title: 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 (phi = 14-15 degrees), 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.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Fechter
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors; D001665:Binding Sites; D002417:Cattle; D004247:DNA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051790:G-Box Binding Factors; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000138:chemical synthesis* / Q000494:pharmacology*; D013379:Substrate Specificity; D013816:Thermodynamics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000166:Acridines; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051790:G-Box Binding Factors; D007364:Intercalating Agents; D009757:Nylons; D014157:Transcription Factors; D004247:DNA