A D-amino acid peptide inhibitor of NF-kappa B nuclear localization is efficacious in models of inflammatory disease

S M Fujihara; J S Cleaveland; L S Grosmaire; K K Berry; K A Kennedy; J J Blake; J Loy; B M Rankin; J A Ledbetter; S G Nadler

doi:10.4049/jimmunol.165.2.1004

A D-amino acid peptide inhibitor of NF-kappa B nuclear localization is efficacious in models of inflammatory disease

J Immunol. 2000 Jul 15;165(2):1004-12. doi: 10.4049/jimmunol.165.2.1004.

Authors

S M Fujihara¹, J S Cleaveland, L S Grosmaire, K K Berry, K A Kennedy, J J Blake, J Loy, B M Rankin, J A Ledbetter, S G Nadler

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.

PMID: 10878377
DOI: 10.4049/jimmunol.165.2.1004

Abstract

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.

MeSH terms

Amino Acid Sequence
Animals
Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Cell Line
Cytokines / antagonists & inhibitors
Cytokines / biosynthesis
Disease Models, Animal
Humans
Immunoglobulin kappa-Chains / biosynthesis
Immunosuppressive Agents / administration & dosage
Immunosuppressive Agents / pharmacology
Inflammation / immunology
Inflammation / metabolism
Inflammation / prevention & control
Lipopolysaccharides / pharmacology
Lymphocyte Activation / drug effects
Mice
Mice, Inbred BALB C
Molecular Sequence Data
NF-kappa B / antagonists & inhibitors*
NF-kappa B / metabolism*
Nuclear Localization Signals* / drug effects
Peptides / administration & dosage
Peptides / chemical synthesis
Peptides / pharmacology*
Receptors, Antigen, B-Cell / biosynthesis
Shock, Septic / immunology
Shock, Septic / metabolism*
Shock, Septic / pathology
Shock, Septic / prevention & control
T-Lymphocytes / drug effects
T-Lymphocytes / immunology

Substances

Anti-Inflammatory Agents, Non-Steroidal
BMS 205820
BMS 214572
Cytokines
Immunoglobulin kappa-Chains
Immunosuppressive Agents
Lipopolysaccharides
NF-kappa B
Nuclear Localization Signals
Peptides
Receptors, Antigen, B-Cell