Inhibition of DNA binding by NF-kappa B with pyrrole-imidazole polyamides

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.