Anti-inflammatory compounds and uses thereof
The present invention provides anti-inflammatory compounds, pharmaceutical compositions thereof, and methods of use thereof for treating inflammatory disorders. The present invention also provides methods of identifying anti-inflammatory compounds and methods of inhibiting NF-κB-dependent target gene expression in a cell.
1. A method of modulating NF-κB induction in a cell comprising contacting a cell with an effective amount of an anti-inflammatory compound comprising at least one NF-kB Essential Modulator (NEMO) binding domain fused with at least one cell membrane translocation domain, wherein the anti-inflammatory compound is less than one-hundred amino acids in length, and wherein the anti-inflammatory compound inhibits NF-κB activation, thereby modulating NF-κB induction in a cell.
2. The method of claim 1 , wherein the anti-inflammatory compound blocks the interaction between one or more IKKs and NEMO.
3. The method of claim 2 , wherein the IKK is selected from the group consisting of IKKα and IKKβ.
4. The method of claim 1 , wherein the NEMO binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO:2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.
5. A method for treating a subject suffering from an inflammatory disorder comprising administering to said subject an effective amount of anti-inflammatory compound comprising at least one NF-kB Essential Modulator (NEMO) binding domain fused with at least one cell membrane translocation domain, wherein the anti-inflammatory compound is less than one-hundred amino acids in length, and wherein the anti-inflammatory compound inhibits NF-κB activation, thereby treating said subject suffering from an inflammatory disorder.
6. The method of claim 5 , wherein the anti-inflammatory compound inhibits the recruitment of leukocytes into sites of acute and chronic inflammation.
7. The method of claim 5 , wherein the anti-inflammatory compound down-regulates the expression of E-selectin on endothelial cells.
8. The method of claim 5 , wherein the anti-inflammatory compound inhibits osteoclast differentiation.
9. A method of modulating NF-κB-dependent target gene expression in a cell comprising contacting a cell with an effective amount of an anti-inflammatory compound comprising at least one NF-κB Essential Modulator (NEMO) binding domain fused with at least one cell membrane translocation domain, wherein the anti-inflammatory compound is less than one-hundred amino acids in length, and wherein the anti-inflammatory compound inhibits NF-κB activation, thereby modulating NF-κB-dependent target gene expression in a cell.
10. The method of claim 9 , wherein the anti-inflammatory compound blocks the interaction between one or more IKKs and NEMO.
11. The method of claim 10 , wherein the IKK is IKKβ.
12. The method of claim 9 , wherein the NF-κB-dependent target gene is E-selectin.
13. A method of treating an NFkB-mediated condition in a subject, comprising administering to the subject an anti-inflammatory compound comprising at least one NF-κB Essential Modulator (NEMO) binding domain fused with at least one cell membrane translocation domain, wherein the anti-inflammatory compound is less than one-hundred amino acids in length, and wherein the anti-inflammatory compound inhibits NF-κB activation, in an amount and for a period of time effective to inhibit the binding of NF-κB Essential Modulator (NEMO) to an IκB protein kinase (IKK), thereby treating an NFkB-mediated condition in a subject.
14. The method of claim 13 , wherein the NFkB-mediated condition is an inflammation disorder, an autoimmune disease, transplant rejection, osteoporosis, cancer, Alzheimer's disease, atherosclerosis, a viral infection, or ataxia telangiectasia.
15. The method of claim 14 , wherein the inflammation disorder is selected from the group consisting of asthma, allergies, uticaria, anaphylaxis, cutaneous inflammation, sepsis, psoriasis, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, vasculitis, and bursitis.
16. The method of claim 14 , wherein the inflammation disorder is selected from the group consisting of dermititis, eczema, psoriasis, osteoarthritis, psoriatic arthritis, lupus and spondylarthritis.
17. The method of claim 13 , wherein the membrane translocation domain is selected from the group consisting of the third helix of the antennapedia homeodomain and HIV-1 Tat protein.
18. The method of claim 13 , wherein the NEMO binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19.
19. The method of any one of claims 1 , 5 , 9 , or 13 , wherein the compound is a small molecule.
20. The method of claim 1 , wherein the compound modulates NF-κB-dependent target gene expression.
21. The method of claim 20 , wherein the NF-κB-dependent target gene is E-selectin.
22. The method of claim 1 , wherein the compound modulates NF-κB induction.
23. The method of claim 1 , wherein the compound inhibits osteoclast differentiation.
24. The method of claim 1 or 9 , wherein the cell is contacted in vivo.
25. The method of claim 1 or 9 , wherein the cell is contacted in vitro.