcc gtg aag agc cga tca cga cga gcg ccg ccg tgc gtg tgg aag 293 Pro Ala Val Lys Ser Arg Ser Arg Arg Ala Pro Pro Cys Val Trp Lys 80 85 90 gtg tgt ccc gct ccc ccc tgg ctg gtc acc aaa cgt aaa cag gaa acc 341 Val Cys Pro Ala Pro Pro Trp Leu Val Thr Lys Arg Lys Gln Glu Thr 95 100 105 agc gac tac tgacgtcata cctcaataga ccgactcatg acttcaacgc 390 Ser Asp Tyr 110 tgaattgacg tcaccgagag ctccaacgtc acagcaggag cgagagagag agagagagag 450 agagaaagag agagagaaag gctggagtat ttctctttct tttggttttt cgtgttgaag 510 tgtgatcagc tgggctggtt caaaattgtt gaataaagtt gaatgaaaat caaaaaaaaa 570 aaaaaaaaaa aagtactctg cgttgttact cgagcttaag ggcgaattc 619 167 110 PRT Conus nobilis 167 Met Gln Thr Ala Tyr Trp Val Met Met Met Val Val Val Met Met Val 1 5 10 15 Gly Val Thr Val Ala Gly Ser Leu Ser Val Phe Asp Asp Asp Asn Asp 20 25 30 Ser Asp Pro Ala Val Lys Arg Ala Ile Thr Trp Ser Arg Phe Leu Gly 35 40 45 Ala Ser Pro Ala Phe Leu Ala Gln Gln Arg Ala Leu Ala Pro Phe Ala 50 55 60 Asn Arg Pro Ile Asn Glu Gln Lys Arg Phe Arg Pro Ala Val Lys Ser 65 70 75 80 Arg Ser Arg Arg Ala Pro Pro Cys Val Trp Lys Val Cys Pro Ala Pro 85 90 95 Pro Trp Leu Val Thr Lys Arg Lys Gln Glu Thr Ser Asp Tyr 100 105 110 168 37 PRT Conus nobilis PEPTIDE (1)..(37) Xaa at residues 3, 13, 14, 21, 23 and 24 may be Pro or hydroxy-Pro; Xaa at residues 17 and 25 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 33 may be Glu or Gla; 168 Phe Arg Xaa Ala Val Lys Ser Arg Ser Arg Arg Ala Xaa Xaa Cys Val 1 5 10 15 Xaa Lys Val Cys Xaa Ala Xaa Xaa Xaa Leu Val Thr Lys Arg Lys Gln 20 25 30 Xaa Thr Ser Asp Xaa 35 169 494 DNA Conus nobilis CDS (21)..(242) 169 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca cac ttc tta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val Pro His Phe Leu Thr Pro Gln His Ile Leu 30 35 40 caa agt ctg act tcc cgt aat ggt tct ggc agc agt aat cag aaa gaa 197 Gln Ser Leu Thr Ser Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu 45 50 55 gcg caa cta tgc atc tgg aag gta tgt cca cca acc cca tgg aga 242 Ala Gln Leu Cys Ile Trp Lys Val Cys Pro Pro Thr Pro Trp Arg 60 65 70 tgatcacaag gaaaaagatg aacggcgtca gacaaccgcc acaactgtag tgggacatcg 302 ttgatacgac ttcagcaaat attttaacat cactgtggtt gtgaagaaat cagttgtttt 362 aaaagattgg atttttcctt gtttaagagt tgtactgata tcagctctgc actatgaaat 422 aaagctgatg tgacaagcaa aaaaaaaaaa aaaaagtact ctgcgttgtt actcgagctt 482 aagggcgaat tc 494 170 74 PRT Conus nobilis 170 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Phe Leu Thr Pro Gln His Ile Leu Gln Ser Leu Thr Ser 35 40 45 Arg Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu Ala Gln Leu Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Thr Pro Trp Arg 65 70 171 25 PRT Conus nobilis PEPTIDE (1)..(25) Xaa at residue 10 may be Glu or Gla; Xaa at residues 16 and 24 may be Trp or bromo-Trp; Xaa at residues 20, 21 and 23 may be Pro or hydroxy-Pro 171 Asn Gly Ser Gly Ser Ser Asn Gln Lys Xaa Ala Gln Leu Cys Ile Xaa 1 5 10 15 Lys Val Cys Xaa Xaa Thr Xaa Xaa Arg 20 25 172 604 DNA Conus nobilis CDS (21)..(350) 172 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg atg atg gtg 53 Met Gln Thr Ala Tyr Trp Val Met Met Met Val 1 5 10 gtg gtg atg atg gtg ggg gtt act gtc gct ggc tca ctg tct gtg ttt 101 Val Val Met Met Val Gly Val Thr Val Ala Gly Ser Leu Ser Val Phe 15 20 25 gat gac gac aat gac tct gac cca gct gtc aag cgc gcc atc acg tgg 149 Asp Asp Asp Asn Asp Ser Asp Pro Ala Val Lys Arg Ala Ile Thr Trp 30 35 40 tct cga ttc ctg ggc gcg tct cca gcc ttc ctg gca cag cag cga gcg 197 Ser Arg Phe Leu Gly Ala Ser Pro Ala Phe Leu Ala Gln Gln Arg Ala 45 50 55 ctg gct ccc ttc gcc aac cga ccc atc aat gag cag aaa cgt ttc cga 245 Leu Ala Pro Phe Ala Asn Arg Pro Ile Asn Glu Gln Lys Arg Phe Arg 60 65 70 75 cct gcc gtg aag agc cga tca cga cga gcg ccg ccg tgc gta tgg aag 293 Pro Ala Val Lys Ser Arg Ser Arg Arg Ala Pro Pro Cys Val Trp Lys 80 85 90 gtg tgt ccc gct ccc ccc tgg ctg gtc acc aaa cgt aaa cag gaa acc 341 Val Cys Pro Ala Pro Pro Trp Leu Val Thr Lys Arg Lys Gln Glu Thr 95 100 105 agc gac tac tgacgtcata cctcaataga ccgactcatg acttcaacgc 390 Ser Asp Tyr 110 tgaattgacc tcaccgagag ctccaacgtc acagcaggag cgagagagag agagagagag 450 agagagagag aaaggctgga gtatttctct ttctttcggt ttttcgtgtt gaagtgtgat 510 cagctgggct ggttcaaaat tgttgaataa agttgaataa aaaaaaaaaa aaaaaaagta 570 ctctgcgttg ttactcgagc ttaagggcga attc 604 173 110 PRT Conus nobilis 173 Met Gln Thr Ala Tyr Trp Val Met Met Met Val Val Val Met Met Val 1 5 10 15 Gly Val Thr Val Ala Gly Ser Leu Ser Val Phe Asp Asp Asp Asn Asp 20 25 30 Ser Asp Pro Ala Val Lys Arg Ala Ile Thr Trp Ser Arg Phe Leu Gly 35 40 45 Ala Ser Pro Ala Phe Leu Ala Gln Gln Arg Ala Leu Ala Pro Phe Ala 50 55 60 Asn Arg Pro Ile Asn Glu Gln Lys Arg Phe Arg Pro Ala Val Lys Ser 65 70 75 80 Arg Ser Arg Arg Ala Pro Pro Cys Val Trp Lys Val Cys Pro Ala Pro 85 90 95 Pro Trp Leu Val Thr Lys Arg Lys Gln Glu Thr Ser Asp Tyr 100 105 110 174 37 PRT Conus nobilis PEPTIDE (1)..(37) Xaa at residues 3, 13, 14, 21, 23 and 24 may be Pro or hydroxy-Pro; Xaa at residues 17 and 25 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 33 may be Glu or Gla; 174 Phe Arg Xaa Ala Val Lys Ser Arg Ser Arg Arg Ala Xaa Xaa Cys Val 1 5 10 15 Xaa Lys Val Cys Xaa Ala Xaa Xaa Xaa Leu Val Thr Lys Arg Lys Gln 20 25 30 Xaa Thr Ser Asp Xaa 35 175 391 DNA Conus parius CDS (21)..(275) 175 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg gtg tgg att aca gcc cct ttg tct gaa ggt ggt aaa ccg aag 101 Met Val Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Pro Lys 15 20 25 cac gca att cgg ggt ttg gtg cca gac gac tta acc cca cag ctt atc 149 His Ala Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile 30 35 40 ttg cga agt ctg att tcc cgt cgt agt tct ttc ggc aag gat gcg aaa 197 Leu Arg Ser Leu Ile Ser Arg Arg Ser Ser Phe Gly Lys Asp Ala Lys 45 50 55 ccc ccc ttt agt tgt tca ggc ctc cga ggg ggt tgc gtc cta cct ccc 245 Pro Pro Phe Ser Cys Ser Gly Leu Arg Gly Gly Cys Val Leu Pro Pro 60 65 70 75 aat ctc agg cca aag ttc aac aaa ggt gga taacaaaccc aagcgttcct 295 Asn Leu Arg Pro Lys Phe Asn Lys Gly Gly 80 85 agttatacga atgccagcaa ataaaagcag tttgattgtg aaaaaaaaaa aaaaaaaaag 355 tactctgcgt tgttactcga gcttaagggc gaattc 391 176 85 PRT Conus parius 176 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val Trp Ile 1 5 10 15 Thr Ala Pro Leu Ser Glu Gly Gly Lys Pro Lys His Ala Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile 35 40 45 Ser Arg Arg Ser Ser Phe Gly Lys Asp Ala Lys Pro Pro Phe Ser Cys 50 55 60 Ser Gly Leu Arg Gly Gly Cys Val Leu Pro Pro Asn Leu Arg Pro Lys 65 70 75 80 Phe Asn Lys Gly Gly 85 177 25 PRT Conus parius PEPTIDE (1)..(25) Xaa at residues 1, 3, 15, 16 and 20 may be Pro or hydroxy-Pro 177 Xaa Xaa Phe Ser Cys Ser Gly Leu Arg Gly Gly Cys Val Leu Xaa Xaa 1 5 10 15 Asn Leu Arg Xaa Lys Phe Asn Lys Gly 20 25 178 390 DNA Conus parius CDS (19)..(273) 178 gaattcgccc ttggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 51 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg atg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ccg aag 99 Met Val Met Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Pro Lys 15 20 25 ctc ata att cgg ggt ttg gtg cca aac gac tta acc cca cag cgt atc 147 Leu Ile Ile Arg Gly Leu Val Pro Asn Asp Leu Thr Pro Gln Arg Ile 30 35 40 ttg cga agt ctg att tcc ggg cgt act tat ggc atc tat gat gcg aaa 195 Leu Arg Ser Leu Ile Ser Gly Arg Thr Tyr Gly Ile Tyr Asp Ala Lys 45 50 55 ccc ccc ttt agt tgt gca ggc ctc cga ggg ggt tgc gtc cta cct ccc 243 Pro Pro Phe Ser Cys Ala Gly Leu Arg Gly Gly Cys Val Leu Pro Pro 60 65 70 75 aat ctc agg cca aag ttc aag gaa ggt cga taaaaaaccc aagcgttcct 293 Asn Leu Arg Pro Lys Phe Lys Glu Gly Arg 80 85 agttatacga atgccagcaa ataaaagcag tttgattgcg aaaaaaaaaa aaaaaaaaaa 353 gtactctgcg ttgttactcg agcttaaggg cgaattc 390 179 85 PRT Conus parius 179 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Met Trp Ile 1 5 10 15 Thr Ala Pro Leu Ser Glu Gly Gly Lys Pro Lys Leu Ile Ile Arg Gly 20 25 30 Leu Val Pro Asn Asp Leu Thr Pro Gln Arg Ile Leu Arg Ser Leu Ile 35 40 45 Ser Gly Arg Thr Tyr Gly Ile Tyr Asp Ala Lys Pro Pro Phe Ser Cys 50 55 60 Ala Gly Leu Arg Gly Gly Cys Val Leu Pro Pro Asn Leu Arg Pro Lys 65 70 75 80 Phe Lys Glu Gly Arg 85 180 24 PRT Conus parius PEPTIDE (1)..(24) Xaa at residues 1, 2, 15, 16 and 20 may be Pro or hydroxy-Pro; Xaa at residue 24 may be Glu or Gla 180 Xaa Xaa Phe Ser Cys Ala Gly Leu Arg Gly Gly Cys Val Leu Xaa Xaa 1 5 10 15 Asn Leu Arg Xaa Lys Phe Lys Xaa 20 181 489 DNA Conus planorbis CDS (21)..