Treatment of IL-17 mediated disease by blocking SEFIR-SEFIR interactions
A method of treating an IL-17 mediated disease in a subject by administering to the subject a therapeutically effective amount of a of a cell-permeable decoy peptide that competitively inhibits binding of the SEFIR domain of IL-17R to the SEFIR domain of Act1. In particular, it has been determined that the αC helix region of the SEFIR domain of both IL-17R and Act1 plays an important role in the association of IL-17R and Act1. To facilitate cell permeation, the decoy peptide is preferably conjugated to a protein transduction domain. Examples of IL-17 mediated diseases include various human and animal inflammatory and autoimmune diseases such as asthma.
1. A decoy peptide consisting of less than about 50 amino acids substantially homologous to at least a portion of the amino acid sequence of the αC helix region of the SEFIR domain of Act 1 and comprising the amino acid sequence HGLHXKY (SEQ ID NO: 1), wherein the decoy peptide competitively inhibits the binding of interleukin-17 receptor (IL-17R) to adaptor protein nuclear factor κB activator 1 (Act 1).
2. The decoy peptide of claim 1 , wherein the decoy peptide comprises the amino acid sequence HGLHTKY (SEQ ID NO: 4).
3. The decoy peptide of claim 1 , wherein the decoy peptide comprises the amino acid sequence LDEDEHGLHTKY (SEQ ID NO: 5).
4. The decoy peptide of claim 1 , wherein the decoy peptide further comprises a protein transduction domain.
5. The decoy peptide of claim 4 , wherein the protein transduction domain is derived from antennapedia.
6. The decoy peptide of claim 4 , wherein the protein transduction domain has the amino acid sequence DRQIKIWFQNRRMKWKK (SEQ ID NO: 11).
7. The decoy peptide of claim 4 , wherein the decoy peptide has the amino acid sequence DRQIKIWFQNRRMKWKKLDEDEHGLHTKY (SEQ ID NO: 17).
8. A method of treating an interleukin-17 (IL-17) mediated disease in a subject, comprising administering to the subject having the interleukin-17 mediated disease a therapeutically effective amount of the decoy peptide of claim 1 .
9. The method of claim 8 , wherein the decoy peptide comprises the amino acid sequence HGLHTKY (SEQ ID NO: 4).
10. The method of claim 8 , wherein the decoy peptide comprises the amino acid sequence LDEDEHGLHTKY (SEQ ID NO: 5).
11. The method of claim 8 , wherein the decoy peptide further comprises a protein transduction domain.
12. The method of claim 11 , wherein the protein transduction domain is derived from antennapedia.
13. The method of claim 12 , wherein the protein transduction domain has the amino acid sequence DRQIKIWFQNRRMKWKK (SEQ ID NO: 11).
14. The method of claim 13 , wherein the decoy peptide has the amino acid sequence DRQIKIWFQNRRMKWKKLDEDEHGLHTKY (SEQ ID NO: 17).
15. The method of claim 8 , wherein the IL-17 mediated disease is an inflammatory disease or an autoimmune disease.
16. The method of claim 15 , wherein the IL-17 mediated disease is an inflammatory disease selected from the group consisting of asthma, inflammatory bowel disease, multiple sclerosis, experimental autoimmune encephalomyelitis, and allergen-induced pulmonary inflammation.
17. The method of claim 16 , wherein the disease is asthma.
18. The method of claim 15 , wherein the IL-17 mediated disease is an autoimmune disease selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, allograft rejection, drug-induced lupus and psoriasis.
19. The method of claim 8 , wherein the IL-17 is IL-17A.
20. The method of claim 8 , wherein the IL-17 is IL-17E.