Nucleic Acids Research, 2003, Vol. 31, No. 4 1282-1291
© 2003 Oxford University Press
Inhibition of human papilloma virus E2 DNA binding protein by covalently linked polyamides
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, Building 41, Room B307, NCI, NIH, Bethesda, MD 20892-5055, USA
*To whom correspondence should be addressed. Tel: +1 317 651 6391; Fax: +1 317 277 2126; Email: parekhbs{at}lilly.com Correspondence may also be addressed to Sam John. Tel: +1 301 496 8305; Fax: +1 301 496 4951; Email: sam@mail.nih.gov
Present addresses:
Thomas D. Schaal, Sangamo Biosciences, Richmond, CA, USA
William G. Mallet, Genentech Inc., South San Francisco, CA, USA
Dustin L. McMinn, Tularik Inc., South San Francisco, CA, USA
Nam V. Nguyen, Cell Genesys, Foster City, CA, USA
Michelle M. Sopko, Sunesis Inc., South San Francisco, CA, USA
Bhavin S. Parekh, Eli Lilly and Co., Indianapolis, IN, USA
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.
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