(251) 181 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg atg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Met Met Met 1 5 10 atg gtg tgg att aca ggc cat ctg tct gaa ggt ggc aaa ttg aag gat 101 Met Val Trp Ile Thr Gly His Leu Ser Glu Gly Gly Lys Leu Lys Asp 15 20 25 gca att agg ggt ttg gtg cca gac gac ttg acc tca atg ttt gcg ttg 149 Ala Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Ser Met Phe Ala Leu 30 35 40 cat ctt ccg gtt tcc cat tct cgg tct agc agc aat ggt ctg aag aga 197 His Leu Pro Val Ser His Ser Arg Ser Ser Ser Asn Gly Leu Lys Arg 45 50 55 gct gac cta tgt atc cac aag att tgt cca cca cgg tat cac caa agc 245 Ala Asp Leu Cys Ile His Lys Ile Cys Pro Pro Arg Tyr His Gln Ser 60 65 70 75 caa caa taaaagacgt cagacaacca ccacaacttt agtatgacat cgttaatagg 301 Gln Gln acttcagcaa gtattttaac atcactgtgg ttgtgatgaa atcagtcgcc ttaaaagatt 361 ggctttttcc ttgtttaaga gttgtacttg tatcagcttt gcacttcgaa ataaagttga 421 tgtgatgaac caaaaaaaaa aaaaaaaaaa agtactctgc gttgttactc gagcttaagg 481 gcgaattc 489 182 77 PRT Conus planorbis 182 Met Gln Thr Ala Tyr Trp Val Met Met Met Met Met Val Trp Ile Thr 1 5 10 15 Gly His Leu Ser Glu Gly Gly Lys Leu Lys Asp Ala Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Ser Met Phe Ala Leu His Leu Pro Val Ser 35 40 45 His Ser Arg Ser Ser Ser Asn Gly Leu Lys Arg Ala Asp Leu Cys Ile 50 55 60 His Lys Ile Cys Pro Pro Arg Tyr His Gln Ser Gln Gln 65 70 75 183 26 PRT Conus planorbis PEPTIDE (1)..(26) Xaa at residues 18 and 19 may be Pro or hydroxy-Pro; Xaa at residue 21 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Ty 183 Ser Ser Ser Asn Gly Leu Lys Arg Ala Asp Leu Cys Ile His Lys Ile 1 5 10 15 Cys Xaa Xaa Arg Xaa His Gln Ser Gln Gln 20 25 184 834 DNA Conus pulicarius CDS (1)..(246) misc_feature (1)..(834) n may be any nucleotide 184 atg cag acg gcc tac tgg gtg atg gtg atg atg atg atg gtg tgg gtt 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Met Val Trp Val 1 5 10 15 aca gcg cct gtg tct gaa ggt ggt aaa ttg agc gac gta att cgg ggt 96 Thr Ala Pro Val Ser Glu Gly Gly Lys Leu Ser Asp Val Ile Arg Gly 20 25 30 ttg gtg cca gac gac ata acc cca cag att att ttg caa agt ctg aat 144 Leu Val Pro Asp Asp Ile Thr Pro Gln Ile Ile Leu Gln Ser Leu Asn 35 40 45 gcc agt cgt cat gct tac aga cgt gtt cgt ctg aga gga cag ata tgt 192 Ala Ser Arg His Ala Tyr Arg Arg Val Arg Leu Arg Gly Gln Ile Cys 50 55 60 atc tgg aag gta tgt cca cca cta cta caa tgg ata cat cca tta gta 240 Ile Trp Lys Val Cys Pro Pro Leu Leu Gln Trp Ile His Pro Leu Val 65 70 75 80 aaa aga tgaatgacat cagacaaccg ccacaactgt agtacgacat cgttaacacg 296 Lys Arg acttcagcaa atattctaac atcacagtgg gttgtgaaga natcgggttg gctttaaaaa 356 aaanaatggg ggnttttccc cntgggttta aaaaaanntn ggnnccgggn aannncccnn 416 nntnnncccc ccccnntngg gagaaaaaaa aaannccnnt nnnggggggn nnncnaaaaa 476 aaaaaaaaaa aaaaaaaaaa aaaaancccc nggggggntg ntttnncccc ccnccccngg 536 gggggggggn gntttnnccc cccccccgng gggggggggg nttttnnttt nngggggngc 596 cccccccccc cccnnncnnn nnaanaannn nngggggggg ggaanaaaaa nannnnnnnn 656 nnnnnnnnnn ttttntcnnt cnnccgngnn gnnaaaaaaa aaanttnatt tntnnannnc 716 nncnnnccnn cnncnnaccc nnccccnncc ncnncanncn nagannanga ggggggggng 776 nnnnggngna nnnnnannnn nnngaannng aggngngnnn cncgncnncg cncnngnc 834 185 82 PRT Conus pulicarius misc_feature (1)..(834) n may be any nucleotide 185 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Met Val Trp Val 1 5 10 15 Thr Ala Pro Val Ser Glu Gly Gly Lys Leu Ser Asp Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Ile Thr Pro Gln Ile Ile Leu Gln Ser Leu Asn 35 40 45 Ala Ser Arg His Ala Tyr Arg Arg Val Arg Leu Arg Gly Gln Ile Cys 50 55 60 Ile Trp Lys Val Cys Pro Pro Leu Leu Gln Trp Ile His Pro Leu Val 65 70 75 80 Lys Arg 186 26 PRT Conus pulicarius PEPTIDE (1)..(26) Xaa at residues 10 and 19 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 14, 15 and 22 may be Pro or hydroxy-Pro 186 Val Arg Leu Arg Gly Gln Ile Cys Ile Xaa Lys Val Cys Xaa Xaa Leu 1 5 10 15 Leu Gln Xaa Ile His Xaa Leu Val Lys Arg 20 25 187 471 DNA Conus pulicarius CDS (1)..(246) 187 atg cag acg gcc tac tgg gtg atg gtg atg atg atg atg gtg tgg gtt 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Met Val Trp Val 1 5 10 15 aca gcg cct gtg tct gaa ggt ggt aaa ttg agc gac gta att cgg ggt 96 Thr Ala Pro Val Ser Glu Gly Gly Lys Leu Ser Asp Val Ile Arg Gly 20 25 30 ttg gtg cca gac gac tta acc cca cag att atc ttg caa agt ctg aat 144 Leu Val Pro Asp Asp Leu Thr Pro Gln Ile Ile Leu Gln Ser Leu Asn 35 40 45 gcc agt cgt cat gct tac aga cgt gtt cgt ccg aga gga cag ata tgt 192 Ala Ser Arg His Ala Tyr Arg Arg Val Arg Pro Arg Gly Gln Ile Cys 50 55 60 atc tgg aag gta tgt cca cca cta cta caa tgg ata cat cca tta gta 240 Ile Trp Lys Val Cys Pro Pro Leu Leu Gln Trp Ile His Pro Leu Val 65 70 75 80 aaa aga tgaatgacat cagacaaccg ccacaactgt agtacggcat cgttaacacg 296 Lys Arg acttcagcaa atattttaac atcacagtgg ttgtgaagaa atcggttgct ttaaaaaaag 356 attgggtttt tccttgttta agagttgtac tgatatcagt tctgcactat gaaataaagc 416 tgatgtgacg aacaaaaaaa aaaaaaaaaa aaagtactct gcgttgttac tcgag 471 188 82 PRT Conus pulicarius 188 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Met Val Trp Val 1 5 10 15 Thr Ala Pro Val Ser Glu Gly Gly Lys Leu Ser Asp Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Leu Thr Pro Gln Ile Ile Leu Gln Ser Leu Asn 35 40 45 Ala Ser Arg His Ala Tyr Arg Arg Val Arg Pro Arg Gly Gln Ile Cys 50 55 60 Ile Trp Lys Val Cys Pro Pro Leu Leu Gln Trp Ile His Pro Leu Val 65 70 75 80 Lys Arg 189 26 PRT Conus pulicarius PEPTIDE (1)..(26) Xaa at residues 3, 14, 15 and 22 may be Pro or hydroxy-Pro; Xaa at residues 10 and 19 may be Trp (D or L) or bromo-Trp (D or L) 189 Val Arg Xaa Arg Gly Gln Ile Cys Ile Xaa Lys Val Cys Xaa Xaa Leu 1 5 10 15 Leu Gln Xaa Ile His Xaa Leu Val Lys Arg 20 25 190 471 DNA Conus pulicarius CDS (1)..(246) 190 atg cag acg gcc tac tgg gtg atg gtg atg atg atg atg gtg tgg gtt 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Met Val Trp Val 1 5 10 15 aca gcg cct gtg tct gaa ggt ggt aaa ttg agc gac gta att cgg ggt 96 Thr Ala Pro Val Ser Glu Gly Gly Lys Leu Ser Asp Val Ile Arg Gly 20 25 30 ttg gtg cca gac gac ata acc cca cag att atc ttg caa agt ctg aat 144 Leu Val Pro Asp Asp Ile Thr Pro Gln Ile Ile Leu Gln Ser Leu Asn 35 40 45 gcc agt cgt cat gct tac aga cct gtt cgt ctg aga gga cag ata tgt 192 Ala Ser Arg His Ala Tyr Arg Pro Val Arg Leu Arg Gly Gln Ile Cys 50 55 60 atc tgg aag gta tgt cca cca cta cta caa tgg ata cat cca tta gta 240 Ile Trp Lys Val Cys Pro Pro Leu Leu Gln Trp Ile His Pro Leu Val 65 70 75 80 aaa aga tgaatgacat cagacaaccg ccacaactgt agtacgacat cgttaacacg 296 Lys Arg acttcagcaa atattttaac atcacagtgg ttgtgaagaa atcggttgct ttaaaaaaag 356 attgggtttt tccttgttta agagttgtac tgatatcagt tctgcactat gaaataaagc 416 tgatgtgacg aacaaaaaaa aaaaaaaaaa aaagtactct gcgttgttac tcgag 471 191 82 PRT Conus pulicarius 191 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Met Val Trp Val 1 5 10 15 Thr Ala Pro Val Ser Glu Gly Gly Lys Leu Ser Asp Val Ile Arg Gly 20 25 30 Leu Val Pro Asp Asp Ile Thr Pro Gln Ile Ile Leu Gln Ser Leu Asn 35 40 45 Ala Ser Arg His Ala Tyr Arg Pro Val Arg Leu Arg Gly Gln Ile Cys 50 55 60 Ile Trp Lys Val Cys Pro Pro Leu Leu Gln Trp Ile His Pro Leu Val 65 70 75 80 Lys Arg 192 27 PRT Conus pulicarius PEPTIDE (1)..(27) Xaa at residues 1, 15, 16 and 23 may be Pro or hydroxy-Pro; Xaa at residues 11 and 20 may be Trp (D or L) or bromo-Trp (D or L) 192 Xaa Val Arg Leu Arg Gly Gln Ile Cys Ile Xaa Lys Val Cys Xaa Xaa 1 5 10 15 Leu Leu Gln Xaa Ile His Xaa Leu Val Lys Arg 20 25 193 375 DNA Conus rattus CDS (1)..(282) 193 atg cag acg gcc tac tgg gtg atg gtg atg atg gtg gtg gtg ggg ttc 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Val Val Val Gly Phe 1 5 10 15 acc gtc ggg ggt cac gtc cat caa tct cac agt cct aca tcg cgc agc 96 Thr Val Gly Gly His Val His Gln Ser His Ser Pro Thr Ser Arg Ser 20 25 30 cat ggt gat gac tcc att cat gac aag acg att cat caa cat ctg ttt 144 His Gly Asp Asp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 40 45 gcc cgt ctt cct ctg gag aac aac gac gac cat cgt tct gtg gat ctt 192 Ala Arg Leu Pro Leu Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 cct gca ggg acc agc gca ggc gac atg aaa cca caa cgc caa aga cgt 240 Pro Ala Gly Thr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln Arg Arg 65 70 75 80 ctc tgc tgc atc ttt gcc att ctt tgg ttc tgt tgt ctc ggt 282 Leu Cys Cys Ile Phe Ala Ile Leu Trp Phe Cys Cys Leu Gly 85 90 taacagtaca aattgcaatg cactggccga ttgaaagaac tgcaataaac ggaaaaaaaa 342 aaaaaaaaaa agtactctgc gttgttactc gag 375 194 94 PRT Conus rattus 194 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Val Val Val Gly Phe 1 5 10 15 Thr Val Gly Gly His Val His Gln Ser His Ser Pro Thr Ser Arg Ser 20 25 30 His Gly Asp Asp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 40 45 Ala Arg Leu Pro Leu Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 Pro Ala Gly Thr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln Arg Arg 65 70 75 80 Leu Cys Cys Ile Phe Ala Ile Leu Trp Phe Cys Cys Leu Gly 85 90 195 13 PRT Conus rattus PEPTIDE (1)..(13) Xaa at residue 9 may be Trp (D or L) or bromo-Trp (D or L 195 Leu Cys Cys Ile Phe Ala Ile Leu Xaa Phe Cys Cys Leu 1 5 10 196 494 DNA Conus striatus CDS (21)..