Maurotoxin, pi1 and hstx1 derivatives

Abstract

Derivatives of Maurotoxin (MTX) in which the native disulfide bridge pattern (Cys3-Cys24, Cys9-Cys29, Cys19, Cys31-Cys34) has been disrupted are useful for the treatment of pathologies associated with dysfunctioning and/or activation of Ca 2+ -activated and/or voltage-gated K + channel subtypes, such as IKCa1 or Kv1.2. One preferred group of derivatives is that in which one or more of the Cys residues have been replaced with ?-aminobutyrate (Abu) residues, thus breaking one or more of the four disulphide bridges. Within this group, the preferred derivative is that in which the Cys residues at position 9, 19, 29 and 34 have been replaced with a ?-aminobutyrate residues. However, the derivative in which the Cys residues at positions 19 and 34 have been replaced with (Abu) residues is excluded Another preferred group of derivatives is that in which one or two of the amino acid residues of maurotoxin have been replaced by different amino acid residues resulting in the disulfide bridge pattern being changed to Cys3-Cys24, Cys9-Cys29, Cys13-Cys31, Cys19-Cys34. Within this group, the preferred compounds are that which the Arg residue at position 14 has been replaced by a Gln residue, that in which the Lys residue at position 15 has been replaced by a Gln residue, that in which the Arg residue at position 14 and Lys residue at position 15 have both been replaced by Gin residues, those in which neither of the residues at positions 32 and 33 is a Gly or Pro residue, and that in which the Gly residue at position 33 has been replaced by an Ala residue. Pi1 and HsTx1 derivatives with disrupted native disulfide bridge patterns are similarly useful.

1 . A maurotoxin derivative in which the native disulfide bridge pattern (Cys3-Cys24, Cys9-Cys29, Cys13-Cys19, Cys31-Cys34) has been disrupted, but not including the derivative in which the Cys residues at positions 19 and 34 have been replaced with α-aminobutyrate (Abu) residues.  
     
     
         2 . A maurotoxin derivative according to  claim 1  in which the Cys residues at positions 9, 19, 29 and 34 have been replaced with Abu residues.  
     
     
         3 . A maurotoxin derivative according to  claim 1  in which one or two of the amino acid residues of maurotoxin have been replaced by different amino acid residues resulting in the disulfide bridge pattern being changed to Cys3-Cys24, Cys9-Cys29, Cys13-Cys31, Cys19-Cys34.  
     
     
         4 . A maurotoxin derivative according to  claim 3  in which the Arg residue at position 14 has been replaced by a Gln residue ([Q14]-MTX) [SEQ. ID NO. 5].  
     
     
         5 . A maurotoxin derivative according to  claim 3  in which the Lys residue at position 15 has been replaced by a Gln residue ([Q15]-MTX) [SEQ. ID NO. 6].  
     
     
         6 . A maurotoxin derivative according to  claim 3  in which the Arg residue at position 14 and Lys residue at position 15 have both been replaced by Gln residues ([Q14,Q15]-MTX) [SEQ. ID NO. 7].  
     
     
         7 . A maurotoxin derivative according to  claim 3  in which neither of the residues at positions 32 and 33 is a Gly or Pro residue.  
     
     
         8 . A maurotoxin derivative according to  claim 3  or  claim 7  in which the Gly residue at position 33 has been replaced by an Ala residue ([A33]-MTX) [SEQ. ID NO. 4].  
     
     
         9 . A Pi1 derivative in which the native disulfide bridge pattern (Cys4-Cys25, Cys10-Cys30, Cys14-Cys32, Cys20-Cys35) has been disrupted.  
     
     
         10 . A Pi1 derivative in which the C-terminal extremity is amidated (Cys-NH 2 ) that confers an increased affinity for Ca 2+ -activated K +  channels.  
     
     
         11 . A HsTx1 derivative in which the native disulfide bridge pattern (Cys3-Cys24, Cys9-Cys29, Cys13-Cys31, Cys19-Cys34) has been disrupted.  
     
     
         12 . Use of a maurotoxin derivative, or a Pi1 derivative, or a HsTx1 derivative, according to any preceding claim for the treatment of a pathology, including a neurological disorder, that is associated with dysfunctioning and/or activation of Ca 2+ -activated and/or voltage-gated K +  channel subtypes, such as IKCa1 or Kv1.2.  
     
     
         13 . Use of a maurotoxin derivative, or a Pi1 derivative, or a HsTx1 derivative, as an immuno-modulating drug, that is associated with an action (blockade, modulation and/or activation) on Ca 2+ -activated and/or voltage-gated K +  channel subtypes expressed on the surface of immune cells (e.g. T cells).  
     
     
         14 . A pharmaceutical composition comprising a maurotoxin derivative, or a Pi1 derivative, or a HsTx1 derivative, according to any of  claims 1  to  11  in admixture with a pharmaceutically acceptable diluent or carrier.