SOCS-box containing peptides

Abstract

The present invention relates generally to amino acid sequences obtainable from SOCS proteins and which are capable of interacting with intracellular molecules. The present invention further relates to nucleic acid molecules encoding said amino acid sequences. The amino acid sequences and the nucleic acid molecules encoding same of the present invention are useful in modulating degradation of proteinaceous molecules such as but not limited to SOCS proteins and proteinaceous molecules associate therewith. The present invention provides a mechanism for modulating cytokine or cytokine-like molecule signaling by modulating the degradation of activated signal transduction molecules or their negative regulators, i.e. the SOCS proteins.

1 . A method for facilitating the termination of cell signalling by a cytokine or cytokine-like molecule, said method comprising promoting interaction between a SOCS-box-containing peptide, polypeptide or protein or a chemical analogue thereof and one or more other molecules wherein the resulting complex is subjected to degradation via the ubiquitination or proteasomal compartments.  
     
     
         2 . Use of a SOCS-box-containing peptide, polypeptide or protein or a chemical analogue thereof together with one or more other molecules to couple said SOCS-box-containing peptide, polypeptide or protein and/or one or more other molecules to the ubiquitination or proteasomal compartments thereby terminating or substantially reducing cytokine- or cytokine-like molecule-mediated cell signalling.  
     
     
         3 . A method according to  claim 1  or  2  wherein the one or more other molecules are elongin B and/or elongin C.  
     
     
         4 . A method according to  claim 1  or  2  wherein the one or more other molecules are selected from elongin B, elongin C, elongin A or VHL or combinations of elongin B, C and/or A, and/or VHL.  
     
     
         5 . A method according to  claim 1  wherein said peptide, polypeptide or protein or a chemical analogue thereof is encoded by a sequence of nucleotides encoding the amino acid sequence:— 
         X 1  X 2  X 3  X 4  X 5  X 6  X 7  X 8  X 9  X 10  X 11  X 12  X 13  X 14  X 15  X 16  [X i ] n  X 17  X 18  X 19  X 20  X 21  X 22  X 23  [Xj] n  X 24  X 25  X 26  X 27  X 28    wherein: 
 X 1  is L, I, V, M, A or P;  
 X 2  is any amino acid residue;  
 X 3  is P, T or S;  
 X 4  is L, I, V, M, A or P;  
 X 5  is any amino acid;  
 X 6  is any amino acid;  
 X 7  is L, I, V, M, A, F, Y or W;  
 X 8  is C, T or S;  
 X 9  is R, K or H;  
 X 10  is any amino acid;  
 X 11  is any amino acid;  
 X 12  is L, I, V, M, A or P;  
 X 13  is any amino acid;  
 X 14  is any amino acid;  
 X 15  is any amino acid;  
 X 16  is L, I, V, M, A, P, G, C, T or S;  
 [X i ] n  is a sequence of n amino acids wherein n is from 1 to 50 amino acids and wherein the sequence X i  may comprise the same or different amino acids selected from any amino acid residue;  
 X 17  is L, I, V, M, A or P;  
 X 18  is any amino acid;  
 X 19  is any amino acid;  
 X 20  L, I, V, M, A or P;  
 X 21  is P;  
 X 22  is L, I, V, M, A, P or G;  
 X 23  is P or N;  
 [X j]   n  is a sequence of n amino acids wherein n is from 0 to 50 amino acids and wherein the sequence X j  may comprise the same or different amino acids selected from any amino acid residue;  
 X 24  is L, I, V, M, A or P;  
 X 25  is any amino acid;  
 X 26  is any amino acid;  
 X 27  is Y or F;  
 X 28  is L, I, V, M, A or P.  
   
     
     
         6 . An agonist or antagonist of cytokine- or cytokine-like molecule-mediated cell signalling, said agonist or antagonist facilitating or otherwise promoting or reducing or otherwise preventing complex formation between two or more of:—
 (i) a SOCS-box-containing peptide, polypeptide or protein or functional equivalent thereof or chemical analogue thereof;    (ii) elongin B and/or C or functional equivalents thereof or chemical analogues thereof; and/or    (iii) elongin A and/or VHL or functional equivalents thereof or chemical analogues thereof.    
     
     
         7 . An agonist or antagonist according to  claim 6  wherein said agonist or antagonist is an isolated, naturally occurring molecule.  
     
     
         8 . A method of modulating activity of SOCS in a human, said method comprising administering to said mammal an effective amount of a molecule for a time and under conditions sufficient to increase or decrease elongin B and/or elongin C binding to a SOCS box.  
     
     
         9 . A method of modulating levels of a SOCS protein in a cell said method comprising contacting a cell containing a SOCS gene with an effective amount of an inhibitor of elongin B- and/or elongin C-interaction with a SOCS box encoded by said SOCS gene for a time and under conditions sufficient to modulate levels of said SOCS protein.  
     
     
         10 . A method of modulating signal transduction in a cell containing a SOCS gene comprising contacting said cell with an effective amount of an inhibitor of elongin B and/or elongin C interaction with a SOCS box encoded by said SOCS gene for a time sufficient to modulate levels of SOCS protein with the cell.  
     
     
         11 . Use of one or more of:—
 (i) elongin B or a functional equivalent or chemical analogue thereof;    (ii) elongin C or a functional equivalent or chemical analogue thereof;    (iii) elongin A or a functional equivalent or chemical analogue thereof;    (iv) VHL or a functional equivalent or chemical analogue thereof;    (v) a peptide, polypeptide or protein comprising a SOCS box;    (vi) an agonist or antagonist of one or more of (i)-(v);    (vii) an agonist or antagonist of a complex formed by two or more of (i) to (v);    (viii) a chemical analogue or derivative of one or more of (i)-(vii);    in the manufacture of a medicament in the treatment of a condition in a subject.    
     
     
         12 . A genetically modified animal comprising a mutation in genetic material encoding a SOCS-box-containing protein such that said SOCS-box in said SOCS-box containing protein is not capable of functionally interacting with one or more of elongin A, B or C, VHL or a cytokine or cytokine-like molecule.