(287) 196 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca cac atc tta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val Pro His Ile Leu Thr Pro Gln His Ile Leu 30 35 40 caa agt ctg att tcc cct ctt cgt tct aac aac ggt cgt tcg agt gga 197 Gln Ser Leu Ile Ser Pro Leu Arg Ser Asn Asn Gly Arg Ser Ser Gly 45 50 55 gca caa ata tgc atc tgg aag gta tgt cca cca tcc cca tgg aga caa 245 Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Gln 60 65 70 75 cca caa gaa atg atg aat gac atc aga caa ccg cca caa ctg 287 Pro Gln Glu Met Met Asn Asp Ile Arg Gln Pro Pro Gln Leu 80 85 tagtacgaca tcgttgatac gactttagca aatattttaa catcactgtg gttgtgaaga 347 aatcagttgc tttaaaagat tggatttttc cttgtttaag agttgtactg atatcagctc 407 tgcactatga aataaagctg atgtgacaaa caaaaaaaaa aaaaaaaaaa gtactctgcg 467 ttgttactcg agcttaaggg cgaattc 494 197 89 PRT Conus striatus 197 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Ile Ser 35 40 45 Pro Leu Arg Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Gln Pro Gln Glu Met Met 65 70 75 80 Asn Asp Ile Arg Gln Pro Pro Gln Leu 85 198 38 PRT Conus striatus PEPTIDE (1)..(38) Xaa at residues 14 and 22 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 18, 19, 21, 25, 35 and 36 may be Pro or hydroxy-Pro; Xaa at residue 27 may be Glu or Gla 198 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa Xaa Arg Gln Xaa Gln Xaa Met Met Asn Asp Ile 20 25 30 Arg Gln Xaa Xaa Gln Leu 35 199 412 DNA Conus striolatus CDS (1)..(240) 199 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gac cct ctg tct gaa ggt ggt aaa ttg aac gac gta att cgg ggt ttg 96 Asp Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca cgc atc tta acc cca cag cat acc ttg cga agt ccg act tcc 144 Val Pro Arg Ile Leu Thr Pro Gln His Thr Leu Arg Ser Pro Thr Ser 35 40 45 ctt ctt cgt tct aac acc ggt ggt tcg agt gga gca caa ata tgc atc 192 Leu Leu Arg Ser Asn Thr Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 tgg aag gta tgt cca cca tcc cca tgg aga cga tca caa gga aaa aga 240 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Ser Gln Gly Lys Arg 65 70 75 80 tgaatgacgt cagacaagcg ccacaactgt agtacgacat cgttgatacg acttcagcaa 300 gtattttaac atcactgtgg ttgtgaagaa atcagttgct ttaaaagatt ggatttttcc 360 ttgtttaaga gttgtactga tatcagctct gccctgtgaa ataaagctga tg 412 200 80 PRT Conus striolatus 200 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Asp Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Arg Ile Leu Thr Pro Gln His Thr Leu Arg Ser Pro Thr Ser 35 40 45 Leu Leu Arg Ser Asn Thr Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Ser Gln Gly Lys Arg 65 70 75 80 201 26 PRT Conus striolatus PEPTIDE (1)..(26) Xaa at residues 14 and 22 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 18, 19 and 21 may be Pro or hydroxy-Pro 201 Ser Asn Thr Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa Xaa Arg Arg Ser Gln 20 25 202 412 DNA Conus striolatus CDS (1)..(240) 202 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt ggt aaa ttg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca cac atc tta acc cca cag cat atc ttg caa agt ctg att tcc 144 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Ile Ser 35 40 45 cct ctt cgt tct aac aac ggt cgt tcg agt gga gca caa ata tgc atc 192 Pro Leu Arg Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 tgg aag gta tgt cca cca tcc cca tgg aga cga tca caa gga aaa aga 240 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Ser Gln Gly Lys Arg 65 70 75 80 tgaatgacgt cagacaagcg ccacaactgt agtacgacat cgttgatacg acttcagcaa 300 gtattttaac atcactgtgg ttgtgaagaa atcagttgct ttaaaagatt ggatttttcc 360 ttgtttaaga gttgtactga tatcagctct gcactgtgaa ataaagctga tg 412 203 80 PRT Conus striolatus 203 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Ile Ser 35 40 45 Pro Leu Arg Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Ser Gln Gly Lys Arg 65 70 75 80 204 26 PRT Conus striolatus PEPTIDE (1)..(26) Xaa at residues 14 and 22 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 18, 19 and 21 may be Pro or hydroxy-Pro 204 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa Xaa Arg Arg Ser Gln 20 25 205 497 DNA Conus striolatus CDS (21)..(257) 205 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aaa gac cct ctg tct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Lys Asp Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca cac atc tta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val Pro His Ile Leu Thr Pro Gln His Ile Leu 30 35 40 caa agt ctg att tcc cct ctt cgt tct aac aac ggt cgt tcg agt gga 197 Gln Ser Leu Ile Ser Pro Leu Arg Ser Asn Asn Gly Arg Ser Ser Gly 45 50 55 gca caa ata tgc aac tgg aag gta tgt cca cca tcc cca tgg aga cga 245 Ala Gln Ile Cys Asn Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg 60 65 70 75 cca cga gga aaa tgatgaatga catcagacaa ccgccacaac tgtagtacga 297 Pro Arg Gly Lys cttcgttgat acgactttag caaatatttt aacatcactg tggttgtgaa gaaatcagtt 357 gctttaaaag attggatttt tccttgttta agagttgtac tgatatcagc tctgcactat 417 gaaataaagc tgatgtgaca aacaaaaaaa aaaaaaaaaa aaagtactct gcgttgttac 477 tcgagcttaa gggcgaattc 497 206 79 PRT Conus striolatus 206 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Lys 1 5 10 15 Asp Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Ile Ser 35 40 45 Pro Leu Arg Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Asn 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Pro Arg Gly Lys 65 70 75 207 26 PRT Conus striolatus PEPTIDE (1)..(26) Xaa at residues 14 and 22 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 18, 19, 21 and 25 may be Pro or hydroxy-Pro 207 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Asn Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa Xaa Arg Arg Xaa Arg 20 25 208 496 DNA Conus striolatus CDS (21)..(287) 208 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ctg tct gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca cac atc tta acc cca cag cat atc ttg 149 Val Ile Arg Gly Leu Val Pro His Ile Leu Thr Pro Gln His Ile Leu 30 35 40 caa agt ctg att tcc cct ctt cgt tct aac aac ggt cgt tcg agt gga 197 Gln Ser Leu Ile Ser Pro Leu Arg Ser Asn Asn Gly Arg Ser Ser Gly 45 50 55 gca caa ata tgc atc tgg aag gta tgt cca cca tcc cca tgg aga caa 245 Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Gln 60 65 70 75 cca caa gaa atg atg aat gac atc aga caa ccg cca caa ctg 287 Pro Gln Glu Met Met Asn Asp Ile Arg Gln Pro Pro Gln Leu 80 85 tagtacgaca tcgttgatac gactttagca aatattttaa catcactgtg gttgtgaaga 347 aatcagttgc tttaaaagat tggatttttc cttgtttaag agttgtactg atatcagctc 407 tgcactatga aataaagctg atgtgacaaa cgaaaaaaaa aaaaaaaaaa aagtactctg 467 cgttgttact cgagcttaag ggcgaattc 496 209 89 PRT Conus striolatus 209 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro His Ile Leu Thr Pro Gln His Ile Leu Gln Ser Leu Ile Ser 35 40 45 Pro Leu Arg Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Val Cys Pro Pro Ser Pro Trp Arg Gln Pro Gln Glu Met Met 65 70 75 80 Asn Asp Ile Arg Gln Pro Pro Gln Leu 85 210 38 PRT Conus striolatus PEPTIDE (1)..(38) Xaa at residues 14 and 22 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 18, 19, 21, 25, 35 and 36 may be Pro or hydroxy-Pro; Xaa at residue 27 may be Glu or Gla 210 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile Xaa Lys Val 1 5 10 15 Cys Xaa Xaa Ser Xaa Xaa Arg Gln Xaa Gln Xaa Met Met Asn Asp Ile 20 25 30 Arg Gln Xaa Xaa Gln Leu 35 211 413 DNA Conus sulcatus CDS (1)..(234) 211 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc tct ctg tct gaa ggt ggt aaa ccg aac gac gtc att cgg ggt ttt 96 Ala Ser Leu Ser Glu Gly Gly Lys Pro Asn Asp Val Ile Arg Gly Phe 20 25 30 gtg cca gac gac tta acc cca cag ctt atc ttg cga agt ctg att tcc 144 Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile Ser 35 40 45 cgt cgt cgt tct gac aag gat gtt ggg aag aga atg gaa tgt tac tgg 192 Arg Arg Arg Ser Asp Lys Asp Val Gly Lys Arg Met Glu Cys Tyr Trp 50 55 60 aag gca tgt aga ccc acg cta tcg aga cga cat gat ctt ggg 234 Lys Ala Cys Arg Pro Thr Leu Ser Arg Arg His Asp Leu Gly 65 70 75 taaaagatga atgacgtcag acaacagcca caactatagt atgacatcgt taatacgact 294 tcagcaaata ttttaacatc actgtggttg tgaagaaatc agttgcttta aaagattgga 354 tttttccgtg tttaagagtt gtactgatat cagctctgcc ctgtgaaata aagctgatg 413 212 78 PRT Conus sulcatus 212 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Ser Leu Ser Glu Gly Gly Lys Pro Asn Asp Val Ile Arg Gly Phe 20 25 30 Val Pro Asp Asp Leu Thr Pro Gln Leu Ile Leu Arg Ser Leu Ile Ser 35 40 45 Arg Arg Arg Ser Asp Lys Asp Val Gly Lys Arg Met Glu Cys Tyr Trp 50 55 60 Lys Ala Cys Arg Pro Thr Leu Ser Arg Arg His Asp Leu Gly 65 70 75 213 27 PRT Conus sulcatus PEPTIDE (1)..