O-superfamily conotoxin peptides

Abstract

The invention relates to relatively short peptides (termed O-Superfamily conotoxins herein), about 20-40 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogous to the naturally available peptides, and which preferably include two disulfide bonds.

1 . An isolated O-Superfamily conopeptide selected from the peptides set forth in Table 2.  
     
     
         2 . An isolated conotoxin peptide selected from the group consisting of the mature toxin peptide sequences disclosed in Table 1 except the peptides Di6.2, Af6.9, KK1, KK2, δ-GmVIA, M6.4, δ-PVIA, δ-PVIA-OH, δ-NgVIA, δ-TxVIA, and Israel TxVIA.  
     
     
         3 . The isolated conotoxin peptide of  claim 2 , wherein Xaa 1  is Glu.  
     
     
         4 . The isolated conotoxin peptide of  claim 2 , wherein Xaa 5  is Tyr.  
     
     
         5 . The isolated conotoxin peptide of  claim 2 , wherein Xaa 4  is Trp.  
     
     
         6 . The isolated conotoxin peptide of  claim 2 , wherein Xaa 2  is Gln.  
     
     
         7 . The isolated conotoxin peptide of  claim 2 , wherein Xaa 3  is Pro.  
     
     
         8 . The isolated conotoxin peptide of  claim 2 , wherein Xaa 3  is hydroxy-Pro.  
     
     
         9 . The isolated conotoxin peptide of  claim 2 , wherein Xaa 5  is  125 I-Tyr, mono-iodo Tyr or di-iodo-Tyr.  
     
     
         10 . The isolated conotoxin peptide of  claim 2 , wherein Xaa 4  is 6-bromo-Trp.  
     
     
         11 . The isolated conotoxin peptide of  claim 2 , wherein Xaa 1  is Gla.  
     
     
         12 . The isolated conotoxin peptide of  claim 2 , wherein Xaa 2  is pyro-Glu.  
     
     
         13 . An isolated nucleic acid comprising a nucleic acid coding for an O-Superfamily conotoxin precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Table 1.  
     
     
         14 . The nucleic acid of  claim 13  wherein the nucleic acid comprises a nucleotide sequence selected from the group of nucleotide sequences set forth in Table 1 or their full length complements.  
     
     
         15 . An isolated conotoxin protein precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Table 1.  
     
     
         16 . A pharmaceutical composition comprising a conotoxin peptide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, said conotoxin peptide being the conotoxin peptide of  claim 1 .  
     
     
         17 . A pharmaceutical composition comprising a conotoxin peptide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, said conotoxin peptide selected from the group consisting of the conotoxin peptides of  claim 2 .  
     
     
         18 . A method for regulating the flow of sodium through sodium channels in an individual in need thereof which comprises administering a therapeutically effective amount of a conotoxin peptide of  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         19 . A method for treating or preventing disorders associated with voltage gated ion channel disorders in which comprises administering to a patient in need thereof a therapeutically effective amount of a conotoxin peptide of  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         20 . The method of  claim 18 , wherein said individual in need thereof suffers from a disorder selected from the group consisting of multiple sclerosis, other demyelinating diseases (such as acute disseminated encephalomyelitis, optic neuromyelitis, adrenoleukodystrophy, acute transverse myelitis, progressive multifocal leukoencephalopathy), sub-acute sclerosing panencephalomyelitis (SSPE), metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, spinal cord injury, botulinum toxin poisoning, Huntington's chorea, compression and entrapment neurophathies (such as carpal tunnel syndrome, ulnar nerve palsy), cardiovascular disorders (such as cardiac arrhythmias, congestive heart failure), reactive gliosis, hyperglycemia, immunosuppression, cocaine addiction, cancer, cognitive dysfunction, disorders resulting from defects in neurotransmitter release (such as Eaton-Lambert syndrome), and reversal of the actions of curare and other neuromuscular blocking drugs.  
     
     
         21 . The method of  claim 19 , wherein said disorder is a neurologic disorder.  
     
     
         22 . The method of  claim 19 , wherein said neurologic disorder is a seizure.  
     
     
         23 . The method of  claim 22 , wherein said seizure is seizure is associated with epilepsy.  
     
     
         24 . The method of  claim 21 , wherein said neurologic disorder is a neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia.  
     
     
         25 . The method of  claim 24 , wherein said neurotoxic injury is associated with stroke, cerebrovascular accident, brain or spinal cord trauma, myocardial infarct, physical trauma, drownings, suffocation, perinatal asphyxia, or hypoglycemic events.  
     
     
         26 . The method of  claim 19 , wherein said disorder is pain.  
     
     
         27 . The method of  claim 26 , wherein said pain is migraine, acute pain, persistent pain, neuropathic pain or nociceptive pain.  
     
     
         28 . The method of  claim 19 , wherein said disorder is inflammation.  
     
     
         29 . The method of  claim 19 , wherein said disorder is a cardiovascular disorder.  
     
     
         30 . A method of alleviating pain which comprises administering to a mammal that is either exhibiting pain or is about to be subjected to a pain-causing event a pain-alleviating amount of an active agent comprising a conotoxin peptide of  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         31 . A method for treating disorders associated with radical depolarization of excitable membranes by activating a K ATP  channel which comprises administering to an individual in need thereof an effective amount of an active agent comprising a conotoxin peptide of  claim 1  or a pharmaceutically acceptible salt thereof.  
     
     
         32 . The method of  claim 31 , wherein said disorder is cardiac ischemia.  
     
     
         33 . The method of  claim 31 , wherein said disorder is cerebral ischemia.  
     
     
         34 . The method of  claim 31 , wherein said disorder is asthma.  
     
     
         35 . The method of  claim 31 , wherein said disorder is ocular ischemia.  
     
     
         36 . A method of identifying compounds that mimic the therapeutic activity of a O-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 O-Superfamily conotoxin.  
     
     
         37 . A substantially pure O-superfamily-conotoxin peptide derivative comprising a permutant of the peptide of  claim 1 .  
     
     
         38 . A substantially pure O-superfamily-conotoxin peptide derivative comprising a permutant of the peptide of  claim 2 .  
     
     
         39 . A pharmaceutical composition comprising a conotoxin peptide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, said conotoxin peptide being the conotoxin protein precursor of  claim 15 .  
     
     
         40 . The method of  claim 18 , wherein the demyelinating disease is selected from the group consisting of acute disseminated encephalomyelitis, optic neuromyelitis, adrenoleukodystrophy, acute transverse myelitis and progressive multifocal leukoencephalopathy.  
     
     
         41 . The method of  claim 18 , wherein the compression and entrapment neurophathy is selected from the group consisting of carpal tunnel syndrome and ulnar nerve palsy.  
     
     
         42 . The method of  claim 18 , wherein the cardiovascular disorder is select4ed from the group consisting of cardiac arrhythmias and congestive heart failure.