Inhibition of human papilloma virus E2 DNA binding protein by covalently linked polyamides.
Polyamides are a class of heterocyclic small molecules with the potential of controlling gene expression by binding to the minor groove of DNA in a sequence-specific manner. To evaluate the feasibility of this class of compounds as antiviral therapeutics, molecules were designed to essential sequence elements occurring numerous times in the HPV genome. This sequence element is bound by a virus-encoded transcription and replication factor E2, which binds to a 12 bp recognition site as a homodimeric protein. Here, we take advantage of polyamide:DNA and E2:DNA co-crystal structural information and advances in polyamide synthetic chemistry to design tandem hairpin polyamides that are capable of displacing the major groove-binding E2 homodimer from its DNA binding site. The binding of tandem hairpin polyamides and the E2 DNA binding protein to the DNA site is mutually exclusive even though the two ligands occupy opposite faces of the DNA double helix. We show with circular permutation studies that the tandem hairpin polyamide prevents the intrinsic bending of the E2 DNA site important for binding of the protein. Taken together, these results illustrate the feasibility of inhibiting the binding of homodimeric, major groove-binding transcription factors by altering the local DNA geometry using minor groove-binding tandem hairpin polyamides.
Schaal
Thomas D
TD
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, Building 41, Room B307, NCI, NIH, Bethesda, MD 20892-5055, USA.
Mallet
William G
WG
McMinn
Dustin L
DL
Nguyen
Nam V
NV
Sopko
Michelle M
MM
John
Sam
S
Parekh
Bhavin S
BS
D001665:Binding Sites / Q000235:genetics; D004279:DNA, Viral / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins; D008954:Models, Biological; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000737:chemistry / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009757:Nylons; D009841:Oligonucleotides; D009856:Oncogene Proteins, Viral