(27) Xaa at residue 11 may be Glu or Gla; Xaa at residue 13 may be Tyr, 125I-Tyr, mono-iodo-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr; Xaa at residue 14 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residue 19 may be Pro or hydroxy-Pro 213 Arg Ser Asp Lys Asp Val Gly Lys Arg Met Xaa Cys Xaa Xaa Lys Ala 1 5 10 15 Cys Arg Xaa Thr Leu Ser Arg Arg His Asp Leu 20 25 214 472 DNA Conus terebra CDS (1)..(234) 214 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt gat aaa ttg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca gat aac tta gcc cca cag ctt gtt ttg caa agt ctg gat tcc 144 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 cgt cgt cat cct cac ggc att cgt cag gat gga gcc caa ata tgt atc 192 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile 50 55 60 tgg aag ata tgt cca cca tcc cca tgg aaa cga ctt gga tct 234 Trp Lys Ile Cys Pro Pro Ser Pro Trp Lys Arg Leu Gly Ser 65 70 75 taagaaaaga aacaattgac gtcagacaac cgccacaact tgagtacgac atcgttaata 294 caacttcagc aaatatgaaa ttttcagcat cactgtggtt gtgaagaaat cagttgcttt 354 aaaagattgg atttgtcctt gtttaagagt tgtactgatg tcatctctgc actgtgaaat 414 aaagctgatg tgacaaacaa aaaaaaaaaa aaaaaagtac tctgcgttgt tactcgag 472 215 78 PRT Conus terebra 215 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu Gln Ser Leu Asp Ser 35 40 45 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Ile Cys Pro Pro Ser Pro Trp Lys Arg Leu Gly Ser 65 70 75 216 28 PRT Conus terebra PEPTIDE (1)..(28) Xaa at residues 2, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residues 15 and 23 may be Trp (D or L) or bromo-Trp (D or L) 216 His Xaa His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile Xaa Lys 1 5 10 15 Ile Cys Xaa Xaa Ser Xaa Xaa Lys Arg Leu Gly Ser 20 25 217 474 DNA Conus terebra CDS (1)..(234) 217 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg tgg att aca 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 gcc cct ctg tct gaa ggt gat aaa ttg aac gac gta att cgg ggt ttg 96 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 gtg cca gat aac tta gcc cca cag ctt gtt ttg cat agt ctg gat tcc 144 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu His Ser Leu Asp Ser 35 40 45 cgt cgt cat cct cac ggc att cgt cag gat gga gcc caa ata tgt atc 192 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile 50 55 60 tgg aag ata tgt cca cca tcc cca tgg aga cga ctt gga tct 234 Trp Lys Ile Cys Pro Pro Ser Pro Trp Arg Arg Leu Gly Ser 65 70 75 taagaaaaga aacaattgac gtcagacaac cgccacatct tgagtacgac atcgttaata 294 cgacttcagc aaatatgaaa ttttcagcat cactgtggtt gtgaagaaat cagttgcctt 354 aaaagattgg atttgtcctt gtttaagagt tgtactgatg tcatctctgc actatgaaat 414 aaagctgatg tgacaaacaa aaaaaaaaaa aaaaaaaagt actctgcgtt gttactcgag 474 218 78 PRT Conus terebra 218 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Asp Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asn Leu Ala Pro Gln Leu Val Leu His Ser Leu Asp Ser 35 40 45 Arg Arg His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile 50 55 60 Trp Lys Ile Cys Pro Pro Ser Pro Trp Arg Arg Leu Gly Ser 65 70 75 219 28 PRT Conus terebra PEPTIDE (1)..(28) Xaa at residues 2, 19, 20 and 22 may be Pro or hydroxy-Pro; Xaa at residues 15 and 23 may be Trp (D or L) or bromo-Trp (D or L) 219 His Xaa His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile Xaa Lys 1 5 10 15 Ile Cys Xaa Xaa Ser Xaa Xaa Arg Arg Leu Gly Ser 20 25 220 485 DNA Conus vexillum CDS (21)..(236) 220 gaattcgccc ttatggatcc atg cag atg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Met Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aaa ggc cct gtg tcc gaa ggt ggt aaa ttg aac gac 101 Met Val Trp Ile Lys Gly Pro Val Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttg gtg cca gac gac ttg acc cca gtg tct gcc ttg 149 Val Ile Arg Gly Leu Val Pro Asp Asp Leu Thr Pro Val Ser Ala Leu 30 35 40 cat cat ccg gtt tcc cat cgt cgg tct cac agc agt agt ttg tgg tgt 197 His His Pro Val Ser His Arg Arg Ser His Ser Ser Ser Leu Trp Cys 45 50 55 gta tgt cca ttc agg gtg tgt cca cca tgc cat gga aga tgacctggtc 246 Val Cys Pro Phe Arg Val Cys Pro Pro Cys His Gly Arg 60 65 70 ccaaaccaac aaaataacgt cagacaaccg ccacaacttt agtacgacat cccttaatac 306 gacttcagca agtattttaa catcactatg gtgtgatgaa atcagttgct ttaaaagatt 366 ggatttttcc ttgtttaaga gttgcactga taacagccca gcagtatgaa ataaagttga 426 tgtggcaaaa aaaaaaaaaa aagtactctg cgttgttact cgagcttaag ggcgaattc 485 221 72 PRT Conus vexillum 221 Met Gln Met Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Lys 1 5 10 15 Gly Pro Val Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Leu 20 25 30 Val Pro Asp Asp Leu Thr Pro Val Ser Ala Leu His His Pro Val Ser 35 40 45 His Arg Arg Ser His Ser Ser Ser Leu Trp Cys Val Cys Pro Phe Arg 50 55 60 Val Cys Pro Pro Cys His Gly Arg 65 70 222 19 PRT Conus vexillum PEPTIDE (1)..(19) Xaa at residue 7 may be Trp (D or L) or bromo-Trp (D or L); Xaa at residues 11, 16 and 17 may be Pro or hydroxy-Pro 222 Ser His Ser Ser Ser Leu Xaa Cys Val Cys Xaa Phe Arg Val Cys Xaa 1 5 10 15 Xaa Cys His 223 481 DNA Conus vexillum CDS (21)..(257) 223 gaattcgccc ttatggatcc atg cag acg gcc tac tgg gtg atg gtg atg atg 53 Met Gln Thr Ala Tyr Trp Val Met Val Met Met 1 5 10 atg gtg tgg att aca gcc cct ttg tct gaa ggt ggt aaa ctg aac gat 101 Met Val Trp Ile Thr Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp 15 20 25 gta att cgg ggt ttc gcg cta gat gac tta gcc caa agc cgt att atg 149 Val Ile Arg Gly Phe Ala Leu Asp Asp Leu Ala Gln Ser Arg Ile Met 30 35 40 caa agt ctg gtt ttc agt cat cag cct ctt cca acg gca tcc ata tgt 197 Gln Ser Leu Val Phe Ser His Gln Pro Leu Pro Thr Ala Ser Ile Cys 45 50 55 atc tgg aag ata tgt cca cca gac cca tgg aga cga cat gat ctt cag 245 Ile Trp Lys Ile Cys Pro Pro Asp Pro Trp Arg Arg His Asp Leu Gln 60 65 70 75 aaa agt aac aaa tgacgtcaga caaccgccac aacttgaata caacatcatt 297 Lys Ser Asn Lys aatacgactt cagcaaatat tttagcatca ctgtgattgt tcggaagtca gttgctttaa 357 aagattggat ttgtccctgt tgtattgatg tcaactctgc actatgaaat aaagctgatg 417 tgacaagcaa aaaaaaaaaa aaaaaaagta ctctgcgttg ttactcgagc ttaagggcga 477 attc 481 224 79 PRT Conus vexillum 224 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Trp Ile Thr 1 5 10 15 Ala Pro Leu Ser Glu Gly Gly Lys Leu Asn Asp Val Ile Arg Gly Phe 20 25 30 Ala Leu Asp Asp Leu Ala Gln Ser Arg Ile Met Gln Ser Leu Val Phe 35 40 45 Ser His Gln Pro Leu Pro Thr Ala Ser Ile Cys Ile Trp Lys Ile Cys 50 55 60 Pro Pro Asp Pro Trp Arg Arg His Asp Leu Gln Lys Ser Asn Lys 65 70 75 225 38 PRT Conus vexillum PEPTIDE (1)..(38) Xaa at residues 11, 14, 24, 25 and 27 may be Pro or hydroxy-Pro; Xaa at residues 20 and 28 may be Trp (D or L) or bromo-Trp (D or L) 225 Ile Met Gln Ser Leu Val Phe Ser His Gln Xaa Leu Xaa Thr Ala Ser 1 5 10 15 Ile Cys Ile Xaa Lys Ile Cys Xaa Xaa Asp Xaa Xaa Arg Arg His Asp 20 25 30 Leu Gln Lys Ser Asn Lys 35 226 384 DNA Conus vexillum CDS (1)..(285) 226 atg cag acg gcc tac tgg gtg atg gtg atg atg atg gtg gtg ggg ttc 48 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val Gly Phe 1 5 10 15 acc gtc gag agt cac gtc cat cag tct cac agt cct aca tcg cgc agc 96 Thr Val Glu Ser His Val His Gln Ser His Ser Pro Thr Ser Arg Ser 20 25 30 cat ggt gat gac tcc att cat gac aag acg att cat caa cat ctg ttt 144 His Gly Asp Asp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 40 45 gcc cgt ctt cct ctg gag aac aac gac gac cat cgt tct gtg gat ctt 192 Ala Arg Leu Pro Leu Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 cct gca ggg act agc gca ggc gac atg aaa cca caa cgc cag aaa cgt 240 Pro Ala Gly Thr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln Lys Arg 65 70 75 80 ttc tgc tgc atc ttt gcc ccg att ctt ttg ttc tgt tgt ttc ggt 285 Phe Cys Cys Ile Phe Ala Pro Ile Leu Leu Phe Cys Cys Phe Gly 85 90 95 taacagcaca aattacactg cactggccga ttgaaagaac tgcaataaac ggtaaagcaa 345 aaaaaaaaaa aaaaaaagta ctctgcgttg ttactcgag 384 227 95 PRT Conus vexillum 227 Met Gln Thr Ala Tyr Trp Val Met Val Met Met Met Val Val Gly Phe 1 5 10 15 Thr Val Glu Ser His Val His Gln Ser His Ser Pro Thr Ser Arg Ser 20 25 30 His Gly Asp Asp Ser Ile His Asp Lys Thr Ile His Gln His Leu Phe 35 40 45 Ala Arg Leu Pro Leu Glu Asn Asn Asp Asp His Arg Ser Val Asp Leu 50 55 60 Pro Ala Gly Thr Ser Ala Gly Asp Met Lys Pro Gln Arg Gln Lys Arg 65 70 75 80 Phe Cys Cys Ile Phe Ala Pro Ile Leu Leu Phe Cys Cys Phe Gly 85 90 95 228 14 PRT Conus vexillum PEPTIDE (1)..