A D-amino acid peptide inhibitor of NF-kappa B nuclear localization is efficacious in models of inflammatory disease.
The transcription factor NF-kappa B regulates many genes involved in proinflammatory and immune responses. The transport of NF-kappa B into the nucleus is essential for its biologic activity. We describe a novel, potent, and selective NF-kappa B inhibitor composed of a cell-permeable peptide carrying two nuclear localization sequences (NLS). This peptide blocks NF-kappa B nuclear localization, resulting in inhibition of cell surface protein expression, cytokine production, and T cell proliferation. The peptide is efficacious in vivo in a mouse septic shock model as well as a mouse model of inflammatory bowel disease, demonstrating that NF-kappa B nuclear import plays a role in these acute inflammatory disease models.
Fujihara
S M
SM
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Cleaveland
J S
JS
Grosmaire
L S
LS
Berry
K K
KK
Kennedy
K A
KA
Blake
J J
JJ
Loy
J
J
Rankin
B M
BM
Ledbetter
J A
JA
Nadler
S G
SG
D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; C411484:BMS 205820; C411485:BMS 214572; D016207:Cytokines; D007145:Immunoglobulin kappa-Chains; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019913:Nuclear Localization Signals; D010455:Peptides; D011947:Receptors, Antigen, B-Cell