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 in vivo with an effective amount of an anti-inflammatory compound comprising at least one NF-kB Essential Modulator (NEMO) binding domain, wherein the anti-inflammatory compound further comprises at least one membrane translocation domain, 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 IκB protein kinase (IKK) and NEMO.
3. The method of claim 2 , wherein the IKK is selected from the group consisting of IKKα and IKKβ.
4. A method for treating a subject suffering from an inflammatory disorder comprising administering to said subject an anti-inflammatory compound comprising at least one NF-kB Essential Modulator (NEMO) binding domain in an amount and for a period of time effective to inhibit NF-kB activation, wherein the anti-inflammatory compound further comprises at least one membrane translocation domain, thereby treating said subject suffering from an inflammatory disorder.
5. The method of claim 4 , wherein the anti-inflammatory compound inhibits the recruitment of leukocytes into sites of acute and chronic inflammation.
6. The method of claim 4 , wherein the anti-inflammatory compound down-regulates the expression of E-selectin on endothelial cells.
7. The method of claim 4 , wherein the anti-inflammatory compound inhibits osteoclast differentiation.
8. A method of modulating NF-κB-dependent target gene expression in a cell comprising contacting a cell in vivo with an effective amount of an anti-inflammatory compound comprising at least one NF-κB Essential Modulator (NEMO) binding domain, wherein the anti-inflammatory compound further comprises at least one membrane translocation domain, thereby modulating NF-κB-dependent target gene expression in a cell.
9. The method of claim 8 , wherein the anti-inflammatory compound blocks the interaction between one or more IκB protein kinase (IKK) and NEMO.
10. The method of claim 9 , wherein the IKK is IKKβ.
11. The method of claim 8 , wherein the NF-κB-dependent target gene is E-selectin.
12. 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 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), wherein the anti-inflammatory compound further comprises at least one membrane translocation domain, and 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, thereby treating an NFkB-mediated condition in a subject.
13. The method of claim 12 , 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.
14. The method of claim 12 , wherein the inflammation disorder is selected from the group consisting of dermatitis, eczema, psoriasis, osteoarthritis, psoriatic arthritis, lupus and spondylarthritis.
15. The method of claim 12 , wherein the membrane translocation domain is selected from the group consisting of the third helix of the antennapedia homeodomain and HIV-1 Tat protein.
16. The method of any one of claims 1 , 4 , 8 , and 12 , wherein the compound is a small molecule.
17. The method of claim 1 , wherein the compound modulates NF-κB-dependent target gene expression.
18. The method of claim 17 , wherein the NF-κB-dependent target gene is E-selectin.
19. The method of claim 1 , wherein the compound modulates NF-κB induction.
20. The method of claim 1 , wherein the compound inhibits osteoclast differentiation.
21. A method of modulating NF-κB induction in a cell comprising contacting a cell in vitro with an effective amount of an anti-inflammatory compound comprising at least one NF-kB Essential Modulator (NEMO) binding domain, wherein the anti-inflammatory compound further comprises at least one membrane translocation domain, thereby modulating NF-κB induction in a cell.
22. A method of modulating NF-κB-dependent target gene expression in a cell comprising contacting a cell in vitro with an effective amount of an anti-inflammatory compound comprising at least one NF-κB Essential Modulator (NEMO) binding domain, wherein the anti-inflammatory compound further comprises at least one membrane translocation domain, thereby modulating NF-κB-dependent target gene expression in a cell.