(14) Xaa at residue 7 may be Pro or hydroxy-Pro 228 Phe Cys Cys Ile Phe Ala Xaa Ile Leu Leu Phe Cys Cys Phe 1 5 10 229 40 PRT Conus tulipa 229 Glx Thr Asp Val Leu Leu Glu Ala Thr Leu Leu Thr Thr Pro Ala Pro 1 5 10 15 Glu Gln Arg Leu Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg Pro Tyr 20 25 30 Pro Trp Arg Arg Arg Asp Leu Asn 35 40 230 40 PRT Conus magus 230 Glx Thr Asp Val Leu Leu Asp Ala Thr Leu Leu Thr Thr Pro Ala Pro 1 5 10 15 Glu Gln Arg Leu Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg Pro Tyr 20 25 30 Pro Trp Arg Arg Arg Asn Leu Asn 35 40 231 40 PRT Conus geographus 231 Glx Thr Asp Val Leu Leu Glu Ala Thr Leu Leu Thr Thr Pro Ala Pro 1 5 10 15 Glu Gln Arg Leu Phe Cys Phe Trp Lys Ser Cys Thr Trp Arg Pro Tyr 20 25 30 Pro Trp Arg Arg Arg Asp Leu Asn 35 40 232 21 PRT Conus tulipa 232 Leu Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg Pro Tyr Pro Trp Arg 1 5 10 15 Arg Arg Asp Leu Asn 20 233 21 PRT Conus magus 233 Leu Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg Pro Tyr Pro Trp Arg 1 5 10 15 Arg Arg Asn Leu Asn 20 234 21 PRT Conus geographus 234 Leu Phe Cys Phe Trp Lys Ser Cys Thr Trp Arg Pro Tyr Pro Trp Arg 1 5 10 15 Arg Arg Asp Leu Asn 20 235 19 PRT Conus generalis 235 Ser His Ser Ser Ser Leu Trp Cys Val Cys Pro Phe Arg Val Cys Pro 1 5 10 15 Pro Cys His 236 19 PRT Conus vexillum 236 Ser His Ser Ser Ser Leu Trp Cys Val Cys Pro Phe Arg Val Cys Pro 1 5 10 15 Pro Cys His 237 33 PRT Conus flavidus 237 His Asp His Gly Ile Arg Pro Lys Arg Val Asp Ile Cys Asn Trp Arg 1 5 10 15 Ile Cys Ala Pro Asn Pro Leu Arg Arg His Asp Leu Lys Lys Gly Asn 20 25 30 Asn 238 33 PRT Conus emaciatus 238 His Thr His Gly Ile Arg Pro Lys Gly Asp Gly Ile Cys Ile Trp Lys 1 5 10 15 Val Cys Pro Pro Asp Pro Trp Arg Arg His Arg Leu Lys Lys Arg Asn 20 25 30 Asn 239 33 PRT Conus aurisiacus 239 His Thr His Gly Ile Arg Pro Lys Gly Asp Gly Ile Cys Ile Trp Lys 1 5 10 15 Val Cys Pro Pro Asp Pro Trp Arg Arg His His Leu Lys Lys Arg Asn 20 25 30 Asn 240 28 PRT Conus terebra 240 His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile Trp Lys 1 5 10 15 Ile Cys Pro Pro Ser Pro Trp Lys Arg Leu Gly Ser 20 25 241 28 PRT Conus terebra 241 His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile Trp Lys 1 5 10 15 Ile Cys Pro Pro Ser Pro Trp Arg Arg Leu Gly Ser 20 25 242 28 PRT Conus litoglyphus 242 His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile Trp Lys 1 5 10 15 Ile Cys Pro Pro Ser Pro Trp Lys Arg Leu Gly Ser 20 25 243 28 PRT Conus litoglyphus 243 His Pro His Gly Ile Arg Gln Asp Gly Ala Gln Ile Cys Ile Trp Lys 1 5 10 15 Ile Cys Pro Pro Ser Pro Trp Arg Arg Leu Gly Ser 20 25 244 23 PRT Conus consors 244 Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Pro Ser Pro 20 245 25 PRT Conus consors 245 Asp Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Pro Ser Pro Trp Lys 20 25 246 28 PRT Conus consors 246 Ala Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Pro Gln 20 25 247 26 PRT Conus striolatus 247 Ser Asn Thr Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Trp Lys Val 1 5 10 15 Cys Pro Pro Ser Pro Trp Arg Arg Ser Gln 20 25 248 26 PRT Conus striolatus 248 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Asn Trp Lys Val 1 5 10 15 Cys Pro Pro Ser Pro Trp Arg Arg Pro Arg 20 25 249 26 PRT Conus striolatus 249 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile Trp Lys Val 1 5 10 15 Cys Pro Pro Ser Pro Trp Arg Arg Ser Gln 20 25 250 38 PRT Conus striolatus 250 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile Trp Lys Val 1 5 10 15 Cys Pro Pro Ser Pro Trp Arg Gln Pro Gln Glu Met Met Asn Asp Ile 20 25 30 Arg Gln Pro Pro Gln Leu 35 251 38 PRT Conus striatus 251 Ser Asn Asn Gly Arg Ser Ser Gly Ala Gln Ile Cys Ile Trp Lys Val 1 5 10 15 Cys Pro Pro Ser Pro Trp Arg Gln Pro Gln Glu Met Met Asn Asp Ile 20 25 30 Arg Gln Pro Pro Gln Leu 35 252 25 PRT Conus aurisiacus 252 Leu His Ser Asp Ser Ser Asp Gln Lys Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Pro Pro Pro Trp Arg 20 25 253 34 PRT Conus aurisiacus 253 Leu His Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Trp Thr 1 5 10 15 Gly Ala Gly Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Pro Pro 20 25 30 Trp Arg 254 37 PRT Conus aurisiacus 254 Leu Arg Ser Asp Ser Ser Asp Gln Lys Gly Gly Met Asn Ala Ser Thr 1 5 10 15 Gly Ala Gly Ala Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Ser Pro 20 25 30 Trp Arg Arg Thr Gln 35 255 28 PRT Conus circumcisus 255 Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Leu Ser Pro Trp Arg Arg Pro Gln 20 25 256 32 PRT Conus circumcisus 256 Leu Arg Ser Asp Ser Ser Gly Gln Lys Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Leu Ser Pro Trp Arg Arg Pro Gln Gly Lys Asp Glu 20 25 30 257 28 PRT Conus achatinus 257 Leu Arg Ser Asp Asn Gly Gly Ser Ser Gly Ala Gln Ile Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Pro Ser Pro Trp Arg Arg Pro Gln 20 25 258 22 PRT Conus stercusmuscarum 258 Leu Gly Ile Gly Ser Ser Asp Gln Asn Ala Gln Ile Cys Ile Trp Lys 1 5 10 15 Val Cys Pro Pro Ser Pro 20 259 25 PRT Conus consors 259 Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu Ala Gln Leu Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Pro Ser Pro Trp Arg 20 25 260 25 PRT Conus consors 260 Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu Ala Gln Leu Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Pro Thr Pro Trp Arg 20 25 261 25 PRT Conus magus 261 Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu Ala Gln Leu Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Pro Ser Pro Trp Arg 20 25 262 25 PRT Conus nobilis 262 Asn Gly Ser Gly Ser Ser Asn Gln Lys Glu Ala Gln Leu Cys Ile Trp 1 5 10 15 Lys Val Cys Pro Pro Thr Pro Trp Arg 20 25 263 27 PRT Conus sulcatus 263 Arg Ser Asp Lys Asp Val Gly Lys Arg Met Glu Cys Tyr Trp Lys Ala 1 5 10 15 Cys Arg Pro Thr Leu Ser Arg Arg His Asp Leu 20 25 264 40 PRT Conus bocki 264 Arg Ser Asp Lys Asp Asp Pro Gly Gly Gln Glu Cys Tyr Trp Asn Val 1 5 10 15 Cys Ala Pro Asn Gln Gly Asp His Met Ile Leu Arg Lys Lys Met Asn 20 25 30 Asp Asp Arg Gln Pro Pro Gln Leu 35 40 265 19 PRT Conus betulinus 265 Arg Ser Asp Ser Asp Val Arg Glu Val Pro Val Cys Ser Trp Lys Ile 1 5 10 15 Cys Pro Pro 266 22 PRT Conus loroisii 266 Arg Ser Asp Ser Asp Val Arg Glu Val Tyr Ile Leu Cys Ile Trp Lys 1 5 10 15 Ile Cys Pro Pro Leu Pro 20 267 32 PRT Conus gladiator 267 His Pro Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Trp Lys Val 1 5 10 15 Cys Pro Pro Trp Pro Val Arg Ser Pro Gly Pro Gln Pro Lys Asn Lys 20 25 30 268 32 PRT Conus gladiator 268 His Pro Ala Asn Val Arg Gln Gln Gly Lys Ile Cys Val Trp Lys Val 1 5 10 15 Cys Pro Pro Ser Pro Val Arg Ser Pro Gly Pro Leu Pro Lys Asn Lys 20 25 30 269 41 PRT Conus musicus 269 Gly Met Gly Pro Gly Asp Leu Ser Leu Gln Lys Met Phe Pro Ser Leu 1 5 10 15 Ala Leu Gly Pro Gly Gly Asp Val Ile Cys Arg Trp Lys Val Cys Pro 20 25 30 Pro Thr Pro Trp Lys Arg Leu Ile Lys 35 40 270 49 PRT Conus musicus 270 Gly Met Val Pro Gly Asp Leu Ala Leu Gln Tyr Leu Phe Pro Ser Leu 1 5 10 15 Ala Phe Asn Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro 20 25 30 Pro Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Gly Gln Pro Pro Gln 35 40 45 Leu 271 49 PRT Conus musicus 271 Gly Met Val Pro Gly Asp Leu Val Leu Gln Tyr Leu Phe Pro Ser Leu 1 5 10 15 Ala Phe Ser Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro 20 25 30 Pro Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Arg Gln Pro Pro Gln 35 40 45 Leu 272 49 PRT Conus musicus 272 Gly Met Val Pro Gly Asp Leu Val Leu Gln Tyr Leu Phe Pro Ser Leu 1 5 10 15 Ala Phe Asn Pro Pro Asp Ile Cys Thr Trp Lys Val Cys Pro Pro Pro 20 25 30 Pro Trp Arg Arg Pro Lys Lys Ile Thr Asp Val Arg Gln Pro Pro Gln 35 40 45 Leu 273 29 PRT Conus miles 273 Glx Gln Asp Gln Ser Pro His His Val Cys Cys Ala Ile Gly Pro Val 1 5 10 15 Leu Pro Phe Cys Cys Val Ser Trp Leu His Lys Leu His 20 25 274 14 PRT Conus miles 274 Leu Cys Cys Ile Phe Ala Pro Ile Leu Trp Phe Cys Cys His 1 5 10 275 13 PRT Conus rattus 275 Leu Cys Cys Ile Phe Ala Ile Leu Trp Phe Cys Cys Leu 1 5 10 276 15 PRT Conus capitaneus 276 Gly Phe Cys Cys Asp Phe Pro Pro Ile Phe Trp Phe Cys Cys Ile 1 5 10 15 277 25 PRT Conus miles 277 Glx Gly Phe Cys Cys Val Val Ile Pro Ile Leu Trp Phe Cys Cys Gly 1 5 10 15 Gly Tyr Arg Thr Asn Gly Thr Ala Asp 20 25 278 14 PRT Conus vexillum 278 Phe Cys Cys Ile Phe Ala Pro Ile Leu Leu Phe Cys Cys Phe 1 5 10 279 45 PRT Conus sulcatus 279 Glx Ser Gly Cys Arg Val Pro Phe Glu Leu Lys Cys Ile Trp Lys Phe 1 5 10 15 Cys Thr Ile Tyr Pro Ser Arg Pro Phe Ala Ser Leu Glu Glu Lys Asp 20 25 30 Glu Cys Gln Thr Val Thr Ile Thr Val Thr Trp Asp Phe 35 40 45 280 45 PRT Conus cinereus 280 Ser Ser Gly Cys Ser Val Ser Leu Gly Phe Lys Cys Phe Trp Lys Ser 1 5 10 15 Cys Thr Val Ile Pro Val Arg Pro Phe Val Ser Leu Glu Glu Glu Asn 20 25 30 Glu Cys Gln Lys Val Gln Ile Ser Ala Val Trp Gly Pro 35 40 45 281 25 PRT Conus parius 281 Pro Pro Phe Ser Cys Ser Gly Leu Arg Gly Gly Cys Val Leu Pro Pro 1 5 10 15 Asn Leu Arg Pro Lys Phe Asn Lys Gly 20 25 282 24 PRT Conus parius 282 Pro Pro Phe Ser Cys Ala Gly Leu Arg Gly Gly Cys Val Leu Pro Pro 1 5 10 15 Asn Leu Arg Pro Lys Phe Lys Glu 20 283 29 PRT Conus wittigi 283 Ser Ser Asp Gly Ser Asp Pro Lys Ala Lys Lys Gln Cys Met Trp Lys 1 5 10 15 Arg Cys Ile Pro Asp Gln Ser Arg Leu Glu Glu Asp Glu 20 25 284 30 PRT Conus cinereus 284 Ser Ser Asp Gly Lys Ala Lys Lys Gln Cys Ala Trp Lys Thr Cys Val 1 5 10 15 Pro Thr Gln Trp Arg