Peptide-based stat inhibitor

Abstract

A peptide or peptidomimetic comprising the amino acid sequence of the second helix of a STAT protein, or a variant of such sequence, wherein the peptide or peptidomimetic comprises about 40 or fewer amino acids and binds to a STAT protein, as well as a method of inhibiting a STAT protein in a cell, a method of treating or preventing a disease associated with STAT overexpression in a host, and related compounds, compositions, and methods.

1 . An isolated peptide or peptidomimetic of 40 or fewer amino acids in length that binds to a STAT protein, wherein the peptide or peptidomimetic comprises at least one of:
 (a) the amino acid sequence of Tyr Leu Lys His Xaa1 Gln Xaa2 Leu or reverse thereof wherein   Xaa1 is Leu or Val,   Xaa2 is Glu or Gln;   (b) the amino acid sequence of Xaa1 Xaa2 Xaa3 Xaa4 Leu Xaa5 Gln Xaa6 Xaa7 Xaa8 Xaa9 Tyr or reverse thereof wherein   Xaa1=Gln, Glu   Xaa2=Gly, Ile   Xaa3=Asp, Lys   Xaa4=Ala, Phe   Xaa5=Arg, Glu   Xaa6=any amino acid   Xaa7=Gln, Asp   Xaa8=Val, Gln   Xaa9=Leu, Phe   
     
     
         2 . The peptide or peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence of Gln Lys Tyr Leu Lys His Leu Gln Glu Leu Tyr Arg Thr Asp (SEQ ID NO: 44) or the reverse sequence thereof. 
     
     
         3 . The peptide or peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence of SEQ ID NO: 4 or the reverse sequence thereof. 
     
     
         4 . The peptide or peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence of SEQ ID NO: 5 or the reverse sequence thereof. 
     
     
         5 . The peptide or peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence of Lys Tyr Leu Lys His Leu Gln Glu Leu Tyr Arg Thr Asp (SEQ ID NO: 45) or the reverse sequence thereof. 
     
     
         6 . The peptide or peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence of Ile Gln Arg Tyr Leu Lys His Leu Gln Gln Leu Tyr Arg Thr Asp (SEQ ID NO: 47) or the reverse sequence thereof. 
     
     
         7 . The peptide or peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence of Ile Gln Arg Tyr Leu Lys His Leu Gln Gln Leu Tyr Arg Thr Asn (SEQ ID NO: 49) or the reverse sequence thereof. 
     
     
         8 . The peptide or peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence of Tyr Leu Lys His Val Gln Glu Leu Phe Lys Ser Asp (SEQ ID NO: 57) or the reverse sequence thereof. 
     
     
         9 . The peptide or peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence of Gln Gly Asp Ala Leu Arg Gln Xaa Gln Val Leu Tyr (SEQ ID NO: 62) or the reverse sequence thereof wherein Xaa is norleucine. 
     
     
         10 . The peptide or peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic comprises the amino acid sequence of Tyr Leu Val Gln Xaa Gln Arg Leu Ala Asp Gly Gln (SEQ ID NO: 67) or the reverse sequence thereof wherein Xaa is any amino acid. 
     
     
         11 . The peptide or peptidomimetic of  claim 1 , wherein the amino acids are D-amino acids. 
     
     
         12 . The peptide or peptidomimetic of  claim 1  further comprising a cell-penetrating motif. 
     
     
         13 . The peptide or peptidomimetic of  claim 12 , wherein the cell-penetrating motif is a protein transduction domain or fatty acid, optionally attached to the peptide or peptidomimetic via a linker sequence. 
     
     
         14 . The peptide or peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic comprises a terminal acetyl or palmitoyl group. 
     
     
         15 . The peptide or peptidomimetic of  claim 14 , wherein the peptide or peptidomimetic comprises a terminal ε-palmitoyl modified lysine residue. 
     
     
         16 . The peptide of peptidomimetic of  claim 1 , wherein the peptide or peptidomimetic binds the N-terminal domain of a STAT protein. 
     
     
         17 . A pharmaceutical composition comprising the peptide or peptidomimetic of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         18 . The pharmaceutical composition of  claim 17 , further comprising one or more active agents or drugs. 
     
     
         19 . An isolated peptide or peptidomimetic of 40 or fewer amino acids in length that binds to a STAT protein, wherein the peptide or peptidomimetic comprises at least one of:
 (a) the amino acid sequence of Tyr Leu Lys His Xaa1 Gln Xaa2 Leu or inverse thereof, wherein   Xaa1 is Leu or Val;   Xaa2 is Glu or Gln;   (b) the amino acid sequence of Xaa1 Xaa2 Xaa3 Xaa4 Leu Xaa5 Gln Xaa6 Xaa7 Xaa8 Xaa9 Tyr or inverse thereof, wherein   Xaa1=Gln, Glu   Xaa2=Gly, Ile   Xaa3=Asp, Lys   Xaa4=Ala, Phe   Xaa5=Arg, Glu   Xaa6=any amino acid   Xaa7=Gln, Asp   Xaa8=Val, Gln   Xaa9=Leu, Phe   
     
     
         20 . The isolated peptide or peptidomimetic of  claim 19 , wherein the peptide or peptidomimetic comprises at least one of the amino acid sequences of SEQ ID NO: 4, 5, 44, 45, 47, 49, 57, 62 or 67 or reverse thereof.