Selective inhibitors of nuclear factor-κB activation and uses thereof
The present invention provides cell permeable NF-κB inhibitors consist of a polypeptide derived from the p65 subunit of NF-κB and a protein transduction domain derived from antennapedia third helix sequence. The inhibitor suppressed NF-κB activation induced by TNF, LPS, IL-1, okadaic acid, PMA, H 2 O 2 and cigarette smoke condensate. NF-κB-regulated reporter gene expression induced by TNF, TNFR1, TRADD, TRAF2, NIK, IKK and p65 was suppressed by the inhibitor. The inhibitor enhanced TNF- and chemotherapeutic agent-induced apoptosis. Overall these results demonstrate a NF-κB inhibitor that can selectively inhibit NF-κB activation induced by various inflammatory stimuli, downregulate NF-κB mediated gene expression and upregulate apoptosis.
1. A cell permeable NF-κB inhibitor polypeptide comprising:
(i) a sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13; and
(ii) a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein.
2. A cell permeable NF-κB inhibitor polypeptide having the amino acid sequence of SEQ ID NO. 4 or 10.
3. A composition comprising the inhibitor of claim 1 and a pharmacological acceptable carrier.
4. A polypeptide of the p65 subunit of NF-κB, wherein said polypeptide can inhibit NF-κB activity when said polypeptide is delivered into a cell, and said polypeptide comprises a sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:12, and SEQ ID NO:13.
5. The inhibitor of claim 1 , wherein the transduction sequence is SEQ ID NO:3.
6. The inhibitor of claim 1 , consisting of:
(i) a sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13; and
(ii) a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein.
7. The inhibitor of claim 6 , wherein the transduction sequence is SEQ ID NO:3.
8. The inhibitor of claim 1 , comprising SEQ ID NO:5.
9. The inhibitor of claim 1 , comprising SEQ ID NO:6.
10. The inhibitor of claim 1 , comprising SEQ ID NO:7.
11. The inhibitor of claim 1 , comprising SEQ ID NO:8.
12. The inhibitor of claim 1 , comprising SEQ ID NO:9.
13. The inhibitor of claim 1 , comprising SEQ ID NO:11.
14. The inhibitor of claim 1 , comprising SEQ ID NO:12.
15. The inhibitor of claim 1 , comprising SEQ ID NO:13.
16. The inhibitor of claim 1 , wherein the transduction sequence is SEQ ID NO:3.
17. The inhibitor of claim 1 , wherein the transduction sequence is a herpes virus structural protein transduction sequence.
18. The inhibitor of claim 1 , wherein the transduction sequence is an HIV tat protein.
19. The inhibitor of claim 2 , having the amino acid sequence of SEQ ID NO.4.
20. The inhibitor of claim 2 , having the amino acid sequence of SEQ ID NO:10.
21. The polypeptide of claim 4 , wherein the polypeptide comprises SEQ ID NO:6.
22. The polypeptide of claim 4 , wherein the polypeptide comprises SEQ ID NO:7.
23. The polypeptide of claim 4 , wherein the polypeptide comprises SEQ ID NO:12.
24. The polypeptide of claim 4 , wherein the polypeptide comprises SEQ ID NO:13.
25. The inhibitor of claim 6 , consisting of SEQ ID NO:5 and a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein.
26. The inhibitor of claim 6 , consisting of SEQ ID NO:6 and a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein.
27. The inhibitor of claim 6 , consisting of SEQ ID NO:7 and a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein.
28. The inhibitor of claim 6 , consisting of SEQ ID NO:8 and a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein.
29. The inhibitor of claim 6 , consisting of SEQ ID NO:9 and a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein.
30. The inhibitor of claim 6 , consisting of SEQ ID NO:11 and a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein.
31. The inhibitor of claim 6 , consisting of SEQ ID NO:12 and a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein.
32. The inhibitor of claim 6 , consisting of SEQ ID NO:13 and a transduction sequence selected from the group consisting of SEQ ID NO:3, a herpes virus structural protein transduction sequence, and HIV tat protein.
33. The inhibitor of claim 6 , wherein the transduction sequence consists of SEQ ID NO:3.
34. The inhibitor of claim 6 , wherein the transduction sequence consists of a herpes virus structural protein transduction sequence.
35. The inhibitor of claim 6 , wherein the transduction sequence consists of an HIV tat protein.