Arg Arg Asp Leu Lys Glu Lys Asp Glu 20 25 30 285 30 PRT Conus cinereus 285 Ser Ser Asp Gly Lys Ala Lys Arg Asn Cys Phe Trp Lys Ala Cys Val 1 5 10 15 Pro Glu Gln Trp Arg Gln Arg Asp Pro Lys Glu Lys Asp Glu 20 25 30 286 30 PRT Conus cinereus 286 Ser Ser Asp Gly Lys Ala Lys Arg Asn Cys Phe Trp Lys Ala Cys Val 1 5 10 15 Pro Glu Gln Trp Arg Gln Arg Asp Leu Lys Glu Lys Asp Glu 20 25 30 287 37 PRT Conus nobilis 287 Phe Arg Pro Ala Val Lys Ser Arg Ser Arg Arg Ala Pro Pro Cys Val 1 5 10 15 Trp Lys Val Cys Pro Ala Pro Pro Trp Leu Val Thr Lys Arg Lys Gln 20 25 30 Glu Thr Ser Asp Tyr 35 288 37 PRT Conus nobilis 288 Phe Arg Pro Ala Val Lys Ser Arg Ser Arg Arg Ala Pro Pro Cys Val 1 5 10 15 Trp Lys Val Cys Pro Ala Pro Pro Trp Leu Val Thr Lys Arg Lys Gln 20 25 30 Glu Thr Ser Asp Tyr 35 289 37 PRT Conus miles 289 Phe Arg Pro Ala Met Gln Ser Arg Ser Gly Gly Met Ser Leu Cys Leu 1 5 10 15 Trp Lys Val Cys Pro Ala Ala Pro Trp Leu Val Ala Lys Arg Lys Gln 20 25 30 Glu Thr Ser Asp Tyr 35 290 21 PRT Conus tulipa 290 His Phe Asn Ser Val Val Pro Thr Val Tyr Ile Cys Met Trp Lys Val 1 5 10 15 Cys Pro Pro Ser Pro 20 291 21 PRT Conus purpurascens 291 Glx Ser Glu Glu Glu Lys Ile Cys Leu Trp Lys Ile Cys Pro Pro Pro 1 5 10 15 Pro Trp Arg Arg Ser 20 292 21 PRT Conus purpurascens 292 Glu Ser Asn Gly Val Glu Ile Cys Met Trp Lys Val Cys Pro Pro Ser 1 5 10 15 Pro Trp Arg Arg Ser 20 293 38 PRT Conus vexillum 293 Ile Met Gln Ser Leu Val Phe Ser His Gln Pro Leu Pro Thr Ala Ser 1 5 10 15 Ile Cys Ile Trp Lys Ile Cys Pro Pro Asp Pro Trp Arg Arg His Asp 20 25 30 Leu Gln Lys Ser Asn Lys 35 294 38 PRT Conus muriculatus 294 Ile Met Gln Ser Leu Val Phe Ser His Gln Pro Leu Pro Thr Ala Ser 1 5 10 15 Ile Cys Ile Trp Lys Ile Cys Pro Pro Asp Pro Trp Arg Arg His Asp 20 25 30 Leu Gln Lys Ser Asn Lys 35 295 26 PRT Conus pulicarius 295 Val Arg Leu Arg Gly Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Leu 1 5 10 15 Leu Gln Trp Ile His Pro Leu Val Lys Arg 20 25 296 26 PRT Conus pulicarius 296 Val Arg Pro Arg Gly Gln Ile Cys Ile Trp Lys Val Cys Pro Pro Leu 1 5 10 15 Leu Gln Trp Ile His Pro Leu Val Lys Arg 20 25 297 27 PRT Conus pulicarius 297 Pro Val Arg Leu Arg Gly Gln Ile Cys Ile Trp Lys Val Cys Pro Pro 1 5 10 15 Leu Leu Gln Trp Ile His Pro Leu Val Lys Arg 20 25 298 30 PRT Conus mustelinus 298 Leu Val Ser His Thr Ser Ser Lys Tyr Pro Gly Val Thr Phe Cys Pro 1 5 10 15 Trp Lys Val Cys Pro Pro Ala Pro Trp Arg Ile Leu Gly Val 20 25 30 299 22 PRT Conus baileyi 299 His Ser Asp Ser Ile Ile Leu Arg Gly Leu Cys Ile Trp Lys Val Cys 1 5 10 15 Glu Pro Pro Pro Gln Arg 20 300 26 PRT Conus planorbis 300 Ser Ser Ser Asn Gly Leu Lys Arg Ala Asp Leu Cys Ile His Lys Ile 1 5 10 15 Cys Pro Pro Arg Tyr His Gln Ser Gln Gln 20 25 301 36 PRT Conus litteratus 301 His Arg Val Phe His Leu Asp Asn Thr Tyr Leu Lys Ile Pro Ile Cys 1 5 10 15 Ala Trp Lys Val Cys Pro Pro Thr Pro Trp Arg Arg Arg Asp Leu Lys 20 25 30 Lys Arg Asn Lys 35 302 50 PRT Conus litteratus 302 Ser Pro Val Ser Thr Pro Tyr Pro Glu Phe His Leu Asp Glu Pro Tyr 1 5 10 15 Leu Lys Ile Pro Val Cys Ile Trp Lys Ile Cys Pro Pro Asn Leu Leu 20 25 30 Arg Arg Arg Asp Leu Lys Lys Arg Asn Lys Val Arg Gln Thr Thr Ala 35 40 45 Thr Thr 50 303 26 PRT Conus coronatus 303 Leu Ser Asp Gly Arg Asp Trp Thr Gly Tyr Ile Cys Ile Trp Lys Ala 1 5 10 15 Cys Pro Arg Pro Pro Trp Ile Pro Pro Lys 20 25 304 29 PRT Conus chaldaeus 304 Leu Ser Glu Gly Arg Asn Ser Thr Val His Ile Cys Met Trp Lys Val 1 5 10 15 Cys Pro Pro Pro Pro Trp Arg Arg Pro His Gly Gln Arg 20 25 305 29 PRT Conus chaldaeus 305 Leu Ser Glu Gly Arg Asn Ser Thr Val His Ile Cys Thr Trp Lys Val 1 5 10 15 Cys Pro Pro Pro Pro Trp Arg Arg Pro His Gly Gln Arg 20 25 306 13 PRT Unknown unknown Conus species 306 Glx Cys Met Trp Lys Arg Cys Ile Pro Asp Gln Ser Arg 1 5 10 307 15 PRT Unknown unknown Conus species 307 Val Asp Ile Cys Asn Trp Arg Ile Cys Ala Pro Asn Pro Leu Arg 1 5 10 15 308 13 PRT Conus geographus PEPTIDE (1)..(13) Xaa may be Trp (D or L) 308 Leu Cys Phe Xaa Lys Ser Cys Arg Pro Tyr Pro Trp Arg 1 5 10 309 16 PRT Conus magus PEPTIDE (1)..(16) Xaa may be Trp (D or L) 309 Leu Phe Cys Phe Xaa Trp Lys Ser Cys Trp Pro Arg Pro Tyr Trp Arg 1 5 10 15 310 16 PRT Conus magus PEPTIDE (1)..(16) Xaa may be Trp (D or L) 310 Leu Phe Cys Phe Xaa Lys Ser Cys Trp Pro Arg Pro Tyr Pro Trp Arg 1 5 10 15 311 15 PRT Conus magus PEPTIDE (1)..(15) Xaa may be Phe (D or L) 311 Leu Xaa Cys Phe Trp Lys Ser Cys Trp Pro Arg Pro Tyr Trp Arg 1 5 10 15 312 15 PRT Conus magus PEPTIDE (1)..(15) Xaa at residue 2 may be Phe (D or L); Xaa at residue 5 may be Trp (D or L) 312 Leu Xaa Cys Phe Xaa Lys Ser Cys Trp Pro Arg Pro Tyr Trp Arg 1 5 10 15 313 11 PRT Conus magus PEPTIDE (1)..(11) Xaa may be Phe (D or L) 313 Leu Xaa Cys Phe Trp Lys Ser Cys Trp Pro Arg 1 5 10 314 11 PRT Conus magus PEPTIDE (1)..(11) Xaa may be Trp (D or L) 314 Leu Phe Cys Phe Xaa Lys Ser Cys Trp Pro Arg 1 5 10 315 11 PRT Conus magus PEPTIDE (1)..(11) Xaa at residue 2 may be Phe (D or L); Xaa at residue 5 may be Trp (D or L) 315 Leu Xaa Cys Phe Xaa Lys Ser Cys Trp Pro Arg 1 5 10 316 9 PRT Conus magus PEPTIDE (1)..(9) Xaa may be Phe (D or L) 316 Leu Xaa Cys Phe Trp Lys Ser Cys Trp 1 5 317 9 PRT Conus magus PEPTIDE (1)..(9) Xaa may be Trp (D or L) 317 Leu Phe Cys Phe Xaa Lys Ser Cys Trp 1 5 318 9 PRT Conus magus PEPTIDE (1)..(9) Xaa at residue 2 may be Phe (D or L); Xaa at residue 5 may be Trp (D or L) 318 Leu Xaa Cys Phe Xaa Lys Ser Cys Trp 1 5 319 10 PRT Conus magus PEPTIDE (1)..(10) Xaa may be Trp (D or L) 319 Phe Cys Phe Xaa Lys Ser Cys Trp Pro Arg 1 5 10 320 10 PRT Conus magus PEPTIDE (1)..(10) Xaa may be Lys (D or L) 320 Phe Cys Phe Trp Xaa Ser Cys Trp Pro Arg 1 5 10 321 10 PRT Conus magus PEPTIDE (1)..(10) Xaa may be Trp (D or L) 321 Phe Cys Phe Xaa Phe Ser Cys Trp Pro Arg 1 5 10 322 10 PRT Conus magus 322 Phe Cys Phe Trp Lys Ser Cys Trp Pro Arg 1 5 10 323 21 PRT Conus purpurascens PEPTIDE (1)..(21) Xaa may be Trp (D or L) 323 Glu Ser Asn Gly Val Glu Ile Cys Met Xaa Lys Val Cys Pro Pro Ser 1 5 10 15 Pro Trp Arg Arg Ser 20 324 14 PRT Conus striatus PEPTIDE (1)..(14) Xaa may be Trp (D or L) 324 Met Glu Cys Tyr Xaa Lys Ala Cys Arg Pro Thr Leu Ser Arg 1 5 10 325 16 PRT Conus striatus PEPTIDE (1)..(16) Xaa may be Trp (D or L) 325 Phe Glu Leu Lys Cys Ile Xaa Lys Phe Cys Thr Ile Tyr Pro Ser Arg 1 5 10 15 326 18 PRT Conus striatus PEPTIDE (1)..(18) Xaa may be Trp (D or L) 326 Phe Glu Leu Lys Cys Ile Xaa Lys Phe Cys Thr Ile Tyr Pro Ser Arg 1 5 10 15 Pro Phe 327 14 PRT Conus tulipa PEPTIDE (1)..(14) Xaa may be Trp (D or L) 327 Thr Val Tyr Ile Cys Met Xaa Lys Val Cys Pro Pro Ser Pro 1 5 10 328 22 PRT Conus aurisiacus PEPTIDE (1)..(22) Xaa may be Trp (D or L) 328 Ser Asp Ser Ser Asp Gln Lys Ala Gln Ile Cys Ile Xaa Lys Val Cys 1 5 10 15 Pro Pro Pro Pro Trp Arg 20 329 16 PRT Conus consors PEPTIDE (1)..(16) Xaa may be Trp (D or L) 329 Gly Ala Gln Ile Cys Ile Xaa Lys Val Cys Pro Pro Ser Pro Trp Arg 1 5 10 15 330 30 PRT Conus musicus PEPTIDE (1)..(30) Xaa may be Trp (D or L) 330 Met Phe Pro Ser Leu Ala Leu Gly Pro Gly Gly Asp Val Ile Cys Arg 1 5 10 15 Xaa Lys Val Cys Pro Pro Thr Pro Trp Lys Arg Leu Ile Lys 20 25 30 331 24 PRT Conus flavidus PEPTIDE (1)..(24) Xaa may be Trp (D or L) 331 Val Asp Ile Cys Asn Xaa Arg Ile Cys Ala Pro Asn Pro Leu Arg Arg 1 5 10 15 His Asp Leu Lys Lys Gly Asn Asn 20 332 15 PRT Conus flavidus PEPTIDE (1)..(15) Xaa may be Trp (D or L) 332 Val Asp Ile Cys Asn Xaa Arg Ile Cys Ala Pro Asn Pro Leu Arg 1 5 10 15 333 22 PRT Conus geographus PEPTIDE (1)..(22) Xaa may be Trp (D or L) 333 Arg Leu Phe Cys Phe Xaa Lys Ser Cys Thr Trp Arg Pro Tyr Pro Trp 1 5 10 15 Arg Arg Arg Asp Leu Asn 20 334 17 PRT Conus generalis DISULFID (4)..(14) 334 Ser Leu Trp Cys Val Cys Pro Phe Arg Val Cys Pro Pro Cys His Gly 1 5 10 15 Arg 335 17 PRT Conus generalis DISULFID (6)..(14) 335 Ser Leu Trp Cys Val Cys Pro Phe Arg Val Cys Pro Pro Cys His Gly 1 5 10 15 Arg 336 15 PRT Conus generalis PEPTIDE (1)..(15) Xaa may be Phe (D or L) 336 Ser Leu Trp Cys Val Cys Pro Xaa Arg Val Cys Pro Pro Cys His 1 5 10 15 337 15 PRT Conus generalis PEPTIDE (1)..(15) Xaa may be Phe (D or L) 337 Ser Leu Trp Cys Val Cys Pro Xaa Arg Val Cys Pro Pro Cys His 1 5 10 15 338 6 PRT Conus magus PEPTIDE (1)..(6) Xaa at residues 2 and 5 may be any amino acid; Xaa at residue 3 may be Trp (D or L) or bromo-Trp (D or L) 338 Cys Xaa Xaa Lys Xaa Cys 1 5 339 6 PRT Conus generalis PEPTIDE (1)..(6) Xaa may be Phe (D or L) 339 Cys Pro Xaa Arg Val Cys 1 5 340 21 PRT Conus ebraeus 340 Leu Ser Gly Gly Thr Tyr Ser Arg Val Asp Thr Cys Ile Trp Lys Val 1 5 10 15 Cys Pro Gln Ser Pro 20

Claims (61)

What is claimed is:
1. An isolated peptide selected from the group consisting of:
