Cell-Permeable Peptide Inhibitors Of The JNK Signal Transduction Pathway

Abstract

The invention provides cell-permeable peptides that bind to JNK proteins and inhibit JNK-mediated effects in JNK-expressing cells.

1 . A method of treating a pathophysiology associated with activation of JNK in a subject, the method comprising administering to the subject a cell-permeable bioactive peptide, wherein the peptide:
 (a) is less than 50 amino acids in length;   (b) comprises the amino acid sequence of SEQ ID NO:6; and   (c) inhibits c-jun amino terminal kinase (JNK) phosphorylation of a JNK targeted transcription factor selected from the group consisting of c-Jun, ATF2 and Elk1.   
     
     
         2 . The method of  claim 1 , wherein the peptide comprises the amino acid sequence of SEQ ID NO: 3. 
     
     
         3 . The method of  claim 1 , wherein the peptide comprises the amino acid sequence of SEQ ID NO: 4. 
     
     
         4 . The method of  claim 1 , wherein the peptide further comprises the amino acid sequence of SEQ ID NO: 10. 
     
     
         5 . The method of  claim 1 , wherein the peptide further comprises the amino acid sequence of SEQ ID NO: 8. 
     
     
         6 . The method of  claim 1 , wherein the peptide comprises the amino acid sequence of SEQ ID NO: 16. 
     
     
         7 . The method of  claim 1 , wherein the peptide comprises the amino acid sequence of SEQ ID NO: 14. 
     
     
         8 . The method of  claim 1 , wherein the peptide comprises the amino acid sequence of SEQ ID NO: 15. 
     
     
         9 . The method of  claim 1 , wherein the peptide blocks activation of at least one INK targeted transcription factor. 
     
     
         10 . The method of  claim 1 , wherein the pathophysiology is selected from the group consisting of restenosis, oncogenic transformation, maturation and differentiation of immune cells, proinflammatory cytokines, ionizing radiation as used in radiotherapy, ultraviolet light, free radicals, DNA damaging agents, chemotherapeutic drugs, ischemia, reperfusion, hypoxia, hypothermia, hyperthermia, apoptosis and response to stressful stimuli. 
     
     
         11 . The method of  claim 1 , wherein the administering is delivered by any one administration route selected from the group consisting of intraperitoneal, nasal, intravenous, oral and patch delivery. 
     
     
         12 . A method of treating a pathophysiology associated with activation of JNK in a subject, the method comprising administering to the subject a chimeric peptide comprising a first domain and a second domain, wherein the first domain is a trafficking sequence and the second domain is a JNK inhibitor sequence, and wherein the chimeric peptide comprises D-enantiomeric amino acids. 
     
     
         13 . The method of  claim 12 , wherein the JNK-inhibitor sequence comprises the amino acid sequence of SEQ ID NO: 6. 
     
     
         14 . The method of  claim 12 , wherein JNK-inhibitor sequence comprises the amino acid sequence of SEQ ID NO: 3. 
     
     
         15 . The method of  claim 12 , wherein the JNK-inhibitor sequence comprises the amino acid sequence of SEQ ID NO: 4. 
     
     
         16 . The method of  claim 12 , wherein the trafficking sequence comprises the amino acid sequence of SEQ ID NO: 10. 
     
     
         17 . The method of  claim 12 , wherein the trafficking sequence comprises the amino acid sequence of SEQ ID NO: 8. 
     
     
         18 . The method of  claim 12 , wherein the chimeric peptide comprises the amino acid sequence of SEQ ID NO: 16. 
     
     
         19 . The method of  claim 12 , wherein the chimeric peptide comprises the amino acid sequence of SEQ ID NO: 14. 
     
     
         20 . The method of  claim 12 , wherein the chimeric peptide comprises the amino acid sequence of SEQ ID NO: 15. 
     
     
         21 . The method of  claim 12 , wherein the chimeric peptide comprises an amino acid sequence having a length selected from the group consisting of 150 amino acids, 100 amino acids, 75 amino acids, 50 amino acids, 35 amino acids, or 25 amino acids in length 
     
     
         22 . The method of  claim 12 , wherein the pathophysiology is selected from the group consisting of restenosis, oncogenic transformation, maturation and differentiation of immune cells, proinflammatory cytokines, ionizing radiation as used in radiotherapy, ultraviolet light, free radicals, DNA damaging agents, chemotherapeutic drugs, ischemia, reperfusion, hypoxia, hypothermia, hyperthermia, apoptosis and response to stressful stimuli. 
     
     
         23 . The method of  claim 12 , wherein the administering is delivered by any one administration route selected from the group consisting of intraperitoneal, nasal, intravenous, oral and patch delivery.