Novel x-conotoxin peptides (-ii)

Abstract

An isolated, synthetic or recombinant χ-conotoxin peptide having the ability to inhibit neuronal amine transporter comprising the following sequence of amino acids: Cys Cys Gly Tyr Lys Leu Cys Xaa5 Xaa6 Cys, SEQ ID NO: 3, where Xaa5 and Xaa6 are independently absent or represent any amino acid residue except Cys; or a sequence in which Gly, Tyr, Lys or Leu are subject to conservative amino acid substitution or side chain modification with the proviso that the peptide is not Mr1A, Mr1B, Mar2, CMrV1A, Bn1.5, Mr1.3 or Au1.4; or a salt, ester, amide, prodrug or cyclised derivative thereof.

1 . An isolated, synthetic or recombinant χ-conotoxin peptide having the ability to inhibit a neuronal amine transporter comprising the following sequence of amino acids: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 216) 
                 
                     
                   Xaa1Xaa2 Xaa3 Xaa4 Cys Cys Gly Tyr Lys Leu Cys 
                 
                     
                     
                 
                     
                   Xaa5 Xaa6 Cys, 
                 
             
                
                
                
                
               
            
           
         
       
       wherein Xaa1, Xaa2, Xaa3, and Xaa4 each represent an amino acid, and Xaa5 and Xaa6 are independently absent or represent any amino acid residue except Cys; 
       or a salt, ester, amide, prodrug or cyclised derivative thereof. 
     
     
         2 . The χ-conotoxin peptide of  claim 1 , wherein
 Xaa1 is selected from Trp, DTrp, Tyr, Phe, hPhe, Ala, MeY, Arg, Orn, pGlu, or DpGlu; 
 Xaa2 is selected from Arg, Ala, Asn, Lys, Phe, BHK, Orn, Lys, DArg, Nle, DLys, DMK, DAsn, Thr, Cit, Val, Tyr, or Trp; 
 Xaa3 is selected from Gly, Asp, Lys, Arg, Ala, Nle, Ser or Phe; and 
 Xaa4 is selected from Val, Leu, Nle, Ile, Thr, Ala, Asn, Trp, Phe or Abu. 
 
     
     
         3 . The χ-conotoxin peptide according to  claim 2 , wherein
 Xaa1 is selected from Trp, Tyr, Phe, hPhe, Ala, MeY, or Arg, 
 Xaa2 is selected from Arg, Asn, Lys, BHK, Orn, Lys, DArg, Nle, DLys, DMK, DAsn, Thr, Cit or Val, 
 Xaa3 is selected from Gly, Asp, Lys, Arg, Ala, Nle or Ser, and 
 Xaa4 is selected from Val, Leu, Nle, Ile, Thr, Ala or Abu. 
 
     
     
         4 . The χ-conotoxin peptide according to  claim 3 , consisting of the following sequence of amino acids: 
       
         
           
                 
               
                   (SEQ ID NO: 4) 
                 
                   Xaa1 Xaa2 Xaa3 Xaa4 Cys Cys Gly Tyr Lys Leu Cys 
                 
                     
                 
                   Xaa5 Xaa6 Cys where 
                 
             
                
                
                
                
               
            
           
         
         Xaa1 is selected from Trp, Tyr, Phe, hPhe, Ala, MeY, or Arg, 
         Xaa2 is selected from Arg, Asn, Lys, BHK, Orn, Lys, DArg, Nle, DLys, DMK, DAsn, Thr, Cit or Val, 
         Xaa3 is selected from Gly, Asp, Lys, Arg, Ala, Nle or Ser, 
         Xaa4 is selected from Val, Leu, Nle, Ile, Thr, Ala or Abu, and 
         Xaa5 and Xaa6 are independently absent or represent any amino acid residue except Cys, 
       
       or a salt, ester, amide or prodrug thereof. 
     
     
         5 . The χ-conotoxin peptide of  claim 1 , wherein
 Xaa1 is selected from pGlu, DpGlu, Pro, Hyp or an N-acetylated amino acid residue; 
 Xaa2 is selected from Arg, Asn, Lys, BHK, Orn, Lys, DArg, Nle, DLys, DMK, DAsn, Thr, Cit, or Val, 
 Xaa3 is selected from Gly, Asp, Lys, Arg, Ala, Nle or Ser, and 
 Xaa4 is selected from Val, Leu, Nle, Ile, Thr, Ala or Abu. 
 
     
     
         6 . The peptide according to  claim 2 , wherein Xaa1 is Trp, Tyr or hPhe. 
     
     
         7 . The peptide according to  claim 6 , wherein Xaa1 is Trp. 
     
     
         8 . The peptide according to  claim 2 , wherein Xaa2 is Arg, Lys or Asn. 
     
     
         9 . The peptide according to  claim 5 , wherein Xaa1 is pGlu or DpGlu. 
     
     
         10 . The peptide according to  claim 5 , wherein Xaa2 is a deletion. 
     
     
         11 . The peptide according to  claim 5 , wherein Xaa2 is BHK or Orn. 
     
     
         12 . The peptide according to  claim 2 , wherein Xaa3 is Gly or Asp. 
     
     
         13 . The peptide according to  claim 12 , wherein Xaa3 is Gly. 
     
     
         14 . The peptide according to  claim 2 , wherein Xaa4 is Leu, Nle or Val. 
     
     
         15 . The peptide according to  claim 2 , wherein Xaa5 is selected from the group consisting of His, Arg, Trp, Nal, Glu and a deletion. 
     
     
         16 . The peptide according to  claim 15 , wherein Xaa5 is Arg or His. 
     
     
         17 . The peptide according to  claim 2 , wherein Xaa6 is selected from the group consisting of Hyp, Pro, Ala, Tic, Pip, MeY, DMD, Phe, THZ, Glu, Nle, Tyr and a deletion. 
     
     
         18 . The peptide according to  claim 17 , wherein Xaa6 is Hyp or Pro. 
     
     
         19 . The peptide according to  claim 2 , wherein the Tyr of loop 1 has been replaced with MeY and/or the Leu of loop 1 is replaced with Hle or Nle. 
     
     
         20 . The peptide according to  claim 5 , wherein the Tyr of loop 1 has been replaced with MeY and/or the Leu of loop 1 is replaced with Hle or Nle. 
     
     
         21 . The peptide according to  claim 2  having from 14 to 20 amino acids. 
     
     
         22 . The peptide according to  claim 1 , comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13-18, 20-26, 28-30, 33, 34, 36-41, 43, 46, 50, 53-56, 60, 62, 64, 67-72, 78, 81-86, 88-92, 94, 95, 99, 100, 104-106, 109, 110, 114, 116, 118, 132, 140, 157, 161 and 163. 
     
     
         23 . A composition comprising the peptide according to any one of  claims 1 - 5 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         24 . A method for the treatment or prophylaxis of urinary or cardiovascular conditions or diseases or mood disorders or for the treatment or control of pain or inflammation including the step of administering to a mammal an effective amount of the peptide according to any one of  claims 1 - 5 . 
     
     
         25 . The method according to  claim 24 , wherein the peptide is administered substantially simultaneously or sequentially with other active agents useful in the treatment of the conditions, diseases or disorders.