(a) a peptide selected from the group consisting of peptides comprising amino acid sequences set forth in SEQ ID NOs:3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126, 129, 132, 135, 138, 141, 144, 147, 150, 153, 156, 159, 162, 165, 168, 171, 174, 177, 180, 183, 186, 189, 192, 195, 198, 201, 204, 207, 210, 216, 219, 222, 225, 228-287, 289-315, 319-321, 323-337 and 340; and
(b) analogs and derivatives of the peptide in (a).
2. The peptide of claim 1, wherein Xaa1 is Glu or γ-carboxy-Glu, Xaa2 is Gln or pyro-Glu, Xaa3 is Pro or trans-4-hydroxy-Pro, Xaa4 is D or L Trp or D or L 6-bromo-Trp, and Xaa5 is Tyr, mono-iodo-Tyr, 125I-Tyr, di-iodo-Tyr, O-sulpho-Tyr or O-phospho-Tyr.
3. The peptide derivative of claim 1, in which Arg residues may be substituted by Lys, omithine, homoarginine, 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, homoarginine, nor-Lys, or any synthetic basic amino acid; the Tyr residues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, 125I-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 D or L, may be substituted at the ortho, meta, and/or para positions with a halogen or may be substituted with any synthetic aromatic amino acid; the Trp residues may be substituted with Trp (D), neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, or any aromatic synthetic amino acid; the Asn, Ser, Thr or Hyp residues may be substituted with a glycan; the halogen may be iodo, chloro, fluoro or bromo; 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 Leu may be substituted with Leu (D); the Glu residues may be substituted with Gla or Asp; the acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g. tetrazolyl derivatives of Gly and Ala; the N-terminal Gln may be substituted with pyro-glutamate (Z); the aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains CnH2n+2 up to and including n=8; the Met residues may be substituted with nor-leucine (Nle); the Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L); basic residues in the backbone may be D or L configuration; the central Trp residue within the beta-turn is preferably epimerized to the D-form; pairs of Cys residues may be replaced pairwise with isoteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/Ala combinations; and individual Cys residues may be replaced with homoCys, seleno-Cys or penicillamine, so that disulfide bridges may be formed between Cys-homoCys or Cys-penicillamine, or homoCys-penicllamine.
4. The peptide derivative of claim 3, wherein the glycan is any N-, S- or O-linked mono-, di-, tri-, poly- or oligosaccharide that can be attached to any hydroxy, amino or thiol group of natural or modified amino, wherein the monosaccharides making up the glycan can be unmodified or modified 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, wherein the glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3, and wherein the linkage between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-.
5. The peptide derivative of claim 4, wherein the modification may include one or more O-sulfate, O-phosphate, O-acetyl or acidic groups, and combinations thereof.
6. The peptide derivative of claim 4, wherein the gylcan may also include similar polyhydroxy groups, such as D-penicillamine 2,5 and halogenated derivatives thereof or polypropylene glycol derivatives.
7. The derivative of the peptide of claim 1 in which the peptide is truncated.
8. The peptide derivative of claim 3 in which the peptide derivative is truncated.
9. The peptide derivative of claim 4 in which the peptide derivative is truncated.
10. An peptide of claim 1 containing 4 cysteines which are bridged as [1,4/2,3].
11. An peptide of claim 1 containing 4 cysteines which are bridged as [1,3/2,4].
12. The peptide of claim 1, wherein the peptide is tagged with a radiolabel.
13. The peptide derivative of claim 1 in which a basic or aromatic amino acid in the beta turn is a D-isomer.
14. The peptide derivative of claim 13 in which the peptide derivative is truncated.
15. The peptide of claim 13, wherein the peptide is tagged with a radiolabel.
16. The peptide of claim 14, wherein the peptide is tagged with a radiolabel.
17. An isolated nucleic acid encoding a β-superfamily conopeptide propeptide selected from the group of propeptides comprising amino acid sequences set forth in SEQ ID NO:2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 95, 98, 101, 104, 107, 110, 113, 116, 119, 122, 125, 128, 131, 134, 137, 140, 143, 146, 149, 152, 155, 158, 161, 164, 167, 170, 173, 176, 179, 182, 185, 188, 191, 194, 197, 200, 203, 206, 209, 215, 218, 221, 224, and 227.
18. The isolated nucleic acid of claim 17 wherein the nucleic acid comprises a nucleotide sequence selected from the group of nucleotide sequences set forth in SEQ ID NO:1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, 58, 61, 64, 67, 70, 73, 76, 79, 82, 85, 88, 91, 94, 97, 100, 103, 106, 109, 112, 115, 118, 121, 124, 127, 130, 133, 136, 139, 142, 145, 148, 151, 154, 157, 160, 163, 166, 169, 172, 175, 178, 181, 184, 187, 190, 193, 196, 199, 202, 205, 208, 214, 217, 220, 223, and 226.
19. An isolated β-superfamily conopeptide propeptide selected from the group of propeptides comprising amino acid sequences set forth in SEQ ID NO:2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59, 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 95, 98, 101, 104, 107, 110, 113, 116, 119, 122, 125, 128, 131, 134, 137, 140, 143, 146, 149, 152, 155, 158, 161, 164, 167, 170, 173, 176, 179, 182, 185, 188, 191, 194, 197, 200, 203, 206, 209, 215, 218, 221, 224, and 227.
20. A method for treating cancer which comprises administering an active agent or a pharmaceutically acceptable salt thereof to an individual having cancer, wherein said active agent is a peptide tagged with a radionuclide, wherein said peptide is a β-superfamily conotoxin.
21. The method of claim 20, wherein said β-superfamily conotoxin is selected from the group consisting of:
(a) a peptide selected from the group consisting of peptides comprising amino acid sequences set forth in SEQ ID NO:3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126, 129, 132, 135, 138, 141, 144, 147, 150, 153, 156, 159, 162, 165, 168, 171, 174, 177, 180, 183, 186, 189, 192, 195, 198, 201, 204, 207, 210, 216, 219, 222, 225, 228-287, 289-315, 319-321, 323-337 and 340; and
(b) analogs and derivatives of the peptide in (a).
22. The method of claim 20, wherein the radionuclide is selected from the group consisting of 131iodine, 123iodine, 99mtechnicium, 111indium, 188rhenium, 186rhenium, 67gallium, 90yttrium, 105rhodium, 89strontium, 153samarium, 211astatine, 212bismuth, 213bismuth, 177 lutetium, 64copper, 67copper, 47scandium, 109palladium.
23. The method of claim 21, wherein the radionuclide is selected from the group consisting of 131iodine, 123iodine, 99mtechnicium, 111indium, 188rhenium, 186rhenium, 67gallium, 90yttrium, 105rhodium, 89strontium, 153samarium, 211astatine, 212bismuth, 213bismuth, 177 lutetium, 64copper, 67copper, 47scandium, 109palladium.
24. The method of claim 21, wherein the active agent a peptide derivative in which Arg residues may be substituted by Lys, ornithine, homoarginine, 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, homoarginine, nor-Lys, or any synthetic basic amino acid; the Tyr residues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, 125I-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 D or L, may be substituted at the ortho, meta, and/or para positions with a halogen or may be substituted with any synthetic aromatic amino acid; the Trp residues may be substituted with Trp (D), neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, or any aromatic synthetic amino acid; the Asn, Ser, Thr or Hyp residues may be substituted with a glycan; the halogen may be iodo, chloro, fluoro or bromo; the Tyr residues may also be substituted with the 3-hydroxyl or 2-hydroxylisomers (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 Leu may be substituted with Leu (D); the Glu residues may be substituted with Gla or Asp; the acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g. tetrazolyl derivatives of Gly and Ala; the N-terminal Gln may be substituted with pyro-glutamate (Z); the aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains CnH2n+2 up to and including n=8; the Met residues may be substituted with nor-leucine (Nle); the Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L); basic residues in the backbone may be D or L configuration; the central Trp residue within the beta-turn is preferably epimerized to the D-form; pairs of Cys residues may be replaced pairwise with isoteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/Ala combinations; and individual Cys residues may be replaced with homoCys, seleno-Cys or penicillamine, so that disulfide bridges may be formed between Cys-homoCys or Cys-penicillamine, or homoCys-penicllamine.
