Allosteric Inhibition of Protein−DNA Complexes by Polyamide−Intercalator Conjugates

Abstract

The sequence-specific inhibition of essential protein−DNA contacts in the promoter of a gene is a central issue for the regulation of gene expression by chemical methods. Hairpin polyamides have been shown to inhibit protein−DNA complexes in some but not all cases. For example, polyamides co-occupy the same DNA sequence in the minor groove in the presence of major-groove binding bZip proteins. Four hairpin polyamide−acridine conjugates were synthesized and shown to bind the minor groove of DNA with high affinity in a sequence-specific manner. The polyamide−acridine conjugates were shown to unwind DNA (φ = 14−15°), evidence for intercalation by the acridine moiety. Importantly, the polyamide−intercalator conjugates, which combine sequence-specific groove binding with proximal local unwinding, inhibit major-groove DNA binding by the GCN4 bZip protein. This class of DNA binding molecules creates a sequence-specific allosteric change in DNA structure and has the potential to be a general inhibitor of transcription factor binding independent of the specific protein−DNA structure.