title: Inhibition of DNA binding by NF-kappa B with pyrrole-imidazole polyamides.
abstract: Synthetic ligands that bind to predetermined DNA sequences will offer a chemical approach to gene regulation if inhibition of a broad range of transcription factors can be achieved. NF-kappa B is a transcription factor that regulates a multitude of genes, including those involved in immune, inflammatory, and anti-apoptotic responses. NF-kappa B binds as heterodimer predominantly in the major groove. We report the design of polyamides that bind in the minor groove and target overlapping portions of an NF-kappa B binding site (5'-GGGACTTTCC-3'). We find that compounds that target the 5'-GGGACT-3' portion of the site can inhibit DNA binding by NF-kappa B while those that target the 5'-ACTTTCC-3' portion do not. Addition of NF-kappa B to the list of protein-DNA complexes that can be disrupted by minor groove binding ligands potentially increases the utility of polyamides as regulators of gene expression.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Wurtz
authors.forename: Joel L
authors.initials: JL
authors.lastname: Pomerantz
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000378:metabolism*; D018983:DNA Footprinting; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003850:Deoxyribonuclease I; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009757:Nylons / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D007093:Imidazoles; D016328:NF-kappa B; D009757:Nylons; D011758:Pyrroles; D004247:DNA; D003850:Deoxyribonuclease I