25. The method of claim 24, wherein the the glycan is any N-, S- or O-linked mono-, di-, tri-, poly- or oligosaccharide that can be attached to an hydroxy, amino or thiol group of natural or modified amino, wherein the monosaccharides making up the glycan can be unmodified or modified 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, wherein the glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3, and wherein the linkage between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-.
26. The method of claim 21, wherein the peptide has activity at somatostatin receptors.
27. A method of alleviating pain in an individual which comprises administering to an individual who is either exhibiting pain or is about to be subjected to a pain-causing event a pain-alleviating amount of an active agent or a pharmaceutically acceptible salt thereof, wherein said active agent is a β-superfamily conotoxin.
28. The method of claim 27, wherein the βsuperfamily conotoxin is selected from the group consisting of:
(a) a peptide selected from the group consisting of peptides comprising amino acid sequences set forth in SEQ ID NO:3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126, 129, 132, 135, 138, 141, 144, 147, 150, 153, 156, 159, 162, 165, 168, 171, 174, 177, 180, 183, 186, 189, 192, 195, 198, 201, 204, 207, 210, 216, 219, 222, 225, 228-287, 289-315, 319-321, 323-337 and 340; and
(b) analogs and derivatives of the peptide in (a).
29. The method of claim 28, wherein the active agent a peptide derivative in which Arg residues may be substituted by Lys, ornithine, homoarginine, 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, homoarginine, nor-Lys, or any synthetic basic amino acid; the Tyr residues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, 125I-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 D or L, may be substituted at the ortho, meta, and/or para positions with a halogen or may be substituted with any synthetic aromatic amino acid; the Trp residues may be substituted with Trp (D), neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, or any aromatic synthetic amino acid; the Asn, Ser, Thr or Hyp residues may be substituted with a glycan; the halogen may be iodo, chloro, fluoro or bromo; the Tyr residues may also be substituted with the 3-hydroxyl or 2-hydroxylisomers (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 Leu may be substituted with Leu (D); the Glu residues may be substituted with Gla or Asp; the acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g. tetrazolyl derivatives of Gly and Ala; the N-terminal Gln may be substituted with pyro-glutamate (Z); the aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains CnH2n+2 up to and including n=8; the Met residues may be substituted with nor-leucine (Nle); the Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L); basic residues in the backbone may be D or L configuration; the central Trp residue within the beta-turn is preferably epimerized to the D-form; pairs of Cys residues may be replaced pairwise with isoteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/Ala combinations; and individual Cys residues may be replaced with homoCys, seleno-Cys or penicillamine, so that disulfide bridges may be formed between Cys-homoCys or Cys-penicillamine, or homoCys-penicllamine.
30. The method of claim 29, wherein the the glycan is any N—, S- or O-linked mono-, di-, tri-, poly- or oligosaccharide that can be attached to any hydroxy, amino or thiol group of natural or modified amino, wherein the monosaccharides making up the glycan can be unmodified or modified 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, wherein the glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3, and wherein the linkage between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-.
31. The method of claim 27, wherein the pain is visceral pain.
32. A method for treating or preventing disorders associated with a disorder selected from the group consisting of voltage-gated ion channel disorders, ligand-gated ion channel disorders and receptor disorders, such as disorders of G-protein coupled receptors, in an individual which comprises administering to an individual in need thereof a therapeutically effective amount of an active agent or a pharmaceutically acceptible salt thereof, wherein the active agent is a β-superfamily conotoxin.
33. The method of claim 32, wherein the β-superfamily conotoxin is selected from the group consisting of:
(a) a peptide selected from the group consisting of peptides comprising amino acid sequences set forth in SEQ ID NO:3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126, 129, 132, 135, 138, 141, 144, 147, 150, 153, 156, 159, 162, 165, 168, 171, 174, 177, 180, 183, 186, 189, 192, 195, 198, 201, 204, 207, 210, 216, 219, 222, 225, 228-287, 289-315, 319-321, 323-337 and 340; and
(b) analogs and derivatives of the peptide in (a).
34. The method of claim 33, wherein the active agent a peptide derivative in which Arg residues may be substituted by Lys, ornithine, homoarginine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any synthetic basic amino acid; the Lys residues may be substituted by Arg, omithine, homoarginine, nor-Lys, or any synthetic basic amino acid; the Tyr residues may be substituted with meta-Tyr, ortho-Tyr, nor-Tyr, 125I-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 D or L, may be substituted at the ortho, meta, and/or para positions with a halogen or may be substituted with any synthetic aromatic amino acid; the Trp residues may be substituted with Trp (D), neo-Trp, 6-halo-Trp (D or L), preferably 6-halo, or any aromatic synthetic amino acid; the Asn, Ser, Thr or Hyp residues may be substituted with a glycan; the halogen may be iodo, chloro, fluoro or bromo; the Tyr residues may also be substituted with the 3-hydroxyl or 2-hydroxylisomers (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 Leu may be substituted with Leu (D); the Glu residues may be substituted with Gla or Asp; the acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g. tetrazolyl derivatives of Gly and Ala; the N-terminal Gln may be substituted with pyro-glutamate (Z); the aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains CnH2n+2 up to and including n=8; the Met residues may be substituted with nor-leucine (Nle); the Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L); basic residues in the backbone may be D or L configuration; the central Trp residue within the beta-turn is preferably epimerized to the D-form; pairs of Cys residues may be replaced pairwise with isoteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/Ala combinations; and individual Cys residues may be replaced with homoCys, seleno-Cys or penicillamine, so that disulfide bridges may be formed between Cys-homoCys or Cys-penicillamine, or homoCys-penicllamine.
35. The method of claim 34, wherein the the glycan is any N-, S- or O-linked mono-, di-, tri-, poly- or oligosaccharide that can be attached to any hydroxy, amino or thiol group of natural or modified amino, wherein the monosaccharides making up the glycan can be unmodified or modified 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, wherein the glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3, and wherein the linkage between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-.
36. The method of claim 32, wherein the disorder is a G-protein coupled receptor disorder.
37. The method of claim 36, wherein the G-protein coupled receptor is selected from the group consisting of sst, cortistatin (CST), melanocortin (MCxR, wherein x=1, 2, 3, 4, 5), opioid (μ, δ, κ), neurokinin, bradykinin, galanin, CCKA, CCKB, endothelin, serotonin, adrenergic receptors, angiotensin, neuropeptide-Y, sigma1, sigma2, oxytocin, CGRP, GRPR, histamine, imidazoline, neurotensin, VIP, vasopressin, substance K, chemokine receptors, CRF1, CRF2a, CRF2β, CRF2γ, CRF-BP, orexin, urotensin, glycoprotein IIb/IIIa, thrombin receptors and orphan GPCRs.
38. The method of claim 36, wherein the GPCR is selected from the group consisting of MCH2R/SLT, SP1999/P2Y12, CRTH2, NPFF1, NPFF2, HH4R, h-GPR54, CysLT2, neuromedin receptors, BLTR2, G2A, TA1, LTB4, ghrelin, motilin MTL-R, purinergic receptors, muscarinic receptors, ORL-1, apelin, CB1, CB2 and GPCRs of orphan status having no known cognate ligand.
39. The method of claim 32, wherein the disorder is selected from the group consisting of cancer, neoplasm, solid tumor, diabetic nephropathy, fibrosis, hypophysis tumor, GI disease, IBS, restinosis, angiogenesis disorder, diabetes mellitus, endocrine tumor, diarrhea, pancreatic disease, prostate tumor, bleeding and apoptosis.
40. The method of claim 39, wherein the peptide has activity at somatostatin receptors.
41. The method of claim 32, wherein the disorder is selected from the group consisting of inflammation, pain, diabetes, obesity, sexual dysfunction, acromegaly, glaucoma, cardiovascular, diabetic, retinopathy, depression, myocardial infarction, stroke, epilepsy, anorexia, wasting diseases, seborrheic dermatitis, schizophrenia, mood disorders, chemotherapeutic induced emesis, disorders associated with changes in blood pressure, immune disorders, nerve damage, acne, GI infections, myocardial infarction, angina, thromboembolism and cardiovascular disease.
42. The method of claim 41, wherein the peptide has activity at somatostatin receptors or at melanocortin receptors.
43. The method of claim 32, wherein the receptor is LHRH.
44. The method of claim 43, wherein the disorder is osteoporosis.
45. The method of claim 32, wherein the disorder is associated with a melanocortin system or MCR dysfunction.
46. The method of claim 45, wherein the disorder is selected from the group consisting of erectile dysfunction, obesity inflammation and melanoma.
47. The method of claim 45, wherein the peptide contains a β-turn.
48. The method of claim 47, wherein the peptide is a β-Gel4.1 analogue, derivative thereof or pharmaceutically acceptable salt thereof, wherein the β-Gel4.1 analogue is selected from the group of peptides comprising an amino acid sequence set forth in SEQ ID NOs:334-337,.
49. A method for identifying drug candidates for use as treating or preventing disorders associated with a disorder selected from the group consisting of voltage-gated ion channel disorders, ligand-gated ion channel disorders and receptor disorders, such as disorders of G-protein coupled receptors which comprises screening a drug candidate for its action at or partially at the same functional site as a β-superfamily conotoxin and capable of elucidation of similar functional response as said conotoxin.
50. The method of claim 49, wherein the displacement of a labeled β-superfamily conotoxin from its receptor or other complex by a candidate drug agent is used to identify suitable candidate drugs.
51. The method of claim 49, wherein a biological assay on a test compound to determine the therapeutic activity is conducted and compared to the results obtained from the biological assay of a β-superfamily conotoxin.
52. The method of claim 49, wherein the binding affinity of a small molecule to the receptor of a β-conotoxin is measured and compared to the binding affinity of a β-superfamily conotoxin to its receptor.
53. A method of identifying compounds that mimic the therapeutic activity of a superfamily conotoxin, comprising the steps of: (a) conducting a biological assay on a test compound to determine the therapeutic activity; and (b) comparing the results obtained from the biological assay of the test compound to the results obtained from the biological assay of a β-superfamily conotoxin.
54. A method for characterizing a new site on a voltage-gated ion channel, a ligand-gated ion channel and a receptor, such as a G-protein coupled receptors which comprises contacting a peptide of claim 1 with a channel or receptor and measuring the binding of the peptide with the channel or receptor or by measuring a functional in vitro parameters such as fluorescence, phosphorescence and illuminescence.
55. The method of claim 54, wherein the receptor is a G-protein coupled receptor.
56. The method of claim 54, wherein the peptide is radiolabeled.
57. A method for designing a β-beta turn mimetic of a β-superfamily conotoxin containing a β-turn motif selected from the group consistinf of (i) a —CX1X2KX1C— (SEQ ID NO:338) motif, wherein X1 is any amino acid and X2 is D or L Trp or D or L 6-bromo Trp and (ii) a —CPX3RVC— (SEQ ID NO:339) motif, wherein X3 is D or L Phe, which comprises replacing this motif with a non-peptide turn mimetic β-turn scaffold and then attaching receptor binding domains contained within the N and C-terminal sequences of a β-superfamily conotoxin to the β-turn scaffold to mimic the 3D spatial array within the native β-superfamily conotoxin.
58. A method for identifying a ligand which binds to an orphan G-protein coupled receptor (orphan GPCR) which comprises contacting a peptide of claim 1 or a radiolabeled derivative of the peptide with an orphan GPCR and measuring the amount of binding of the peptide to the orphan GPCR.
59. The method of claim 58, wherein the peptide is radiolabeled.
60. The method of claim 59, wherein the radiolabel is selected from the group consisting of 3H and 125I.
61. The method of claim 58, which further comprises performing a homology search for the peptide which binds to the orphan GPCR to identify other candidate ligands for testing.
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WO2002060923A3 (en) 2004-03-11
US20050271589A1 (en) 2005-12-08

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