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

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.