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-κB is a transcription factor that regulates a multitude of genes, including those involved in immune, inflammatory, and anti-apoptotic responses. NF-κB 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-κB 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-κB while those that target the 5′-ACTTTCC-3′ portion do not. Addition of NF-κB 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.
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