Analogs of sodium channel peptide toxin

Abstract

The present invention relates to a peptide and analogs thereof that selectively inhibit the Na v 1.7 sodium channel. The present invention also relates to pharmaceutical compositions useful for treating or preventing a disorder responsive to the blockade of sodium ion channels, especially Na v 1.7 sodium ion channels. The present invention further provides methods of treating a disorder responsive to the blockade of sodium channels, and particularly Na v 1.7 sodium channels, in a mammal suffering from excess activity of said channels, compositions and methods for providing analgesia by administering a peptide of the invention.

1 . An isolated peptide comprising the amino acid sequence Tyr 1 -Cys 2 -Gln 3 -Lys 4 -Trp 5 -Met 6 -Trp 7 -Thr 8 -Cys 9 -Asp 10 -Ser 11 -Xaa 12 -Arg 13 -Lys 14 -Cys 15 -Cys 16 -Glu 17 -Gly 18 -Xaa 9 -Val 20 -Cys 21 -Arg 22 -Leu 23 -Trp 24 -Cys 25 -Lys 26 -Lys 27 -Xaa 28 -Xaa 29 -Xaa 30 -Xaa 31  (SEQ ID NO: 1),
 or a pharmaceutically acceptable salt thereof,   wherein   each of Xaa 28  and Xaa 29 , is any natural or modified amino acid residue;   Xaa 12  is an alanine residue or a glutamate residue;   Xaa 19  is a leucine residue or a methionine residue;   Xaa 30  is any natural or modified amino acid residue or is absent; and   Xaa 31  is any natural or modified amino acid residue or is absent,   wherein said isolated peptide is not SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, or SEQ ID NO: 29,   and wherein said isolated peptide is not ProTx II (SEQ ID NO: 16) or PaTx I (SEQ ID NO: 17).   
     
     
         2 . The isolated peptide of  claim 1 , wherein Xaa 31  is absent. 
     
     
         3 . The isolated peptide of  claim 1 , wherein Xaa 30  and Xaa 31  are absent. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The isolated peptide of  claim 1 , wherein Xaa 28  is a lysine residue or an isoleucine residue. 
     
     
         7 . The isolated peptide of  claim 1 , wherein Xaa 29  is a leucine residue, an isoleucine residue, an alpha-methylated leucine residue, an N-methylated leucine residue, or a tryptophan residue. 
     
     
         8 . The isolated peptide of  claim 1 , wherein Xaa 30  is present and is tryptophan modified with an amino group, a tryptophan residue, a leucine residue, or an isoleucine residue. 
     
     
         9 - 17 . (canceled) 
     
     
         18 . The isolated peptide of  claim 1 , wherein Xaa 12  is a glutamate residue, Xaa 19  is a methionine residue, Xaa 28  is a lysine residue, Xaa 29  is a leucine residue, Xaa 30  is tryptophan modified with an amino group, and Xaa 31  is absent (SEQ ID NO: 2). 
     
     
         19 . The isolated peptide of  claim 1 , wherein Xaa 12  is a glutamate residue, Xaa 19  is a leucine residue, Xaa 28  is a lysine residue, Xaa 29  is a leucine residue, Xaa 30  is a tryptophan residue, and Xaa 31  is absent (SEQ ID NO: 4). 
     
     
         20 . The isolated peptide of  claim 1 , wherein Xaa 12  is a glutamate residue, Xaa 19  is a methionine residue, Xaa 28  is an isoleucine residue, Xaa 29  is an isoleucine residue, Xaa 30  is absent, and Xaa 31  is absent (SEQ ID NO: 5). 
     
     
         21 - 30 . (canceled) 
     
     
         31 . The isolated peptide of  claim 1 , wherein said isolated peptide is a recombinant peptide. 
     
     
         32 . The isolated peptide of  claim 1 , wherein said isolated peptide is a chemically synthesized peptide. 
     
     
         33 . The isolated peptide of  claim 1 , which is selected from the group consisting of SEQ ID NOs: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and their pharmaceutically acceptable salts. 
     
     
         34 . (canceled) 
     
     
         35 . The isolated peptide of  claim 1 , wherein said isolated peptide contains three cystine bridges with the connectivity C 2  to C 16 , C 9  to C 21  and C 15  to C 25 . 
     
     
         36 . The isolated peptide of  claim 1 , wherein said isolated peptide inhibits Na v 1.7 ion channel activity. 
     
     
         37 . The isolated peptide of  claim 1 , wherein said isolated peptide selectively inhibits Na v 1.7 ion channel activity relative to Na v 1.2 ion channel activity. 
     
     
         38 - 40 . (canceled) 
     
     
         41 . A pharmaceutical composition comprising the isolated peptide of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         42 - 43 . (canceled) 
     
     
         44 . A method of treating pain, said method comprising administering an effective amount of the isolated peptide of  claim 1  to a subject in need thereof. 
     
     
         45 . The method of  claim 44 , wherein said pain is neuropathic pain, chronic pain, acute pain, inflammatory pain, or surgical pain. 
     
     
         46 - 52 . (canceled) 
     
     
         53 . A polynucleotide molecule comprising a nucleotide sequence encoding an amino acid sequence of Tyr 1 -Cys 2 -Gln 3 -Lys 4 -Trp 5 -Met 6 -Trp 7 -Thr 8 -Cys 9 -Asp 10 -Ser 11 -Xaa 12 -Arg 13 -Lys 14 -Cys 15 -Cys 16 -Glu 17 -Gly 18 -Xaa 19 -Val 20 -Cys 21 -Arg 22 -Leu 23 -Trp 24 -Cys 25 -Lys 26 -Lys 27 -Xaa 28 -Xaa 29 -Xaa 30 -Xaa 31  (SEQ ID NO: 1),
 wherein   each of Xaa 28  and Xaa 29 , is any natural or modified amino acid residue;   Xaa 12  is an alanine residue or a glutamate residue;   Xaa 19  is a leucine residue or a methionine residue;   Xaa 30  is any natural or modified amino acid residue or is absent; and   Xaa 31  is any natural or modified amino acid residue or is absent,   wherein said isolated peptide is not SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, or SEQ ID NO: 29.   
     
     
         54 . (canceled) 
     
     
         55 . A host cell comprising a vector, wherein said vector comprises a polynucleotide molecule, and wherein the polynucleotide molecule comprises a nucleotide sequence encoding an amino acid sequence of Tyr 1 -Cys 2 -Gln 3 -Lys 4 -Trp 5 -Met 6 -Trp 7 -Thr 8 -Cys 9 -Asp 10 -Ser 11 -Xaa 12 -Arg 13 -Lys 14 -Cys 15 -Cys 16 -Glu 17 -Gly 18 -Xaa 19 -Val 20 -Cys 21 -Arg 22 -Leu 23 -Trp 24 -Cys 25 -Lys 26 -Lys 27 -Xaa 28 -Xaa 29 -Xaa 30 -Xaa 31  (SEQ ID NO: 1),
 wherein   each of Xaa 28  and Xaa 29 , is any natural or modified amino acid residue;   Xaa 2  is an alanine residue or a glutamate residue;   Xaa 19  is a leucine residue or a methionine residue;   Xaa 30  is any natural or modified amino acid residue or is absent; and   Xaa 31  is any natural or modified amino acid residue or is absent,   
       wherein said isolated peptide is not SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, or SEQ ID NO: 29. 
     
     
         56 . (canceled)