Inhibition of major groove DNA binding bZIP proteins by positive patch polyamides

Cell permeable synthetic ligands that bind to predetermined DNA sequences offer a chemical approach to gene regulation, provided inhibition of a broad range of DNA transcription factors can be achieved. DNA minor groove binding polyamides containing aminoalkyl substituents at the N-1 of a single pyrrole residue display inhibitory effects for a bZIP protein which binds exclusively in the DNA major groove. For major groove protein inhibition, specific protein-DNA contacts along the phosphate backbone were targeted with the positively charged dimethylamino substituent on the backbone of a minor groove binding polyamide hairpin. Remarkably, these polyamides bind DNA with enhanced affinity and uncompromised specificity when compared to polyamides with the aminoalkyl moiety at the C-terminus. By adding bZIP transcription factors to the class of protein-DNA complexes that can be disrupted by minor groove binding ligands, these results may increase the functional utility of polyamides as regulators of gene expression.